niacinamide and Neoplasms studies

nicotinamide : A pyridinecarboxamide that is pyridine in which the hydrogen at position 3 is replaced by a carboxamide group.

Neoplasms: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.

Research Excerpts

Excerpt	Relevance	Reference
"This phase I trial evaluated the combination of the marine-derived cyclodepsipeptide plitidepsin (trade name Aplidin) with sorafenib or gemcitabine in advanced cancer and lymphoma patients."	9.24	Phase I dose-escalation study of plitidepsin in combination with sorafenib or gemcitabine in patients with refractory solid tumors or lymphomas. ( Alfaro, V; Aspeslagh, S; Bahleda, R; Extremera, S; Fudio, S; Gyan, E; Hollebecque, A; Salles, G; Soria, JC; Soto-Matos, A; Stein, M, 2017)
"To determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of sorafenib in children with refractory extracranial solid tumors and evaluate the tolerability of the solid tumor MTD in children with refractory leukemias."	9.16	A phase I trial and pharmacokinetic study of sorafenib in children with refractory solid tumors or leukemias: a Children's Oncology Group Phase I Consortium report. ( Adamson, PC; Balis, FM; Baruchel, S; Blaney, SM; Burke, M; Fox, E; Glade Bender, J; Ingle, AM; Kim, A; Stempak, D; Weigel, B; Widemann, BC, 2012)
"Hypertension is one of the major side effects of sorafenib, and reported incidences vary substantially among clinical trials."	8.90	Incidence and risk of sorafenib-induced hypertension: a systematic review and meta-analysis. ( Chen, J; Guo, H; Li, S; Li, Y; Liang, X; Meng, H; Shi, B; Zhang, D; Zhu, Y, 2014)
"Sorafenib, a multi-kinase inhibitor, has been reported to be associated with hypertension (HTN)."	8.89	Risk of hypertension in cancer patients treated with sorafenib: an updated systematic review and meta-analysis. ( Funakoshi, T; Galsky, MD; Latif, A, 2013)
" Eligible studies were prospective clinical trials of patients with cancer assigned single-drug sorafenib at 400 mg twice daily with data on hypertension available."	8.84	Incidence and risk of hypertension with sorafenib in patients with cancer: a systematic review and meta-analysis. ( Chen, JJ; Kudelka, A; Lu, J; Wu, S; Zhu, X, 2008)
"Several case reports suggest sorafenib exposure and sorafenib-induced hyperbilirubinemia may be related to a (TA)(5/6/7) repeat polymorphism in UGT1A1*28 (UGT, uridine glucuronosyl transferase)."	7.78	Sorafenib is an inhibitor of UGT1A1 but is metabolized by UGT1A9: implications of genetic variants on pharmacokinetics and hyperbilirubinemia. ( Dahut, W; English, BC; Federspiel, J; Figg, WD; Gardner, ER; Giaccone, G; Jain, L; Kim, A; Kirkland, CT; Kohn, E; Kummar, S; Peer, CJ; Richardson, ED; Sissung, TM; Troutman, SM; Venzon, D; Widemann, B; Woo, S; Yarchoan, R, 2012)
"Hypertension (HT) and hand-foot skin reactions (HFSR) may be related to the activity of bevacizumab and sorafenib."	7.76	Hypertension and hand-foot skin reactions related to VEGFR2 genotype and improved clinical outcome following bevacizumab and sorafenib. ( Baum, CE; Dahut, WL; Danesi, R; English, BC; Figg, WD; Giaccone, G; Jain, L; Kohn, EC; Kummar, S; Liewehr, D; Price, DK; Sissung, TM; Venitz, J; Venzon, D; Yarchoan, R, 2010)
" However, adverse effects common to the tyrosine kinase inhibitor class occur at a noticeably higher rate with sorafenib use in thyroid cancer patients."	6.53	Toxic Effects of Sorafenib in Patients With Differentiated Thyroid Carcinoma Compared With Other Cancers. ( Jaffry, A; Jean, GW; Khan, SA; Mani, RM, 2016)
"Blood pressure elevation is likely a pharmacodynamic marker of VEGF signaling pathway (VSP) inhibition and could be useful for optimizing safe and effective VSP inhibitor dosing."	5.35	Rapid development of hypertension by sorafenib: toxicity or target? ( Atkins, MB; Humphreys, BD, 2009)
"Acetaldehyde formation was determined by GC-FID analysis in the head space of incubation mixtures."	5.31	Rat ventral prostate xanthine oxidase bioactivation of ethanol to acetaldehyde and 1-hydroxyethyl free radicals: analysis of its potential role in heavy alcohol drinking tumor-promoting effects. ( Castro, GD; Castro, JA; Costantini, MH; Delgado de Layño, AM, 2001)
"This phase I trial evaluated the combination of the marine-derived cyclodepsipeptide plitidepsin (trade name Aplidin) with sorafenib or gemcitabine in advanced cancer and lymphoma patients."	5.24	Phase I dose-escalation study of plitidepsin in combination with sorafenib or gemcitabine in patients with refractory solid tumors or lymphomas. ( Alfaro, V; Aspeslagh, S; Bahleda, R; Extremera, S; Fudio, S; Gyan, E; Hollebecque, A; Salles, G; Soria, JC; Soto-Matos, A; Stein, M, 2017)
"To determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of sorafenib in children with refractory extracranial solid tumors and evaluate the tolerability of the solid tumor MTD in children with refractory leukemias."	5.16	A phase I trial and pharmacokinetic study of sorafenib in children with refractory solid tumors or leukemias: a Children's Oncology Group Phase I Consortium report. ( Adamson, PC; Balis, FM; Baruchel, S; Blaney, SM; Burke, M; Fox, E; Glade Bender, J; Ingle, AM; Kim, A; Stempak, D; Weigel, B; Widemann, BC, 2012)
"Hypertension is one of the major side effects of sorafenib, and reported incidences vary substantially among clinical trials."	4.90	Incidence and risk of sorafenib-induced hypertension: a systematic review and meta-analysis. ( Chen, J; Guo, H; Li, S; Li, Y; Liang, X; Meng, H; Shi, B; Zhang, D; Zhu, Y, 2014)
"Sorafenib, a multi-kinase inhibitor, has been reported to be associated with hypertension (HTN)."	4.89	Risk of hypertension in cancer patients treated with sorafenib: an updated systematic review and meta-analysis. ( Funakoshi, T; Galsky, MD; Latif, A, 2013)
" The most widely employed activator is resveratrol, a small polyphenol that improves insulin sensitivity and vascular function, boosts endurance, inhibits tumor formation, and ameliorates the early mortality associated with obesity in mice."	4.86	Biochemical effects of SIRT1 activators. ( Baur, JA, 2010)
" Sunitinib and sorafenib are multitargeted TKIs that have been demonstrated to induce hypothyroidism and thyroid dysfunction."	4.85	Hypothyroidism related to tyrosine kinase inhibitors: an emerging toxic effect of targeted therapy. ( Barnabei, A; Corsello, SM; Gasparini, G; Longo, R; Torino, F, 2009)
" Eligible studies were prospective clinical trials of patients with cancer assigned single-drug sorafenib at 400 mg twice daily with data on hypertension available."	4.84	Incidence and risk of hypertension with sorafenib in patients with cancer: a systematic review and meta-analysis. ( Chen, JJ; Kudelka, A; Lu, J; Wu, S; Zhu, X, 2008)
"Ferroptosis is a recently identified form of regulated necrosis that can be experimentally induced in cancer cells with the chemical inducer erastin."	3.80	Sorafenib induces ferroptosis in human cancer cell lines originating from different solid tumors. ( Baert, M; Chauffert, B; Diouf, M; Galmiche, A; Godin, C; Lachaier, E; Louandre, C; Saidak, Z, 2014)
"Several case reports suggest sorafenib exposure and sorafenib-induced hyperbilirubinemia may be related to a (TA)(5/6/7) repeat polymorphism in UGT1A1*28 (UGT, uridine glucuronosyl transferase)."	3.78	Sorafenib is an inhibitor of UGT1A1 but is metabolized by UGT1A9: implications of genetic variants on pharmacokinetics and hyperbilirubinemia. ( Dahut, W; English, BC; Federspiel, J; Figg, WD; Gardner, ER; Giaccone, G; Jain, L; Kim, A; Kirkland, CT; Kohn, E; Kummar, S; Peer, CJ; Richardson, ED; Sissung, TM; Troutman, SM; Venzon, D; Widemann, B; Woo, S; Yarchoan, R, 2012)
"Hypertension (HT) and hand-foot skin reactions (HFSR) may be related to the activity of bevacizumab and sorafenib."	3.76	Hypertension and hand-foot skin reactions related to VEGFR2 genotype and improved clinical outcome following bevacizumab and sorafenib. ( Baum, CE; Dahut, WL; Danesi, R; English, BC; Figg, WD; Giaccone, G; Jain, L; Kohn, EC; Kummar, S; Liewehr, D; Price, DK; Sissung, TM; Venitz, J; Venzon, D; Yarchoan, R, 2010)
"Hypertension is a mechanism-based toxicity of sorafenib and other cancer therapeutics that inhibit the vascular endothelial growth factor (VEGF) signaling pathway."	3.75	Ambulatory monitoring detects sorafenib-induced blood pressure elevations on the first day of treatment. ( Black, HR; Elliott, WJ; Karrison, T; Kasza, KE; Maitland, ML; Moshier, K; Ratain, MJ; Sit, L; Stadler, WM; Undevia, SD, 2009)
"The objective was to develop a pharmacokinetic-pharmacodynamic (PK-PD) model linking everolimus and sorafenib exposure with biomarker dynamics and progression-free survival (PFS) based on data from EVESOR trial in patients with solid tumors treated with everolimus and sorafenib combination therapy and to simulate alternative dosing schedules for sorafenib."	3.30	A PK-PD model linking biomarker dynamics to progression-free survival in patients treated with everolimus and sorafenib combination therapy, EVESOR phase I trial. ( Augu-Denechere, D; Bonnin, N; Colomban, O; Fontaine, J; Freyer, G; Guitton, J; Lopez, J; Maillet, D; Payen, L; Péron, J; Puszkiel, A; Rousset, P; Tartas, S; Tod, M; Trillet-Lenoir, V; You, B, 2023)
"Riluzole was given at 100 mg PO BID in combination with sorafenib, beginning at 200 mg PO daily and escalating in 200 mg increments per level in 28-day cycles."	3.30	A phase I trial of riluzole and sorafenib in patients with advanced solid tumors: CTEP #8850. ( Aisner, J; Cerchio, R; Chan, N; Chen, S; Ganesan, S; Goodin, S; Gounder, M; Li, J; Lin, H; Malhotra, J; Marinaro, C; Mehnert, JM; Portal, DE; Shih, W; Silk, AW; Spencer, KR; Stein, MN, 2023)
"Nicotinamide metabolism is important in carcinogenesis."	3.01	Nicotinamide N-methyl transferase and cancer-associated thrombosis: insights to prevention and management. ( Ardakany, MR; Ebrahimi, S; Jabbari, P; Rezaei, N, 2023)
"Four dosing schedules of pimasertib (once daily [qd], 5 days on, 2 days off; qd, 15 days on, 6 days off; continuous qd; continuous twice daily [bid]) were evaluated in patients with advanced solid tumors."	3.01	Selective Oral MEK1/2 Inhibitor Pimasertib: A Phase I Trial in Patients with Advanced Solid Tumors. ( Aftimos, P; Awada, A; Delord, JP; Dinulescu, M; Faivre, S; Gomez-Roca, C; Houédé, N; Italiano, A; Kefford, R; Kruse, V; Lebbé, C; Leijen, S; Lesimple, T; Massimini, G; Pages, C; Raymond, E; Rottey, S; Schellens, JHM; Scheuler, A, 2021)
"Treatment-related adverse events included fatigue and nausea in the monotherapy arm (13% for each), hypothyroidism (30%) in the ramucirumab arm, diarrhea (54%) in the abemaciclib arm, and nausea (25%) in the merestinib arm."	3.01	Safety and Clinical Activity of a New Anti-PD-L1 Antibody as Monotherapy or Combined with Targeted Therapy in Advanced Solid Tumors: The PACT Phase Ia/Ib Trial. ( Bang, YJ; Bendell, J; Carlsen, M; Chow, KH; Chung, HC; de Miguel, MJ; Gandhi, L; Italiano, A; Lin, CC; Patnaik, A; Schmidt, S; Su, WC; Szpurka, AM; Vangerow, B; Xu, X; Yap, TA; Yu, D; Zhao, Y, 2021)
" No significant drug-drug interactions were observed."	2.90	A phase I study of the HDM2 antagonist SAR405838 combined with the MEK inhibitor pimasertib in patients with advanced solid tumours. ( de Jonge, M; de Weger, VA; Demers, B; Deutsch, E; Goodstal, S; Hsu, K; Langenberg, MHG; Lolkema, M; Macé, S; Schellens, JHM; Thomas, K; Tuffal, G; Varga, A, 2019)
"Sorafenib was administered days 1-28 and radiotherapy (30Gy in 10 fractions) was delivered days 8-12 and 15-19."	2.84	Phase I dose escalation study of concurrent palliative radiation therapy with sorafenib in three anatomical cohorts (Thorax, Abdomen, Pelvis): The TAP study. ( Brade, A; Chung, C; Dawson, L; Longo, J; Milosevic, M; Murray, L; Oza, A; Wan, J; Wang, L, 2017)
"About 26 patients with solid tumors were treated in four different dosing schedules."	2.84	EVESOR, a model-based, multiparameter, Phase I trial to optimize the benefit/toxicity ratio of everolimus and sorafenib. ( Badary, OA; Barrois, C; Cassier, P; Colomban, O; El-Demerdash, E; El-Madani, M; El-Shenawy, SM; Freyer, G; Gagnieu, MC; Guitton, J; Hommel-Fontaine, J; Ibrahim, BM; Lefort, T; Maillet, D; Peron, J; Rodriguez-Lafrasse, C; Tod, M; Valette, PJ; You, B, 2017)
" The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of pimasertib in combination with temsirolimus, safety and pharmacokinetics (PK) were investigated."	2.84	Phase I trial of MEK 1/2 inhibitor pimasertib combined with mTOR inhibitor temsirolimus in patients with advanced solid tumors. ( Fu, S; Guo, W; Janku, F; Kurzrock, R; Mita, A; Mita, M; Naing, A; Natale, R; Piha-Paul, SA; Zhao, C, 2017)
" Plasma levels of refametinib, refametinib metabolite M17, and sorafenib were measured for pharmacokinetic assessments."	2.82	A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer. ( Adjei, AA; Becerra, CH; Braiteh, F; Clendeninn, NJ; El-Khoueiry, A; Garbo, L; Gunawan, S; Hezel, AF; Iverson, C; Krissel, H; Leffingwell, DP; Manhard, KJ; Miner, JN; Rajagopalan, P; Richards, DA; Shen, Z; Sherman, M; Stephenson, JJ; Wilson, DM; Yeh, LT, 2016)
"Sorafenib was administered twice daily and topotecan once daily on days 1-5 and 8-12 of each 28-day course."	2.82	Pediatric phase I trial of oral sorafenib and topotecan in refractory or recurrent pediatric solid malignancies. ( Caracciolo, J; Gill, J; Goldberg, J; Hale, GA; Isakoff, MS; Juan, TH; Lee, JK; Lush, RM; Manning, K; Mascarenhas, L; Neuger, AM; Reed, DR; Sandler, E; Smith, T; Sullivan, DM, 2016)
" Because dosing delays and modifications were associated with the MTD, the recommended phase II dose was declared to be pemetrexed 500 mg/m2 every 14 days with oral sorafenib 400 mg given twice daily on days 1-5."	2.82	Phase I study of pemetrexed with sorafenib in advanced solid tumors. ( Booth, L; Bose, P; Dent, P; Geyer, CE; Gordon, S; Kmieciak, M; Massey, HD; McGuire, WP; Moran, RG; Poklepovic, A; Quigley, M; Roberts, JD; Shafer, DA; Shrader, E; Strickler, K; Tombes, MB; Wan, W, 2016)
"Pimasertib showed a favourable pharmacokinetic profile with high absolute bioavailability and a unique metabolic pathway (conjugation with phosphoethanolamine)."	2.82	Pimasertib, a selective oral MEK1/2 inhibitor: absolute bioavailability, mass balance, elimination route, and metabolite profile in cancer patients. ( Johne, A; Massimini, G; Scheible, H; Udvaros, I; von Richter, O, 2016)
"This phase I study evaluated the safety, tolerability, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of tivantinib combined with sorafenib in patients with advanced solid tumors."	2.80	Phase 1 trial of tivantinib in combination with sorafenib in adult patients with advanced solid tumors. ( Adjei, AA; Chai, F; Dy, GK; Goff, L; Lamar, M; Ma, WW; Martell, R; Means-Powell, JA; Puzanov, I; Saif, MW; Santoro, A; Savage, RE; Schwartz, B; Simonelli, M; Sosman, J; Zucali, P, 2015)
"Patients with advanced solid tumors refractory to standard therapy were eligible."	2.80	Dual antiangiogenic inhibition: a phase I dose escalation and expansion trial targeting VEGF-A and VEGFR in patients with advanced solid tumors. ( Falchook, GS; Fu, S; Hong, DS; Huang, M; Janku, F; Jiang, Y; Kurzrock, R; Lin, Q; Naing, A; Parkhurst, K; Piha-Paul, SA; Tsimberidou, AM; Wheler, JJ; Zinner, R, 2015)
"Entinostat was given orally once every 2 weeks, starting at a dose of 4 mg and escalating to 6 and 10 mg every 2 weeks."	2.80	A phase I study of the histone deacetylase (HDAC) inhibitor entinostat, in combination with sorafenib in patients with advanced solid tumors. ( Adjei, AA; Brady, W; DePaolo, D; Ding, Y; Dy, GK; Fetterly, G; Ma, WW; Ngamphaiboon, N; Reungwetwattana, T; Zhao, Y, 2015)
" The objective of the model-based work would be the determination of the optimized doses and dosing schedules of everolimus and sorafenib, offering the maximization of the predicted modeled benefit/toxicity ratio in patients with solid tumors."	2.80	Multiparameter Phase I trials: a tool for model-based development of targeted agent combinations--example of EVESOR trial. ( Barrois, C; Berger, F; Cassier, P; El-Madani, M; Freyer, G; Guitton, J; Hénin, E; Lachuer, J; Lefort, T; Rodriguez-Lafrasse, C; Slimane, K; Tod, M; Valette, PJ; You, B, 2015)
"Lenalidomide and sorafenib was well tolerated and associated with disease stabilization for ≥6 months in patients with melanoma, adenoid cystic carcinoma, and ovarian adenocarcinoma."	2.79	Phase I clinical trial of lenalidomide in combination with sorafenib in patients with advanced cancer. ( Bedikian, AY; Falchook, G; Fu, S; Ganesan, P; Hong, DS; Janku, F; Kies, M; Kurzrock, R; Laday, S; Naing, A; Piha-Paul, S; Tsimberidou, AM; Wheler, J; Wolff, RA, 2014)
"Patients with advanced metastatic solid tumors ineligible for or progressing on standard-of-care therapies with no history of cholecystitis or biliary disease were randomized 2:1:1 to receive motesanib 125 mg once daily (Arm A); 75 mg twice daily (BID), 14-days-on/7-days-off (Arm B); or 75 mg BID, 5-days-on/2-days-off (Arm C)."	2.78	The effect of different dosing regimens of motesanib on the gallbladder: a randomized phase 1b study in patients with advanced solid tumors. ( Belman, ND; Boccia, RV; Hei, YJ; Hsu, CP; Hurwitz, HI; Lipton, L; McCoy, S; Price, TJ; Rosen, LS; Stephenson, JJ; Tebbutt, NC; Wirth, LJ, 2013)
"Sorafenib is an oral multikinase inhibitor with antiangiogenic and antitumor activity."	2.78	Alternative formulations of sorafenib for use in children. ( Baker, SD; Cai, X; Chen, Z; Christensen, R; Inaba, H; Li, L; Navid, F; Regel, J, 2013)
"One patient with renal cell cancer had a partial response and 5 patients attained stable disease."	2.78	Phase 1 study of sorafenib in combination with bortezomib in patients with advanced malignancies. ( Adjei, AA; Bible, KC; Croghan, G; Erlichman, C; Jett, J; Kaufmann, SH; Kumar, SK; Markovic, SN; Marks, R; Molina, J; Moynihan, T; Qin, R; Quevedo, F; Richardson, R; Tan, A, 2013)
"Sorafenib dose was escalated from 90 to 110 mg/m(2) twice daily with fixed doses of bevacizumab at 5 mg/kg every 3 weeks and cyclophosphamide at 50 mg/m(2) daily."	2.78	Phase I and clinical pharmacology study of bevacizumab, sorafenib, and low-dose cyclophosphamide in children and young adults with refractory/recurrent solid tumors. ( Baker, SD; Billups, CA; Davidoff, AM; Fofana, D; Furman, WL; Hu, S; Leung, W; McCarville, MB; McGregor, LM; Navid, F; Panetta, JC; Reddick, WE; Santana, VM; Spunt, SL; Stewart, CF; Turner, D; Wu, J, 2013)
" Cohort C explored an alternate schedule of 7-day on/7-day off flat dose capecitabine 1,000 mg BID with continuous dosing of sorafenib 400 mg BID."	2.77	A drug interaction study evaluating the pharmacokinetics and toxicity of sorafenib in combination with capecitabine. ( Bendell, JC; Burris, HA; Greco, FA; Hainsworth, JD; Infante, JR; Jones, SF; Lane, CM; Spigel, DR; Yardley, DA, 2012)
" This study investigated the safety, pharmacokinetics, and preliminary efficacy of sorafenib in combination with gemcitabine and cisplatin."	2.77	Phase IB study of sorafenib in combination with gemcitabine and cisplatin in patients with refractory solid tumors. ( Brendel, E; Kornacker, M; Kummer, G; Schultheis, B; Strumberg, D; Xia, C; Zeth, M, 2012)
"Sorafenib is an oral tyrosine kinase inhibitor approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma."	2.77	Saturable absorption of sorafenib in patients with solid tumors: a population model. ( Abbas, H; Billemont, B; Blanchet, B; Coriat, R; Dauphin, A; Goldwasser, F; Harcouet, L; Hornecker, M; Mir, O; Ropert, S; Sassi, H; Taieb, F; Tod, M, 2012)
"Sorafenib is an orally administered multikinase inhibitor that exhibits antiangiogenic and antitumor activity."	2.77	Plasma protein binding of sorafenib, a multi kinase inhibitor: in vitro and in cancer patients. ( Pratz, KW; Rudek, MA; Smith, BD; Villarroel, MC; Wright, JJ; Xu, L, 2012)
"Sorafenib plus 5-FU/LCV was generally well tolerated with encouraging antitumor activity and no clinically relevant drug-drug interactions in patients with advanced solid tumors."	2.77	Phase I trial of sorafenib in combination with 5-fluorouracil/leucovorin in advanced solid tumors. ( Atsmon, J; Brendel, E; Bulocinic, S; Figer, A; Geva, R; Nalbandyan, K; Shacham-Shmueli, E; Shpigel, S, 2012)
"Most common adverse events (AEs) (grade 3-5) included neutropenia (89%), leucopaenia (81%), hand-foot skin reaction (30%) and fatigue (30%)."	2.77	Phase I trial to investigate the safety, pharmacokinetics and efficacy of sorafenib combined with docetaxel in patients with advanced refractory solid tumours. ( Awada, A; Bartholomeus, S; Brendel, E; Christensen, O; de Valeriola, D; Delaunoit, T; Gil, T; Hendlisz, A; Lathia, CD; Lebrun, F; Piccart-Gebhart, M; Radtke, M, 2012)
" Treatment-emergent adverse events were generally mild and included fatigue, nausea, vomiting, and chills."	2.77	Safety and pharmacokinetics of ganitumab (AMG 479) combined with sorafenib, panitumumab, erlotinib, or gemcitabine in patients with advanced solid tumors. ( Chan, E; Deng, H; Friberg, G; Gilbert, J; Hwang, YC; Mahalingam, D; McCaffery, I; Michael, SA; Mita, AC; Mita, MM; Mulay, M; Puzanov, I; Rosen, LS; Sarantopoulos, J; Shubhakar, P; Zhu, M, 2012)
"Fifty-three patients with advanced cancer received oral sorafenib 400 mg bid in continuous 28-day cycles in this open-label study."	2.76	A phase I open-label study evaluating the cardiovascular safety of sorafenib in patients with advanced cancer. ( Appleman, LJ; Cihon, F; Mazzu, A; Mita, AC; Shapiro, GI; Sundaresan, PR; Tolcher, AW, 2011)
"Sorafenib 400 mg was administered twice daily continuously starting at day 2 of cycle 1."	2.76	Pharmacokinetic results of a phase I trial of sorafenib in combination with dacarbazine in patients with advanced solid tumors. ( Armand, JP; Brendel, E; Lathia, C; Ludwig, M; Robert, C; Ropert, S; Soria, JC, 2011)
" Most frequent drug-related adverse events were hand-foot skin reaction (HFSR, 89%), diarrhea (71%), and fatigue (69%)."	2.76	Safety and pharmacokinetics of sorafenib combined with capecitabine in patients with advanced solid tumors: results of a phase 1 trial. ( Awada, A; Besse-Hammer, T; Brendel, E; Delesen, H; Gil, T; Hendlisz, A; Joosten, MC; Lathia, CD; Loembé, BA; Piccart-Ghebart, M; Van Hamme, J; Whenham, N, 2011)
"Sirolimus can be safely combined with sorafenib or sunitinib."	2.76	Two drug interaction studies of sirolimus in combination with sorafenib or sunitinib in patients with advanced malignancies. ( Cohen, EE; Fleming, GF; Gangadhar, TC; Geary, D; House, LK; Janisch, L; Kocherginsky, M; Maitland, ML; Ramirez, J; Ratain, MJ; Undevia, SD; Wu, K, 2011)
" Frequently occurring motesanib-related adverse events included diarrhea (n = 19), nausea (n = 18), vomiting (n = 13), and fatigue (n = 12), which were mostly of worst grade < 3."	2.76	Safety and pharmacokinetics of motesanib in combination with gemcitabine and erlotinib for the treatment of solid tumors: a phase 1b study. ( Adewoye, AH; Desai, J; Johnson, J; Kotasek, D; McCoy, S; Price, T; Siu, LL; Sun, YN; Tebbutt, N; Welch, S, 2011)
"Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously."	2.75	Phase I combination of sorafenib and erlotinib therapy in solid tumors: safety, pharmacokinetic, and pharmacodynamic evaluation from an expansion cohort. ( Bandarchi-Chamkhaleh, B; Chen, EX; Do, T; Duran, I; Le Tourneau, C; MacLean, M; Mak, TW; Metser, U; Nayyar, R; Pham, NA; Quintela-Fandino, M; Siu, LL; Tsao, M; Tusche, MW; Wang, L; Wright, JJ, 2010)
"This phase Ib study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of AMG 102, a fully human monoclonal antibody against hepatocyte growth factor/scatter factor (HGF/SF), in combination with bevacizumab or motesanib in patients with advanced solid tumors."	2.75	A phase Ib study of AMG 102 in combination with bevacizumab or motesanib in patients with advanced solid tumors. ( Anderson, A; Beaupre, DM; Deng, H; Leitch, IM; Oliner, KS; Park, DJ; Rosen, PJ; Shubhakar, P; Sweeney, CJ; Yee, LK; Zhu, M, 2010)
" The most frequently reported adverse events were elevated transaminases, hypophosphatemia, fatigue, anorexia, diarrhoea, nausea, rash and palmar-plantar erythrodysaesthesia."	2.75	A phase I dose-escalation study to evaluate safety and tolerability of sorafenib combined with sirolimus in patients with advanced solid cancer. ( Burger, DM; Desar, IM; Timmer-Bonte, JN; van der Graaf, WT; van Herpen, CM, 2010)
"Sorafenib was administered as a 400-mg dose on day 1 for PK, and continuous daily dosing started on day 8."	2.74	Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. ( Abou-Alfa, G; Dees, EC; Desai, A; Edelman, MJ; Fakih, MG; Frank, RC; Hohl, RJ; Hollis, DR; Hwang, J; Kennedy, EB; Lewis, LD; Millard, F; Miller, AA; Murry, DJ; Owzar, K; Ratain, MJ; Villalona-Calero, MA, 2009)
" Patients were randomized to receive a single oral dose of ketoconazole 400 mg either on day 8 (Sequence 1; n = 7) or day 15 (Sequence 2; n = 7), while pharmacokinetic samples were collected."	2.73	Effect of coadministration of ketoconazole, a strong CYP3A4 inhibitor, on pharmacokinetics and tolerability of motesanib diphosphate (AMG 706) in patients with advanced solid tumors. ( Chen, L; Heath, EI; Ingram, M; Lorusso, P; Malburg, L; McGreivy, J; Melara, R; Pilat, MJ; Sun, YN; Wiezorek, J; Yan, L, 2008)
" Adverse events included hypertension, hand-foot syndrome, diarrhea, transaminitis, and fatigue."	2.73	Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity. ( Annunziata, CM; Azad, NS; Cao, L; Chen, HX; Chow, C; Figg, WD; Jain, L; Kohn, EC; Kotz, HL; Kwitkowski, VE; McNally, D; Minasian, L; Posadas, EM; Premkumar, A; Sarosy, G; Steinberg, SM; Wright, JJ, 2008)
" Sixteen patients (62%) experienced motesanib-related adverse events, most commonly lethargy (n=6), diarrhoea (n=4), fatigue (n=3), headache (n=3), and nausea (n=3)."	2.73	Safety and pharmacokinetics of motesanib in combination with gemcitabine for the treatment of patients with solid tumours. ( Lipton, L; McCoy, S; McGreivy, J; Price, TJ; Rosenthal, MA; Sun, YN, 2008)
"In an extended phase, colorectal cancer (CRC) patients received fixed-dose irinotecan 140 mg and sorafenib 400 mg bid (cohort 4)."	2.73	Results from an in vitro and a clinical/pharmacological phase I study with the combination irinotecan and sorafenib. ( Baas, F; Brendel, E; Christensen, O; Gmehling, D; Mross, K; Radtke, M; Steinbild, S; Unger, C; Voliotis, D, 2007)
" The most frequent adverse events were fatigue (55%), diarrhea (51%), nausea (44%), and hypertension (42%)."	2.73	Safety, pharmacokinetics, and efficacy of AMG 706, an oral multikinase inhibitor, in patients with advanced solid tumors. ( Bass, MB; Benjamin, R; Chang, DD; Herbst, RS; Koutsoukos, A; Kurzrock, R; Mulay, M; Ng, C; Polverino, A; Purdom, M; Rosen, LS; Silverman, J; Sun, YN; Van Vugt, A; Wiezorek, JS; Xu, RY, 2007)
"Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously, with every 28 days considered as a cycle."	2.73	Phase I targeted combination trial of sorafenib and erlotinib in patients with advanced solid tumors. ( Chen, EX; Dancey, J; Duan, L; Duran, I; Hirte, H; Hotté, SJ; Lathia, C; MacLean, M; Pond, GR; Siu, LL; Turner, S; Walsh, S; Wright, JJ, 2007)
"Sorafenib is a novel oral multikinase inhibitor that targets Raf serine/threonine and receptor tyrosine kinases, and inhibits tumor cell proliferation and angiogenesis."	2.73	Phase I and pharmacokinetic study of sorafenib, an oral multikinase inhibitor, in Japanese patients with advanced refractory solid tumors. ( Araki, K; Ebi, H; Kawada, K; Kim, YI; Kitagawa, K; Minami, H; Mukai, H; Nakajima, H; Nakajima, K; Tahara, M, 2008)
"We previously reported a flow cytometry technique to monitor pharmacodynamic effects of the raf kinase inhibitor BAY 43-9006 based on the ability of phorbol ester (PMA) to phosphorylate extracellular-regulated kinase (ERK) in peripheral blood (Chow et al."	2.72	Pharmacodynamic monitoring of BAY 43-9006 (Sorafenib) in phase I clinical trials involving solid tumor and AML/MDS patients, using flow cytometry to monitor activation of the ERK pathway in peripheral blood cells. ( Chow, S; Hedley, D; Tong, FK, 2006)
" Sorafenib demonstrated single-agent activity in Phase I studies, and was tolerated and inhibited tumor growth in combination with doxorubicin in preclinical studies."	2.72	Results of a Phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors. ( Brendel, E; Christensen, O; Flashar, C; Grubert, M; Henning, BF; Hilger, RA; Kupsch, P; Ludwig, M; Passarge, K; Richly, H; Scheulen, ME; Schwartz, B; Seeber, S; Strumberg, D; Voigtmann, R, 2006)
" The most frequently reported adverse events over multiple cycles were gastrointestinal (75%), dermatologic (71%), constitutional (68%), pain (64%), or hepatic (61%) related."	2.71	Phase I safety and pharmacokinetics of BAY 43-9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours. ( Awada, A; Bartholomeus, S; Brendel, E; de Valeriola, D; Gil, T; Haase, CG; Hendlisz, A; Mano, M; Piccart, M; Schwartz, B; Strumberg, D, 2005)
" BAY 43-9006 was well tolerated, with mild to moderate toxicities; only six patients discontinued study therapy due to adverse events."	2.71	Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors. ( Cihon, F; Hirte, HW; Hotte, SJ; Lathia, C; Moore, M; Oza, A; Petrenciuc, O; Schwartz, B; Siu, L, 2005)
" This phase I, open-label, nonrandomized, noncontrolled, single-arm, dose escalation study was done to determine the maximum tolerated dose (MTD), safety profile, pharmacokinetic variables, effect on biomarkers, and tumor response with BAY 43-9006 in 19 patients with advanced, refractory solid tumors."	2.71	Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in patients with advanced, refractory solid tumors. ( Clark, JW; Eder, JP; Lathia, C; Lenz, HJ; Ryan, D, 2005)
"Ten patients with advanced cancers were studied."	2.68	Human tumor blood flow is enhanced by nicotinamide and carbogen breathing. ( Chaplin, DJ; Hill, SA; Hoskin, PJ; Powell, ME; Saunders, MI, 1997)
" Despite being orally bioavailable in cancer patients, pimasertib undergoes faster clearance with a short elimination half-life."	2.58	Pharmacology of Pimasertib, A Selective MEK1/2 Inhibitor. ( Srinivas, NR, 2018)
"Sorafenib is a multikinase-tyrosine kinase inhibitor commonly used in a variety of cancers."	2.55	Risk of serious adverse events and fatal adverse events with sorafenib in patients with solid cancer: a meta-analysis of phase 3 randomized controlled trials†. ( Ando, M; Ando, Y; Gyawali, B; Honda, K; Shimokata, T, 2017)
"The old-fashioned anticancer approaches, aiming at arresting cancer cell proliferation interfering with non-specific targets (e."	2.55	Kinase Inhibitors in Multitargeted Cancer Therapy. ( Bonsignore, R; Gentile, C; Lauria, A; Martorana, A, 2017)
"Failure in cancer drug development exacts heavy burdens on patients and research systems."	2.55	Inefficiencies and Patient Burdens in the Development of the Targeted Cancer Drug Sorafenib: A Systematic Review. ( Carlisle, B; Fergusson, D; Hachem, Y; Kimmelman, J; Mattina, J, 2017)
" However, adverse effects common to the tyrosine kinase inhibitor class occur at a noticeably higher rate with sorafenib use in thyroid cancer patients."	2.53	Toxic Effects of Sorafenib in Patients With Differentiated Thyroid Carcinoma Compared With Other Cancers. ( Jaffry, A; Jean, GW; Khan, SA; Mani, RM, 2016)
" We detected a moderate dose-response in one clinically approved indication, hepatocellular carcinoma, but not in another approved malignancy, renal cell carcinoma, or when data were pooled across all malignancies tested."	2.53	Design and Reporting of Targeted Anticancer Preclinical Studies: A Meta-Analysis of Animal Studies Investigating Sorafenib Antitumor Efficacy. ( Fergusson, D; Henderson, VC; Kimmelman, J; MacKinnon, N; Mattina, J, 2016)
" The development of in vivo tools to study OATP1A/1B functions has greatly advanced our mechanistic understanding of their functional role in drug pharmacokinetics, and their implications for therapeutic efficacy and toxic side effects of anticancer and other drug treatments."	2.53	The impact of Organic Anion-Transporting Polypeptides (OATPs) on disposition and toxicity of antitumor drugs: Insights from knockout and humanized mice. ( Durmus, S; Schinkel, AH; van Hoppe, S, 2016)
"Sorafenib treatment results in long-term efficacy and low incidence of life-threatening toxicities."	2.52	The adverse effects of sorafenib in patients with advanced cancers. ( Gao, ZH; Li, Y; Qu, XJ, 2015)
"Sorafenib is a relatively new multi-kinase inhibitor used to treat a wide range of cancers."	2.52	Risk of treatment-related mortality with sorafenib in cancer patients: a meta-analysis of 20 randomly controlled trials : Risk of sorafenib-associated death. ( Cheng, X; Cheng, Y; Kuang, Y; Pan, X; Yang, X, 2015)
"Diarrhea was the most common GI event."	2.50	Risk of gastrointestinal events with sorafenib, sunitinib and pazopanib in patients with solid tumors: a systematic review and meta-analysis of clinical trials. ( Berardi, R; Burattini, L; Cascinu, S; Conti, A; De Giorgi, U; Iacovelli, R; Muzzonigro, G; Pantano, F; Santini, D; Santoni, M, 2014)
"Sorafenib is a multi-tyrosine kinase inhibitor (TKI)."	2.50	Drug safety evaluation of sorafenib for treatment of solid tumors: consequences for the risk assessment and management of cancer patients. ( Alexandre, J; Blanchet, B; Boissier, E; Boudou-Rouquette, P; Cessot, A; Coriat, R; Durand, JP; Giroux, J; Goldwasser, F; Huillard, O; Thomas-Schoemann, A; Vidal, M, 2014)
"Sorafenib was approved by the FDA in fast track for advanced renal cell cancer and hepatocellular cancer and shows good clinical activity in thyroid cancer."	2.50	Sorafenib: targeting multiple tyrosine kinases in cancer. ( Hasskarl, J, 2014)
"Recently, cancer therapies have been supplemented by vascular endothelial growth factor (VEGF) inhibitors as anti-angiogenic agents."	2.50	Clinicopathological spectrum of kidney diseases in cancer patients treated with vascular endothelial growth factor inhibitors: a report of 5 cases and review of literature. ( Chandran, CB; Flombaum, CD; Glezerman, IG; Salvatore, SP; Seshan, SV; Usui, J, 2014)
"Reducing cancer-treatment toxicity was a largely ignored research agenda, which is now emerging as an active area of investigation."	2.49	Body composition in chemotherapy: the promising role of CT scans. ( Prado, CM, 2013)
"Variability in body composition of cancer patients may be a source of disparities in the metabolism of cytotoxic agents."	2.49	Assessment of nutritional status in cancer--the relationship between body composition and pharmacokinetics. ( Baracos, VE; Maia, YL; Ormsbee, M; Prado, CM; Sawyer, MB, 2013)
"Sorafenib and sunitinib have been approved for the treatment of renal, hepatocellular, gastrointestinal and pancreatic neuoendocrine carcinomas."	2.49	Inhibition of RET activated pathways: novel strategies for therapeutic intervention in human cancers. ( Bottai, G; Santarpia, L, 2013)
"Sorafenib is an oral multikinase inhibitor that acts by inhibiting tumor growth and disrupting tumor microvasculature through antiproliferative, anti-angiogenic and proapoptotic effects."	2.48	Molecular targeted therapies for cancer: sorafenib mono-therapy and its combination with other therapies (review). ( Ibrahim, N; Walsh, WR; Yang, JL; Yu, Y, 2012)
"Resistance of cancer cells to chemotherapy and/or radiotherapy is a major challenge to current anticancer treatment."	2.48	Using NF-κB as a molecular target for theranostics in radiation oncology research. ( Chiang, IT; Hsu, FT; Hwang, JJ; Liu, YC, 2012)
" On the other hand, the optimal combination and dosage of these drugs, selection of the apropriate biomarker and better understanding of the conflicting role of PDGFR and FGFR signaling in angiogenesis remain future challenges."	2.48	[Possibilities for inhibiting tumor-induced angiogenesis: results with multi-target tyrosine kinase inhibitors]. ( Döme, B; Török, S, 2012)
" However, the newer targeted anticancer therapies have different pharmacokinetic (PK) and dosing characteristics compared with traditional cytotoxic drugs, making it possible to estimate the steady-state drug exposure with a single trough-level measurement."	2.48	Evidence for therapeutic drug monitoring of targeted anticancer therapies. ( Balakrishnar, B; Clements, A; Gao, B; Gurney, H; Wong, M; Yeap, S, 2012)
"During the last years novel anticancer treatments targeting specific molecules or genes involved in cancer development are being developed to improve outcome and reduce side-effects."	2.48	Polymorphisms to predict outcome to the tyrosine kinase inhibitors gefitinib, erlotinib, sorafenib and sunitinib. ( Erdem, L; Giovannetti, E; Honeywell, R; Leon, LG; Peters, GJ, 2012)
"Most of the new anticancer treatments currently in developmental stage are based on targeted therapies, acting against numerous tumor cell abnormalities, like growth factors et their receptors, cell proliferation-inducing factors, molecules involved in DNA repair, cell death inducers, tumor invasion and angiogenesis."	2.47	[Indications and current development of new targeted therapies in pediatric oncology]. ( Geoerger, B; Leblond, P, 2011)
"While loss of FBW7 sensitizes cancer cells to certain drugs, FBW7-/- cells are more resistant to other types of chemotherapies."	2.47	The two faces of FBW7 in cancer drug resistance. ( Fukushima, H; Gao, D; Inuzuka, H; Lau, AW; Liu, P; Wan, L; Wang, Z; Wei, W, 2011)
"Targeted therapies against cancer have become more and more important."	2.46	Compounds in clinical Phase III and beyond. ( Bayer, M; Berdel, WE; Kessler, T; Liersch, R; Mesters, RM; Schwöppe, C, 2010)
"Sorafenib was approved by the FDA in fast track for advanced renal cell cancer and hepatocellular cancer and shows good clinical activity in thyroid cancer."	2.46	Sorafenib. ( Hasskarl, J, 2010)
" Strict monitoring of treatment-related adverse effects must be conducted in order to allow the early detection of cardiovascular toxicities and their prompt medication."	2.46	Cardiovascular safety of VEGF-targeting therapies: current evidence and handling strategies. ( Brandes, AA; Franceschi, E; Girardi, F, 2010)
"Tumor tissue is composed of both cancer cells and stromal cells recruited from normal tissue."	2.46	Tumor-stromal cell interactions and opportunities for therapeutic intervention. ( Udagawa, T; Wood, M, 2010)
"Targeted therapies are widely used in cancer because of their effectiveness, even in tumours that are resistant to conventional chemotherapy such as kidney or hepatocellular carcinomas."	2.45	[Targeted therapies and their indications in solid neoplasias]. ( Dreyer, C; Faivre, S; Raymond, E, 2009)
"Increasing use of targeted anticancer agents that inhibit tyrosine kinase signaling (monoclonal antibodies or tyrosine kinase inhibitors) has dramatically improved the survival of patients with malignancies."	2.45	Cardiac dysfunction induced by novel targeted anticancer therapy: an emerging issue. ( Chen, MH, 2009)
"Future potential uses of bevacizumab in cancer therapy will be discussed."	2.45	The role of antiangiogenesis therapy: bevacizumab and beyond. ( Cortés-Funes, H, 2009)
"Sorafenib is an oral multikinase inhibitor that has been proven effective as a single-agent therapy in renal cell carcinoma, and there is a strong rationale for investigating its use in combination with other agents."	2.44	Selected combination therapy with sorafenib: a review of clinical data and perspectives in advanced solid tumors. ( Awada, A; D'Hondt, V; Dal Lago, L, 2008)
"Sorafenib is an oral multikinase inhibitor that inhibits Raf serine/threonine kinases and receptor tyrosine kinases involved in tumor growth and angiogenesis."	2.44	Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors. ( Awada, A; Clark, JW; Eder, JP; Hendlisz, A; Hirte, HW; Lenz, HJ; Moore, MJ; Richly, H; Schwartz, B; Strumberg, D, 2007)
"Clinical trials showing longer survival when chemotherapy is combined with antiangiogenic agents (AAs) have led to growing interest in designing combined modality protocols that exploit abnormalities in tumor vasculature."	2.44	Design of clinical trials of radiation combined with antiangiogenic therapy. ( Senan, S; Smit, EF, 2007)
"Approved for the treatment of advanced renal cell carcinoma by the US FDA and other regulatory agencies, sorafenib is an agent with multiple targets that may also prove beneficial in other malignancies."	2.44	Sorafenib: delivering a targeted drug to the right targets. ( Flaherty, KT, 2007)
"Advances in understanding the role of vascular endothelial growth factor (VEGF) in normal physiology are giving insight into the basis of adverse effects attributed to the use of VEGF inhibitors in clinical oncology."	2.44	Mechanisms of adverse effects of anti-VEGF therapy for cancer. ( Kamba, T; McDonald, DM, 2007)
"Angiogenesis does not initiate malignancy but promotes tumor progression and metastasis."	2.44	[Oral drugs inhibiting the VEGF pathway]. ( Armand, JP; Mir, O; Ropert, S, 2007)
"Molecularly targeted anticancer therapies are now available that have been rationally designed to interact with specific proteins associated with tumour development or progression."	2.44	New developments in multitargeted therapy for patients with solid tumours. ( Faivre, S; Le Tourneau, C; Raymond, E, 2008)
"Sorafenib (Nexavar) is an oral multi-kinase inhibitor that inhibits Raf serine/threonine kinases and receptor tyrosine kinases involved in tumor growth and angiogenesis."	2.44	Safety and anti-tumor activity of sorafenib (Nexavar) in combination with other anti-cancer agents: a review of clinical trials. ( Awada, A; Takimoto, CH, 2008)
" The most common Grade 3/4 adverse events experienced on thalidomide monotherapy were venous thrombosis (3."	2.44	Systematic review to establish the safety profiles for direct and indirect inhibitors of p38 Mitogen-activated protein kinases for treatment of cancer. A systematic review of the literature. ( Claflin, JE; Crean, S; Lahn, M; Linz, H; Noel, JK; Ranganathan, G, 2008)
"Here, we review recent findings that cancer cell sensitivity to TRAIL is greatly increased when the Bcl-2 family protein Mcl-1 is down-regulated by the Raf/vascular endothelial growth factor kinase inhibitor sorafenib, a Food and Drug Administration-approved cancer drug."	2.44	Mcl-1: a gateway to TRAIL sensitization. ( El-Deiry, WS; Kim, SH; Ricci, MS, 2008)
"Sorafenib (BAY 43-9006) is a novel oral bis-aryl urea compound originally developed as an inhibitor to RAF kinase for its anti-proliferative property."	2.43	Sorafenib (BAY 43-9006): review of clinical development. ( Chen, EX; Ng, R, 2006)
"Sorafenib was well tolerated at the RDP, and induced sustained disease stabilization, particularly in patients with skin toxicity/diarrhoea."	2.43	Pooled safety analysis of BAY 43-9006 (sorafenib) monotherapy in patients with advanced solid tumours: Is rash associated with treatment outcome? ( Awada, A; Brueckner, A; Christensen, O; Clark, JW; Hirte, H; Hofstra, E; Piccart, P; Schwartz, B; Seeber, S; Strumberg, D; Voliotis, D, 2006)
"Cachexia is a debilitating wasting syndrome and highly prevalent comorbidity in cancer patients."	1.91	NAD ( Beltrà, M; Corrà, S; Fornelli, C; Hsu, MY; Hulmi, JJ; Kivelä, R; Moletta, L; Penna, F; Pirinen, E; Pöllänen, N; Porporato, PE; Sandri, M; Sartori, R; Tonttila, K; Viscomi, C; Zampieri, S, 2023)
"Multiple solid cancers distantly increase expression of Nnmt and its product 1-methylnicotinamide (MNAM) in the liver."	1.72	Remote solid cancers rewire hepatic nitrogen metabolism via host nicotinamide-N-methyltransferase. ( Bamba, T; Enya, S; Hamanishi, J; Harata, A; Hojo, H; Izumi, Y; Kashio, S; Kawamoto, H; Kawaoka, S; Konishi, R; Mandai, M; Miura, M; Mizuno, R; Nakao, M; Suzuki, Y; Takahashi, M; Yoda, M, 2022)
"The metabolic challenges present in tumors attenuate the metabolic fitness and antitumor activity of tumor-infiltrating T lymphocytes (TILs)."	1.56	Disturbed mitochondrial dynamics in CD8 ( Bock, C; Chao, T; Cheng, WC; Coukos, G; Franco, F; Gao, M; Genolet, R; Ho, PC; Imrichova, H; Jandus, C; Jiang, YF; Liu, PS; Locasale, JW; Rincon-Restrepo, M; Tang, L; Vannini, N; Wang, H; Xiao, Z; Yu, YR; Zippelius, A, 2020)
"Treatment with capecitabine did not significantly increase the mean antioxidant concentration."	1.48	Influence of Sorafenib, Sunitinib and Capecitabine on the Antioxidant Status of the Skin. ( Fuss, H; Jung, S; Lademann, J, 2018)
"In our study, a wide variety of tumors underwent comprehensive genomic profiling for hundreds of known cancer genes using the FoundationOne™ or FoundationOne Heme™ comprehensive genomic profiling assays."	1.43	The distribution of BRAF gene fusions in solid tumors and response to targeted therapy. ( Ali, SM; Chmielecki, J; Chudnovsky, J; Elvin, JA; Gay, L; Gray, A; Johnson, A; Lipson, D; Miller, VA; Nakamura, BN; Roels, S; Ross, JS; Stephens, PJ; Vergilio, JA; Wang, K; Wong, MK; Yelensky, R, 2016)
" The dosage was temporarily reduced in only two patients, and oral steroids were added in four."	1.43	Widespread morbilliform rash due to sorafenib or vemurafenib treatment for advanced cancer; experience of a tertiary dermato-oncology clinic. ( Amitay-Laish, I; Didkovsky, E; Hendler, D; Hodak, E; Lotem, M; Merims, S; Ollech, A; Popovtzer, A; Stemmer, SM, 2016)
"Thirty-six patients with advanced cancer underwent molecular profiling with NGS with the intent of clinical application of available matched targeted agents."	1.43	Pilot Study of a Next-Generation Sequencing-Based Targeted Anticancer Therapy in Refractory Solid Tumors at a Korean Institution. ( Kim, HR; Kim, JH; Kim, S; Kwack, K; Lee, MG; Lim, SM; Moon, YW; Park, HS, 2016)
" The structural difference between sorafenib and t-CUPM significantly reduces inhibitory spectrum of kinases by this analogue, and pharmacokinetic characterization demonstrates a 20-fold better oral bioavailability of t-CUPM than sorafenib in mice."	1.42	Biological evaluation of a novel sorafenib analogue, t-CUPM. ( Hammock, BD; Hwang, SH; Liu, JY; Morisseau, C; Wecksler, AT; Weiss, RH; Wettersten, HI; Wu, J, 2015)
"Treatment with small molecule tyrosine kinase inhibitors (TKIs) has improved survival in many cancers, yet has been associated with an increased risk of adverse events."	1.42	Cardiovascular toxicity of multi-tyrosine kinase inhibitors in advanced solid tumors: a population-based observational study. ( Amir, E; Ethier, JL; Krzyzanowska, MK; Ocana, A; Seruga, B; Srikanthan, A, 2015)
"Effective choice of anticancer drugs is important problem of modern medicine."	1.42	Combinatorial high-throughput experimental and bioinformatic approach identifies molecular pathways linked with the sensitivity to anticancer target drugs. ( Aliper, A; Borisov, N; Buzdin, A; Kholodenko, R; Malakhova, G; Roumiantsev, S; Shepelin, D; Suntsova, M; Vasilov, R; Venkova, L; Zhavoronkov, A, 2015)
" Population pharmacokinetic (POPPK) modeling of motesanib and M4, an active metabolite, was performed to assess sources of variability in cancer patients."	1.42	Population pharmacokinetic modeling of motesanib and its active metabolite, M4, in cancer patients. ( Gosselin, NH; Hsu, CP; Lu, JF; Mouksassi, MS, 2015)
"Sorafenib (SRF) is a multi-kinase inhibitor that has been shown to have antitumor activity against several types of cancers, but the effect of SRF on EBV-transformed B cells is unknown."	1.40	ROS-mediated JNK/p38-MAPK activation regulates Bax translocation in Sorafenib-induced apoptosis of EBV-transformed B cells. ( Choi, Y; Hur, DY; Kim, D; Kim, YS; Lee, HK; Park, GB, 2014)
"Loss-of-function mutations in the Werner syndrome gene are associated with the premature onset of age-related diseases."	1.40	Downregulation of the Werner syndrome protein induces a metabolic shift that compromises redox homeostasis and limits proliferation of cancer cells. ( Cadenas, E; Chen, LY; Comai, L; Iglesias-Pedraz, JM; Li, B; Reddy, S; Yin, F, 2014)
"In an application to data from hepatocellular carcinoma patients, the coupled stepwise approach is seen to facilitate joint interpretation of the different cause-specific Cox models."	1.40	Coupled variable selection for regression modeling of complex treatment patterns in a clinical cancer registry. ( Binder, H; Elsäßer, A; Schmidtmann, I; Weinmann, A, 2014)
"As a result, NNMT-expressing cancer cells have an altered epigenetic state that includes hypomethylated histones and other cancer-related proteins combined with heightened expression of protumorigenic gene products."	1.39	NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink. ( Cravatt, BF; Ulanovskaya, OA; Zuhl, AM, 2013)
"Treatment with sorafenib led to an increased keratinocyte proliferation and a tendency toward increased mitogen-activated protein kinase (MAPK) pathway activation in normal skin."	1.38	Skin tumors induced by sorafenib; paradoxic RAS-RAF pathway activation and oncogenic mutations of HRAS, TP53, and TGFBR1. ( André, J; Arnault, JP; Boussemart, L; Druillennec, S; Dumaz, N; Eggermont, AM; Escudier, B; Eychène, A; Hollville, E; Kamsu-Kom, N; Lacroix, L; Larcher, M; Malka, D; Mateus, C; Robert, C; Sarasin, A; Soria, JC; Spatz, A; Tomasic, G; Vagner, S; Wechsler, J, 2012)
" Furthermore, the RAIN-Droplet model has facilitated the discovery of a novel pro-angiogenic capacity for sorafenib, which may impact the clinical application and dosing regimen of that drug."	1.38	RAIN-Droplet: a novel 3D in vitro angiogenesis model. ( Dong, Z; Nör, JE; Zeitlin, BD, 2012)
"Sorafenib displays major interpatient pharmacokinetic variability."	1.38	Variability of sorafenib toxicity and exposure over time: a pharmacokinetic/pharmacodynamic analysis. ( Billemont, B; Blanchet, B; Boudou-Rouquette, P; Cabanes, L; Coriat, R; Franck, N; Goldwasser, F; Mir, O; Ropert, S; Tod, M, 2012)
" Taken together, the data suggest that premexetred and sorafenib act synergistically to enhance tumor killing via the promotion of a toxic form of autophagy that leads to activation of the intrinsic apoptosis pathway, and predict that combination treatment represents a future therapeutic option in the treatment of solid tumors."	1.37	Sorafenib enhances pemetrexed cytotoxicity through an autophagy-dependent mechanism in cancer cells. ( Bareford, MD; Burow, ME; Cruickshanks, N; Dent, P; Eulitt, P; Fisher, PB; Grant, S; Hamed, HA; Hubbard, N; Moran, RG; Nephew, KP; Park, MA; Tang, Y; Tye, G; Yacoub, A, 2011)
" Taken together, the data suggest that premexetred and sorafenib act synergistically to enhance tumor killing via the promotion of a toxic form of autophagy that leads to activation of the intrinsic apoptosis pathway, and predict that combination treatment represents a future therapeutic option in the treatment of solid tumors."	1.37	Sorafenib enhances pemetrexed cytotoxicity through an autophagy-dependent mechanism in cancer cells. ( Bareford, MD; Burow, ME; Cruickshanks, N; Dent, P; Fisher, PB; Grant, S; Hamed, HA; Moran, RG; Nephew, KP; Tang, Y, 2011)
"Patients with advanced cancer including breast cancer, hepatocellular cancer and urothelial cancer frequently receive a chemotherapy regimen containing doxorubicin."	1.36	Sensitivity of doxorubicin-resistant cells to sorafenib: possible role for inhibition of eukaryotic initiation factor-2alpha phosphorylation. ( Eto, M; Itsumi, M; Naito, S; Shiota, M; Tada, Y; Takeuchi, A; Tatsugami, K; Uchiumi, T; Yokomizo, A, 2010)
"Sorafenib is an inhibitor of multiple kinases (e."	1.36	Initial testing (stage 1) of the multi-targeted kinase inhibitor sorafenib by the pediatric preclinical testing program. ( Carol, H; Gorlick, R; Houghton, PJ; Kang, MH; Keir, ST; Kolb, EA; Lock, R; Maris, JM; Morton, CL; Reynolds, CP; Smith, MA; Watkins, A, 2010)
"Sorafenib is a targeted drug specifically engineered to inhibit Raf serine/threonine kinases, which are part of the reticular activating system (RAS) oncogene pathway."	1.35	Cutaneous drug eruptions induced by sorafenib: a case series. ( Kung, EF; Maddox, JS; Petronic-Rosic, V; Sethi, A, 2008)
"The primary objective of Phase II cancer trials is to evaluate the potential efficacy of a new regimen in terms of its antitumor activity in a given type of cancer."	1.35	Selecting promising treatments in randomized Phase II cancer trials with an active control. ( Cheung, YK, 2009)
"The treatment of some cancer patients has shifted from traditional, non-specific cytotoxic chemotherapy to chronic treatment with molecular targeted therapies."	1.35	Therapeutic Drug Monitoring of the new targeted anticancer agents imatinib, nilotinib, dasatinib, sunitinib, sorafenib and lapatinib by LC tandem mass spectrometry. ( Decosterd, LA; Duchosal, MA; Haouala, A; Leyvraz, S; Montemurro, M; Ris, HB; Rochat, B; Widmer, N; Zaman, K; Zanolari, B, 2009)
"Testing agents in cancers with multiple disease subtypes, in which the activity of a new treatment may vary between subtypes, presents statistical and logistical challenges."	1.35	Multiple Histology Phase II Trials. ( Crowley, J; Leblanc, M; Rankin, C, 2009)
"Blood pressure elevation is likely a pharmacodynamic marker of VEGF signaling pathway (VSP) inhibition and could be useful for optimizing safe and effective VSP inhibitor dosing."	1.35	Rapid development of hypertension by sorafenib: toxicity or target? ( Atkins, MB; Humphreys, BD, 2009)
" Once daily oral dosing of BAY 43-9006 demonstrated broad-spectrum antitumor activity in colon, breast, and non-small-cell lung cancer xenograft models."	1.32	BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. ( Adnane, L; Auclair, D; Bollag, G; Cao, Y; Carter, C; Chen, C; Eveleigh, D; Gawlak, S; Gedrich, R; Liu, L; Lynch, M; McHugh, M; McNabola, A; Post, LE; Riedl, B; Rong, H; Rowley, B; Shujath, J; Tang, L; Taylor, I; Trail, PA; Vincent, P; Voznesensky, A; Wilhelm, SM; Wilkie, D; Zhang, X, 2004)
"Acetaldehyde formation was determined by GC-FID analysis in the head space of incubation mixtures."	1.31	Rat ventral prostate xanthine oxidase bioactivation of ethanol to acetaldehyde and 1-hydroxyethyl free radicals: analysis of its potential role in heavy alcohol drinking tumor-promoting effects. ( Castro, GD; Castro, JA; Costantini, MH; Delgado de Layño, AM, 2001)
" Neither the peak concentration nor the area under the concentration/time curve (AUC) of nicotinamide, nor the main metabolites of nicotinamide appeared to correlate with the incidence of toxicity."	1.29	Nicotinamide pharmacokinetics in normal volunteers and patients undergoing palliative radiotherapy. ( Dennis, MF; Hodgkiss, RJ; Hoskin, PJ; Rojas, A; Saunders, MI; Stratford, MR, 1996)
"Theophylline and MELPH were also found to act synergistically on the induction of SCEs."	1.27	Synergistic induction of sister-chromatid exchanges in lymphocytes from normal subjects and from patients under cytostatic therapy by inhibitors of poly(ADP-ribose)polymerase and antitumour agents. ( Dozi-Vassiliades, J; Hatzitheodoridou, P; Kourakis, A; Mourelatos, D; Tsiouris, J, 1985)

Research

Studies (374)

Authors

Clinical Trials (31)

Trial Overview

Trial Outcomes

Number of Subjects Experienced Any Dose-Limiting Toxicity (DLT) Over the First Cycle - Day 1 to 21

Timeframe	Studies, this research(%)	All Research%
pre-1990	26 (6.95)	18.7374
1990's	20 (5.35)	18.2507
2000's	111 (29.68)	29.6817
2010's	189 (50.53)	24.3611
2020's	28 (7.49)	2.80

Authors	Studies
Abdelghany, L	2
Zhang, X	2
Kawabata, T	1
Goto, S	1
El-Mahdy, N	1
Jingu, K	2
Li, TS	2
Gasparrini, M	1
Audrito, V	1
Wang, W	1
Yang, C	1
Wang, T	1
Deng, H	3
ElMokh, O	1
Matsumoto, S	1
Biniecka, P	1
Bellotti, A	1
Schaeuble, K	1
Piacente, F	1
Gallart-Ayala, H	1
Ivanisevic, J	1
Stamenkovic, I	1
Nencioni, A	3
Nahimana, A	2
Duchosal, MA	2
Mizuno, R	1
Hojo, H	1
Takahashi, M	1
Kashio, S	1
Enya, S	1
Nakao, M	1
Konishi, R	1
Yoda, M	1
Harata, A	1
Hamanishi, J	1
Kawamoto, H	1
Mandai, M	1
Suzuki, Y	1
Miura, M	1
Bamba, T	1
Izumi, Y	1
Kawaoka, S	1
Hofer, SJ	1
Kroemer, G	2
Kepp, O	1
Sun, D	1
Dong, G	2
Wu, Y	1
Du, L	1
Li, M	1
Sheng, C	1
Almeida, KH	1
Avalos-Irving, L	1
Berardinelli, S	1
Chauvin, K	1
Yanez, S	1
Puszkiel, A	1
You, B	3
Payen, L	1
Lopez, J	1
Guitton, J	3
Rousset, P	1
Fontaine, J	1
Péron, J	2
Maillet, D	2
Tartas, S	1
Bonnin, N	1
Trillet-Lenoir, V	1
Colomban, O	2
Augu-Denechere, D	1
Freyer, G	3
Tod, M	8
Beltrà, M	1
Pöllänen, N	1
Fornelli, C	1
Tonttila, K	1
Hsu, MY	1
Zampieri, S	1
Moletta, L	1
Corrà, S	1
Porporato, PE	1
Kivelä, R	1
Viscomi, C	1
Sandri, M	1
Hulmi, JJ	1
Sartori, R	1
Pirinen, E	1
Penna, F	1
Spencer, KR	1
Portal, DE	1
Aisner, J	1
Stein, MN	1
Malhotra, J	1
Shih, W	1
Chan, N	1
Silk, AW	1
Ganesan, S	1
Goodin, S	1
Gounder, M	1
Lin, H	2
Li, J	2
Cerchio, R	1
Marinaro, C	1
Chen, S	1
Mehnert, JM	1
Jabbari, P	1
Ardakany, MR	1
Ebrahimi, S	1
Rezaei, N	1
Xu, Y	1
Sekiya, R	1
Yan, C	1
Megarity, CF	1
Timson, DJ	1
Yamazaki, K	1
Doi, T	1
Ikeda, M	1
Okusaka, T	1
Schueler, A	1
Watanabe, M	1
Ohtsu, A	1
Song, SB	1
Park, JS	1
Chung, GJ	1
Lee, IH	1
Hwang, ES	1
Witkowska-Patena, E	1
Budzyńska, A	1
Giżewska, A	1
Dziuk, M	1
Walęcka-Mazur, A	1
Nikas, IP	1
Paschou, SA	1
Ryu, HS	1
Buqué, A	1
Bloy, N	1
Galluzzi, L	1
Hamity, MV	1
White, SR	1
Blum, C	1
Gibson-Corley, KN	1
Hammond, DL	1
Jones, JK	1
Thompson, EM	1
Yu, YR	1
Imrichova, H	1
Wang, H	2
Chao, T	1
Xiao, Z	1
Gao, M	1
Rincon-Restrepo, M	1
Franco, F	1
Genolet, R	1
Cheng, WC	1
Jandus, C	1
Coukos, G	1
Jiang, YF	1
Locasale, JW	1
Zippelius, A	1
Liu, PS	1
Tang, L	2
Bock, C	1
Vannini, N	1
Ho, PC	1
Delord, JP	1
Italiano, A	2
Awada, A	9
Aftimos, P	1
Houédé, N	1
Lebbé, C	1
Pages, C	1
Lesimple, T	1
Dinulescu, M	1
Schellens, JHM	2
Leijen, S	1
Rottey, S	1
Kruse, V	1
Kefford, R	1
Faivre, S	3
Gomez-Roca, C	1
Scheuler, A	1
Massimini, G	2
Raymond, E	3
Patnaik, A	4
Yap, TA	1
Chung, HC	1
de Miguel, MJ	1
Bang, YJ	1
Lin, CC	1
Su, WC	1
Chow, KH	1
Szpurka, AM	1
Yu, D	2
Zhao, Y	2
Carlsen, M	1
Schmidt, S	1
Vangerow, B	1
Gandhi, L	2
Xu, X	1
Bendell, J	1
Roberti, A	1
Fernández, AF	1
Fraga, MF	1
Zhong, Y	1
Yang, S	1
Cui, J	2
Wang, J	1
Li, L	4
Chen, Y	2
Chen, J	3
Feng, P	1
Huang, S	1
Li, H	1
Han, Y	1
Tang, G	1
Hu, K	1
Hayat, F	1
Sonavane, M	1
Makarov, MV	1
Trammell, SAJ	1
McPherson, P	1
Gassman, NR	1
Migaud, ME	1
Mattiello, L	1
Pucci, G	1
Marchetti, F	1
Diederich, M	1
Gonfloni, S	1
Gao, Y	1
Martin, NI	1
van Haren, MJ	1
Ghanem, MS	1
Monacelli, F	1
Novak Kujundžić, R	1
Prpić, M	1
Đaković, N	1
Dabelić, N	1
Tomljanović, M	1
Mojzeš, A	1
Fröbe, A	1
Trošelj, KG	1
Chu, YY	2
Cheng, HJ	1
Tian, ZH	1
Zhao, JC	1
Li, G	2
Sun, CJ	1
Li, WB	1
Gong, L	1
Giacomini, MM	1
Giacomini, C	1
Maitland, ML	7
Altman, RB	1
Klein, TE	1
Murray, L	1
Longo, J	1
Wan, J	2
Chung, C	1
Wang, L	3
Dawson, L	1
Milosevic, M	1
Oza, A	2
Brade, A	1
Garrido, A	1
Djouder, N	1
Covell, DG	1
Bruner, JK	1
Ma, HS	1
Qin, ACR	1
Rudek, MA	3
Jones, RJ	1
Levis, MJ	1
Pratz, KW	2
Pratilas, CA	1
Small, D	1
Schloss, J	1
Colosimo, M	1
Hori, Y	1
Ito, K	1
Hamamichi, S	1
Ozawa, Y	1
Matsui, J	1
Umeda, IO	1
Fujii, H	1
Srinivas, NR	1
Zhang, C	1
Chi, H	1
Meng, Z	1
Tharmalingham, H	1
Hoskin, P	1
Fuss, H	1
Lademann, J	1
Jung, S	1
Schram, AM	1
Mita, MM	2
Damstrup, L	1
Campana, F	1
Hidalgo, M	1
Grande, E	1
Hyman, DM	1
Heist, RS	1
de Weger, VA	1
de Jonge, M	2
Langenberg, MHG	1
Lolkema, M	1
Varga, A	1
Demers, B	1
Thomas, K	1
Hsu, K	1
Tuffal, G	1
Goodstal, S	1
Macé, S	1
Deutsch, E	1
Ulanovskaya, OA	1
Zuhl, AM	1
Cravatt, BF	1
Poot, AJ	1
van der Wildt, B	1
Stigter-van Walsum, M	1
Rongen, M	1
Schuit, RC	1
Hendrikse, NH	1
Eriksson, J	1
van Dongen, GA	1
Windhorst, AD	1
Montecucco, F	1
Cea, M	1
Bauer, I	1
Soncini, D	1
Caffa, I	1
Lasigliè, D	1
Uccelli, A	1
Bruzzone, S	1
Funakoshi, T	1
Latif, A	1
Galsky, MD	1
Rosen, LS	4
Lipton, L	2
Price, TJ	2
Belman, ND	1
Boccia, RV	1
Hurwitz, HI	1
Stephenson, JJ	2
Wirth, LJ	1
McCoy, S	3
Hei, YJ	1
Hsu, CP	2
Tebbutt, NC	1
Ganesan, P	1
Piha-Paul, S	1
Naing, A	4
Falchook, G	1
Wheler, J	1
Fu, S	3
Hong, DS	4
Kurzrock, R	6
Janku, F	3
Laday, S	1
Bedikian, AY	1
Kies, M	1
Wolff, RA	1
Tsimberidou, AM	2
Navid, F	2
Christensen, R	1
Inaba, H	1
Chen, Z	1
Cai, X	1
Regel, J	1
Baker, SD	3
Prado, CM	2
Kumar, SK	1
Jett, J	1
Marks, R	1
Richardson, R	1
Quevedo, F	1
Moynihan, T	1
Croghan, G	1
Markovic, SN	1
Bible, KC	1
Qin, R	1
Tan, A	1
Molina, J	1
Kaufmann, SH	1
Erlichman, C	1
Adjei, AA	4
Bhatta, SS	1
Wroblewski, KE	1
Agarwal, KL	1
Sit, L	2
Cohen, EE	3
Seiwert, TY	1
Karrison, T	2
Bakris, GL	2
Ratain, MJ	5
Vokes, EE	1
Maia, YL	1
Ormsbee, M	1
Sawyer, MB	1
Baracos, VE	1
Hatzivassiliou, G	1
Haling, JR	1
Chen, H	1
Song, K	1
Price, S	1
Heald, R	1
Hewitt, JF	1
Zak, M	1
Peck, A	1
Orr, C	1
Merchant, M	1
Hoeflich, KP	1
Chan, J	1
Luoh, SM	1
Anderson, DJ	1
Ludlam, MJ	1
Wiesmann, C	1
Ultsch, M	1
Friedman, LS	1
Malek, S	1
Belvin, M	1
Mieszawska, AJ	1
Kim, Y	1
Gianella, A	1
van Rooy, I	1
Priem, B	1
Labarre, MP	1
Ozcan, C	1
Cormode, DP	1
Petrov, A	1
Langer, R	1
Farokhzad, OC	1
Fayad, ZA	1
Mulder, WJ	1
Lazar, V	1
Lassau, N	1
Meurice, G	1
Loriot, Y	1
Peña, C	1
Massard, C	1
Robert, C	6
Robert, T	1
Le Berre, MA	1
de Baere, T	1
Dessen, P	1
Soria, JC	5
Armand, JP	4
Abdulghani, J	1
Allen, JE	1
Dicker, DT	1
Liu, YY	1
Goldenberg, D	1
Smith, CD	1
Humphreys, R	1
El-Deiry, WS	2
Santoni, M	1
Conti, A	1
De Giorgi, U	1
Iacovelli, R	1
Pantano, F	1
Burattini, L	1
Muzzonigro, G	1
Berardi, R	2
Santini, D	1
Cascinu, S	2
Wang, CF	2
Mäkilä, EM	2
Kaasalainen, MH	1
Liu, D	1
Sarparanta, MP	2
Airaksinen, AJ	2
Salonen, JJ	2
Hirvonen, JT	2
Santos, HA	2
Escudero-Ortiz, V	1
Pérez-Ruixo, JJ	1
Valenzuela, B	1
Thomeas, V	2
Chow, S	2
Gutierrez, JO	1
Karovic, S	2
Wroblewski, K	1
Kistner-Griffin, E	1
Karrison, TG	2
Zhang, XJ	1
Zhang, TY	1
Yu, FF	1
Wei, X	1
Li, YS	1
Xu, F	1
Wei, LX	1
He, J	1
Park, GB	1
Choi, Y	1
Kim, YS	1
Lee, HK	1
Kim, D	1
Hur, DY	1
Liu, Y	1
Feng, L	1
Liu, T	1

Trial	Phase	Enrollment	Study Type	Start Date	Status
A Multicenter, Open Label, Phase I Trial of the MEK Inhibitor MSC1936369B Given Orally to Subjects With Solid Tumours[NCT00982865]	Phase 1	182 participants (Actual)	Interventional	2007-12-31	Completed
A Phase 1a/1b Study of a Novel Anti-PD-L1 Checkpoint Antibody (LY3300054) Administered Alone or in Combination With Other Agents in Advanced Refractory Solid Tumors (Phase 1a/1b Anti-PD-L1 Combinations in Tumors-PACT)[NCT02791334]	Phase 1	215 participants (Anticipated)	Interventional	2016-06-29	Active, not recruiting
A Phase 1 Study of Combination Therapy With SAR405838 and Pimasertib in Patients With Advanced Cancer[NCT01985191]	Phase 1	26 participants (Actual)	Interventional	2013-11-30	Completed
An Open-Label, Randomized, Phase 1b Study Evaluating the Effect of Different Doses of AMG 706 on the Gallbladder in Subjects With Advanced Solid Tumors[NCT00448786]	Phase 1	49 participants (Actual)	Interventional	2007-02-28	Completed
A Phase I Study of Lenalidomide in Combination With Bevacizumab, Sorafenib, Temsirolimus, or 5-fluorouracil, Leucovorin, Oxaliplatin (FOLFOX) in Patients With Advanced Cancers[NCT01183663]	Phase 1	180 participants (Actual)	Interventional	2010-08-31	Completed
A Phase I Study of the Raf Kinase/VEGFR Inhibitor BAY 43-9006 in Combination With the Proteasome Inhibitor PS-341 in Patients With Advanced Malignancies[NCT00303797]	Phase 1	50 participants (Actual)	Interventional	2005-12-31	Completed
A Phase 1/2 Study of the Combination of RDEA119 and Sorafenib in Patients With Advanced Cancer[NCT00785226]	Phase 1/Phase 2	62 participants (Actual)	Interventional	2008-11-30	Completed
A Phase I, Open-Label, Single Center Trial to Investigate the Mass Balance, Metabolite Profile and Oral Bioavailability of Pimasertib in Cancer Patients With Locally Advanced or Metastatic Solid Tumors[NCT01713036]	Phase 1	6 participants (Actual)	Interventional	2012-11-30	Completed
EVESOR: a Phase 1 Trial of Everolimus and Sorafenib to Assess the Impact of Doses and Administration Sequences on Pharmacokinetic and Pharmacodynamic Effects of the Combination[NCT01932177]	Phase 1	60 participants (Anticipated)	Interventional	2013-04-30	Recruiting
Phase I Dose Escalation Trial of MEK1/2 Inhibitor MSC1936369B Combined With Temsirolimus in Subjects With Advanced Solid Tumors[NCT01378377]	Phase 1	33 participants (Actual)	Interventional	2011-05-27	Terminated (stopped due to The trial was stopped due to the toxicities observed with the combination of pimasertib and temsirolimus.)
Bevacizumab in Patients With Metastatic Renal Cell Carcinoma or Others Advanced Solid Tumors[NCT01202032]	Phase 1	36 participants (Anticipated)	Interventional	2010-07-31	Completed
A Randomized, Open-label, Multi-center Phase II Study to Compare Bevacizumab Plus Sorafenib Versus Sorafenib for the Third-line Treatment of Patients With Metastatic Renal Cell Carcinoma[NCT02330783]	Phase 2	106 participants (Anticipated)	Interventional	2014-12-31	Recruiting
An Open Label, Pilot Study Evaluating the Effect of Topical Sildenafil as Pre-Treatment for Hand-Foot Skin Reaction[NCT03229512]	Early Phase 1	2 participants (Actual)	Interventional	2017-04-11	Completed
The Effect of Urea Cream on Sorafenib-associated Hand-Foot Skin Reaction in Patients With Korean Hepatocellular Carcinoma Patients: Multicenter, Prospective Randomized Double-Blind Controlled Study[NCT03212625]	Phase 4	288 participants (Actual)	Interventional	2016-01-28	Completed
A Phase I Study of BAY 43-9006 (Sorafenib) in Combination With OSI-774 (Erlotinib; Tarceva) in Advanced Solid Tumors[NCT00126620]	Phase 1	17 participants (Actual)	Interventional	2005-09-30	Completed
Effect of BAY 43-9006 (Sorafenib) on Cardiovascular Safety Parameters in Cancer Patients[NCT00259129]	Phase 1	53 participants (Actual)	Interventional	2005-08-31	Completed
A Phase II Study of BAY 43-9006 (Sorafenib) in Metastatic, Androgen-Independent Prostate Cancer[NCT00090545]	Phase 2	46 participants (Actual)	Interventional	2004-09-01	Completed
A Phase 1b, Open-label, Dose-finding Study of AMG 706 in Combination With Gemcitabine and Erlotinib to Treat Subjects With Solid Tumors[NCT01235416]	Phase 1	57 participants (Actual)	Interventional	2005-09-30	Completed
Single Agent Sorafenib in Advanced Solid Tumors: Phase II Evaluation of Dose Re-Escalation Following a Dose Reduction (IST000375)[NCT00810394]	Phase 2	50 participants (Actual)	Interventional	2008-12-31	Completed
Phase I and Pharmacokinetics Study of Lapatinib in Combination With Sorafenib in Patients With Advanced Refractory Solid Tumors[NCT00984425]	Phase 1	30 participants (Actual)	Interventional	2009-09-30	Completed
Mechanism of Sorafenib Resistance in Patients With Advanced Hepatocellular Carcinoma[NCT02733809]	Phase 4	40 participants (Anticipated)	Interventional	2014-01-31	Recruiting
Accelerated Growth of Synchronous Colorectal Liver Metastases: Effects of Neo-adjuvant Therapy[NCT00659022]	Phase 2	60 participants (Anticipated)	Interventional	2008-07-31	Recruiting
A Phase II Trial of the Effect of Perindopril on HFSR Incidence and Severity in Patients Receiving Regorafenib With Refractory Metastatic Colorectal Carcinoma (mCRC)[NCT02651415]	Phase 2	12 participants (Actual)	Interventional	2016-08-31	Completed
Histological Characterization and Differentiation of Rash From Other EGFR Inhibitors[NCT00709878]		32 participants (Actual)	Observational	2008-04-30	Completed
SORAVE-Sorafenib and Everolimus in Solid Tumors. A Phase I Clinical Trial to Evaluate the Safety of Combined Sorafenib and Everolimus Treatment in Patients With Relapsed Solid Tumors[NCT00933777]	Phase 1	36 participants (Actual)	Interventional	2009-07-31	Completed
Angiogenesis Inhibitors and Hypertension: Clinical Aspects[NCT00511511]		80 participants (Anticipated)	Observational	2007-08-31	Completed
A Study of the Pharmacodynamic Effects of Anti-Vascular Endothelial Growth[NCT00698659]		0 participants	Observational	2007-08-31	Terminated
A Pilot, Pharmacodynamic Correlate Trial of Sirolimus in Combination With Chemotherapy (Idarubicin, Cytarabine) for the Treatment of Newly Diagnosed Acute Myelogenous Leukemia[NCT01822015]	Early Phase 1	55 participants (Actual)	Interventional	2013-03-15	Completed
A Phase II Study of Azacitidine and Sirolimus for the Treatment of High Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia Refractory to or Not Eligible for Intensive Chemotherapy[NCT01869114]	Phase 2	57 participants (Actual)	Interventional	2013-07-08	Active, not recruiting
Personalized Cancer Therapy for Patients With Metastatic Medullary Thyroid or Metastatic Colon Cancer[NCT02363647]		10 participants (Actual)	Interventional	2015-01-31	Terminated (stopped due to No Current Funding)
A Phase 1, First in Human, Open-Label, Dose Finding Study Evaluating the Safety and Pharmacokinetics of AMG 706 in Subjects With Advanced Solid Tumors[NCT00093873]	Phase 1	71 participants (Actual)	Interventional	2003-07-31	Completed
[information is prepared from clinicaltrials.gov, extracted Sep-2024]

DLT was defined as any of following toxicities at any dose level according to using National Cancer Institute Common Terminology Criteria for Adverse Events (AEs) v3.0(CTCAE), probably or possibly related to trial medication by investigator or sponsor: a)Any Grade 3 or more non-haematological toxicity excluding: (i)Grade 3 asymptomatic increase in liver function tests (Aspartate Aminotransferase, Alanine transaminase, Alkaline Phosphatase reversible within 7 days for subjects without liver involvement, or grade 4 for subjects with liver involvement; (ii)Grade 3 vomiting if it is encountered despite adequate and optimal therapy (e.g. serotonin [5HT3] antagonists and corticosteroids); (iii)Grade 3 diarrhoea if it is encountered despite adequate and optimal anti diarrhoea therapy; b)Grade 4 neutropenia of >5 days duration or febrile neutropenia lasting for more than 1 day; c)Grade 4 thrombocytopenia >1 day or grade 3 with bleeding; d)Any treatment delay >2 weeks due to drug-related AEs. (NCT00982865)
Timeframe: Day 1 up to Day 21 of Cycle 1

Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) Leading to Death

Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 1

Intervention	Subjects (Number)
MSC1936369B Regimen 1	2
MSC1936369B Regimen 2 (Without Food Effect + With Food Effect)	6
MSC1936369B Regimen 3 Once Daily (QD)	0
MSC1936369B Regimen 3 Twice Daily	6

Intervention	Subjects (Number)
MSC1936369B Regimen 1	10
MSC1936369B Regimen 2 (Without Food Effect + With Food Effect)	14
MSC1936369B Regimen 3 Once Daily (QD)	2
MSC1936369B Regimen 3 Twice Daily	2

Terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life calculated by natural log 2 divided by λz. As AUCextra was >20% of AUC0-inf, t1/2 derived from λz was regarded as implausible & not calculated for arms MSC1936369B 1mg, 1.5mg, 2.5 mg. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 12 and Cycle 3 Day 1

Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 1

Intervention	Hours (h) (Geometric Mean)
	C1D1	C1D12
MSC1936369B 28 mg	4.781	6.750
MSC1936369B 3.5 mg	3.346	4.985
MSC1936369B 68 mg	5.335	6.926

Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 2 (With Food Effect)

Intervention	Hours (h) (Geometric Mean)
	C1D1	C1D12	C3D1
MSC1936369B 120 mg	5.247	3.964	3.038
MSC1936369B 14 mg	4.599	3.236	2.811
MSC1936369B 45 mg	5.389	4.688	2.931
MSC1936369B 7 mg	3.405	9.249	2.959
MSC1936369B 94 mg	5.351	5.672	2.842

Terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life calculated by natural log 2 divided by λz. Summarized data over Day 1 and Day 2 was reported. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12 and 24 hours post-dose on Cycle 1 Day 1 and Day 2

Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 2 (Without Food Effect)

Intervention	Hour (h) (Geometric Mean)
	Fasted	Fed
MSC1936369B 150 mg	4.452	6.123
MSC1936369B 90 mg	4.898	4.534

Terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life calculated by natural log 2 divided by λz. As AUCextra was >20% of AUC0-inf, t1/2 derived from λz was regarded as implausible & not calculated for arms MSC1936369B 1mg, 2mg, 3.5 mg. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1

Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 2 (Without Food Effect)

Intervention	Hours (h) (Geometric Mean)
	C1D1	C1D15
MSC1936369B 7 mg	2.594	2.335
MSC1936369B 14 mg	5.119	4.443
MSC1936369B 28 mg	5.115	6.646
MSC1936369B 45 mg	4.187	5.277

Terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life calculated by natural log 2 divided by λz. As AUCextra was >20% of AUC0-inf, t1/2 derived from λz was regarded as implausible & not calculated for arms MSC1936369B 1mg, 2mg, 3.5 mg. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1

Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 2 (Without Food Effect)

Intervention	Hours (h) (Geometric Mean)
	C1D15	C3D1
MSC1936369B 5 mg	2.941	2.732

Terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life calculated by natural log 2 divided by λz. As AUCextra was >20% of AUC0-inf, t1/2 derived from λz was regarded as implausible & not calculated for arms MSC1936369B 1mg, 2mg, 3.5 mg. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1

Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 3 Once Daily

Intervention	Hours (h) (Geometric Mean)
	C1D1	C1D15	C3D1
MSC1936369B 120 mg	5.057	4.851	2.863
MSC1936369B 150 mg	4.904	5.479	2.418
MSC1936369B 195 mg	5.641	6.016	2.628
MSC1936369B 68 mg	3.305	6.441	3.477
MSC1936369B 255 mg	4.313	4.847	2.260
MSC1936369B 94 mg	4.826	5.193	2.853

Terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life calculated by natural log 2 divided by λz. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1

Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 3 Twice Daily

Intervention	Hour (h) (Geometric Mean)
	C1D1	C1D15	C3D1
MSC1936369B 60 mg	4.236	5.259	1.780
MSC1936369B 90 mg	4.097	5.599	2.680

Terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life calculated by natural log 2 divided by λz. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, and 10 h post-dose on Cycle 1 Day 1 and Day 15; pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 h post dose on Cycle 3 Day 1

Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 2 (With Food Effect)

Intervention	Hour (h) (Geometric Mean)
	C1D1	C1D15	C3D1
MSC1936369B 45 mg	2.050	2.890	3.144
MSC1936369B 60 mg	2.509	3.265	2.636
MSC1936369B 75 mg	2.814	3.210	3.260

Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution during the terminal phase, calculated as Vz = Dose/AUC0-inf multiplied by λz. Summarized data over Day 1 and Day 2 was reported. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12 and 24 hours post-dose on Cycle 1 Day 1 and Day 2

Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 2 (Without Food Effect)

Intervention	Liter (Geometric Mean)
	Fasted	Fed
MSC1936369B 150 mg	288.1	235.2
MSC1936369B 90 mg	402.4	393.6

Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution during the terminal phase, calculated as Vz = Dose/AUC0-inf multiplied by λz. As AUCextra was >20% of AUC0-inf, Vz/F derived from λz was regarded as implausible & not calculated for arms MSC1936369B 1mg, 2mg, 3.5 mg. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1

Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 2 (Without Food Effect)

Intervention	Liter (Geometric Mean)
	C1D1	C1D15
MSC1936369B 14 mg	473.32	555.9
MSC1936369B 28 mg	319.40	432.5
MSC1936369B 45 mg	331.36	378.0
MSC1936369B 7 mg	339.58	454.6

Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution during the terminal phase, calculated as Vz = Dose/AUC0-inf multiplied by λz. As AUCextra was >20% of AUC0-inf, Vz/F derived from λz was regarded as implausible & not calculated for arms MSC1936369B 1mg, 2mg, 3.5 mg. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1

Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 2 (Without Food Effect)

Intervention	Liter (Geometric Mean)
	C1D15	C3D1
MSC1936369B 5 mg	252.7	352.10

Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution during the terminal phase, calculated as Vz = Dose/AUC0-inf multiplied by λz. As AUCextra was >20% of AUC0-inf, Vz/F derived from λz was regarded as implausible & not calculated for arms MSC1936369B 1mg, 2mg, 3.5 mg. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1

Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 3 Once Daily

Intervention	Liter (Geometric Mean)
	C1D1	C1D15	C3D1
MSC1936369B 120 mg	361.12	646.9	201.39
MSC1936369B 150 mg	463.92	642.1	212.92
MSC1936369B 195 mg	440.55	464.2	274.24
MSC1936369B 255 mg	377.28	295.1	144.24
MSC1936369B 68 mg	366.00	406.6	206.07
MSC1936369B 94 mg	428.99	385.6	244.16

Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution during the terminal phase, calculated as Vz = Dose/AUC0-inf multiplied by λz (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1

Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 3 Twice Daily

Intervention	Liter (Geometric Mean)
	C1D1	C1D15	C3D1
MSC1936369B 60 mg	292.61	366.5	137.0
MSC1936369B 90 mg	336.38	507.7	292.5

Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution during the terminal phase, calculated as Vz = Dose/AUC0-inf multiplied by λz (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, and 10 h post-dose on Cycle 1 Day 1 and Day 15; pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 h post dose on Cycle 3 Day 1

Apparent Volume of Distribution Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 1

Intervention	Liter (Geometric Mean)
	C1D1	C1D15	C3D1
MSC1936369B 45 mg	339.51	297.9	571.8
MSC1936369B 60 mg	292.59	315.0	392.9
MSC1936369B 75 mg	340.43	437.6	362.6

Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution during the terminal phase, calculated as Vz = Dose/AUC0-inf multiplied by λz. As AUCextra was >20% of AUC0-inf, Vz/F derived from λz was regarded as implausible & not calculated for arms MSC1936369B 1mg, 1.5mg, 2.5 mg. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 12 and Cycle 3 Day 1

Apparent Volume of Distribution Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 1

Intervention	Liter (Geometric Mean)
	C1D1	C1D12
MSC1936369B 28 mg	336.32	365.1
MSC1936369B 3.5 mg	640.60	507.8
MSC1936369B 68 mg	307.90	357.8

Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution during the terminal phase, calculated as Vz = Dose/AUC0-inf multiplied by λz. As AUCextra was >20% of AUC0-inf, Vz/F derived from λz was regarded as implausible & not calculated for arms MSC1936369B 1mg, 1.5mg, 2.5 mg. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 12 and Cycle 3 Day 1

Area Under the Concentration Time Curve Extrapolated From Last Observation to Infinity Given as Percentage of AUC 0-∞ (AUC Extra): Regimen 1

Intervention	Liter (Geometric Mean)
	C1D1	C1D12	C3D1
MSC1936369B 120 mg	361.99	351.4	316.63
MSC1936369B 14 mg	396.76	291.9	422.04
MSC1936369B 45 mg	378.56	333.9	348.19
MSC1936369B 7 mg	561.27	594.5	928.91
MSC1936369B 94 mg	389.49	416.3	438.91

AUCextra was defined as a percentage of AUC0-inf obtained by extrapolation: %AUCextra = (1- [AUC0-t / AUC0-inf])*100. %AUCextra was reported in terms of percentage of AUC0-inf. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 12 and Cycle 3 Day 1

Area Under the Concentration Time Curve Extrapolated From Last Observation to Infinity Given as Percentage of AUC 0-∞ (AUC Extra): Regimen 1

Intervention	Percentage of AUC 0-∞ (Geometric Mean)
	C1D1	C1D12
MSC1936369B 1.5 mg	42.23	33.84
MSC1936369B 68 mg	4.08	6.56

Area Under the Concentration Time Curve Extrapolated From Last Observation to Infinity Given as Percentage of AUC 0-∞ (AUC Extra): Regimen 2 (With Food Effect)

Intervention	Percentage of AUC 0-∞ (Geometric Mean)
	C1D1	C1D12	C3D1
MSC1936369B 1 mg	81.33	50.60	55.15
MSC1936369B 120 mg	5.28	2.97	26.05
MSC1936369B 14 mg	5.31	7.83	15.84
MSC1936369B 2.5 mg	43.45	40.60	55.79
MSC1936369B 28 mg	5.39	6.57	28.06
MSC1936369B 3.5 mg	26.80	21.27	32.85
MSC1936369B 45 mg	3.52	8.17	27.67
MSC1936369B 7 mg	13.08	19.82	21.27
MSC1936369B 94 mg	4.09	7.94	16.54

AUCextra was defined as a percentage of AUC0-inf obtained by extrapolation: AUCextra = (1- [AUC0-t / AUC0-inf])*100. AUCextra was reported in terms of percentage of AUC0-inf. Summarized data over Day 1 and Day 2 was reported. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12 and 24 hours post-dose on Cycle 1 Day 1 and Day 2

Area Under the Concentration Time Curve Extrapolated From Last Observation to Infinity Given as Percentage of AUC 0-∞ (AUC Extra): Regimen 2 (Without Food Effect)

Intervention	Percentage of AUC 0-∞ (Geometric Mean)
	Fasted	Fed
MSC1936369B 150 mg	1.74	9.96
MSC1936369B 90 mg	2.54	2.21

Intervention	Percentage of AUC 0-∞ (Geometric Mean)
	C1D15
MSC1936369B 1 mg	40.86

Intervention	Percentage of AUC 0-∞ (Geometric Mean)
	C1D1	C1D15
MSC1936369B 45 mg	1.46	2.96
MSC1936369B 14 mg	12.17	12.45

Area Under the Concentration Time Curve Extrapolated From Last Observation to Infinity Given as Percentage of AUC 0-∞ (AUC Extra): Regimen 3 Once Daily

Intervention	Percentage of AUC 0-∞ (Geometric Mean)
	C1D1	C1D15	C3D1
MSC1936369B 120 mg	2.94	5.82	16.22
MSC1936369B 150 mg	2.64	4.82	17.54
MSC1936369B 195 mg	4.36	5.77	23.45
MSC1936369B 2 mg	55.78	33.34	33.93
MSC1936369B 255 mg	3.57	5.22	11.15
MSC1936369B 28 mg	3.29	6.89	26.32
MSC1936369B 3.5 mg	31.63	35.29	33.77
MSC1936369B 5 mg	27.25	21.93	17.27
MSC1936369B 68 mg	2.66	5.00	15.35
MSC1936369B 7 mg	15.10	19.45	20.68
MSC1936369B 94 mg	2.60	3.40	18.02

AUCextra was defined as a percentage of AUC0-inf obtained by extrapolation: AUCextra = (1- [AUC0-t / AUC0-inf])*100. AUCextra was reported in terms of percentage of AUC0-inf. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1

Area Under the Concentration Time Curve Extrapolated From Last Observation to Infinity Given as Percentage of AUC 0-∞ (AUC Extra): Regimen 3 Twice Daily

Intervention	percentage of AUC 0-∞ (Geometric Mean)
	C1D1	C1D15	C3D1
MSC1936369B 60 mg	1.88	7.95	9.11
MSC1936369B 90 mg	2.11	4.28	17.56

AUCextra was defined as a percentage of AUC0-inf obtained by extrapolation: AUCextra = (1- [AUC0-t / AUC0-inf])*100. AUCextra was reported in terms of percentage of AUC0-inf. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, and 10 h post-dose on Cycle 1 Day 1 and Day 15; pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 h post dose on Cycle 3 Day 1

Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B : Regimen 1

Intervention	Percentage of AUC 0-∞ (Geometric Mean)
	C1D1	C1D15	C3D1
MSC1936369B 45 mg	16.82	11.78	30.63
MSC1936369B 60 mg	7.70	14.14	16.43
MSC1936369B 75 mg	10.90	19.19	21.34

AUC0-inf was calculated by combining AUC0-t and AUCextra. AUC extra represents an extrapolated value obtained by Clast/ λz, where Clast is the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLQ) and λz is the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 12 and Cycle 3 Day 1

Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B : Regimen 1

Intervention	hour*ng/mL (Geometric Mean)
	C1D1	C1D12
MSC1936369B 1.5 mg	6.2	9.4
MSC1936369B 68 mg	1699.7	2108.2

Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B: Regimen 2 (With Food Effect)

Intervention	hour*ng/mL (Geometric Mean)
	C1D1	C1D12	C3D1
MSC1936369B 1 mg	136.2	38.3	15.4
MSC1936369B 120 mg	2773.5	2022.8	3477.6
MSC1936369B 14 mg	234.1	206.3	134.5
MSC1936369B 2.5 mg	55.5	43.8	47.6
MSC1936369B 28 mg	574.2	805.6	489.8
MSC1936369B 3.5 mg	31.4	47.5	34.4
MSC1936369B 45 mg	924.2	960.7	1072.1
MSC1936369B 7 mg	61.3	105.6	55.5
MSC1936369B 94 mg	1836.4	2257.6	1056.0

AUC0-inf was calculated by combining AUC0-t and AUCextra. AUC extra represents an extrapolated value obtained by Clast/ λz, where Clast is the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLQ) and λz is the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase. Summarized data over Day 1 and Day 2 was reported. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12 and 24 hours post-dose on Cycle 1 Day 1 and Day 2

Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B: Regimen 2 (Without Food Effect)

Intervention	hour*ng/mL (Geometric Mean)
	Fasted	Fed
MSC1936369B 150 mg	3344.3	5633.8
MSC1936369B 90 mg	1580.6	1495.7

AUC0-inf was calculated by combining AUC0-t and AUCextra. AUC extra represents an extrapolated value obtained by Clast/ λz, where Clast is the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the Lower Limit of quantification (LLQ) and λz is the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1

Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B: Regimen 2 (Without Food Effect)

Intervention	hour*ng/mL (Geometric Mean)
	C1D15
MSC1936369B 1 mg	15.7

AUC0-inf was calculated by combining AUC0-t and AUCextra. AUC extra represents an extrapolated value obtained by Clast/ λz, where Clast is the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the Lower Limit of quantification (LLQ) and λz is the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1

Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B: Regimen 2 (Without Food Effect)

Intervention	hour*ng/mL (Geometric Mean)
	C1D1	C1D15
MSC1936369B 45 mg	820.4	933.9
MSC1936369B 14 mg	218.4	172.2

AUC0-inf was calculated by combining AUC0-t and AUCextra. AUC extra represents an extrapolated value obtained by Clast/ λz, where Clast is the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the Lower Limit of quantification (LLQ) and λz is the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1

Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B: Regimen 3 Once Daily

Intervention	hour*ng/mL (Geometric Mean)
	C1D1	C1D15	C3D1
MSC1936369B 120 mg	2424.2	2129.0	2461.3
MSC1936369B 195 mg	3602.2	3900.8	3452.9
MSC1936369B 2 mg	23.4	33.3	15.4
MSC1936369B 255 mg	4300.3	6232.1	5651.1
MSC1936369B 28 mg	646.9	669.1	415.6
MSC1936369B 3.5 mg	23.6	21.9	41.2
MSC1936369B 150 mg	2287.8	2029.9	2796.2
MSC1936369B 5 mg	59.1	102.0	49.5
MSC1936369B 68 mg	885.8	1665.2	1655.1
MSC1936369B 7 mg	90.3	89.7	58.1
MSC1936369B 94 mg	1525.6	1893.2	1584.8

Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B: Regimen 3 Twice Daily

Intervention	hour*ng/mL (Geometric Mean)
	C1D1	C1D15	C3D1
MSC1936369B 60 mg	1253.1	1753.9	1597.0
MSC1936369B 90 mg	1581.4	1517.1	1400.3

AUC0-inf was calculated by combining AUC0-t and AUCextra. AUC extra represents an extrapolated value obtained by Clast/ λz, where Clast is the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLQ) and λz is the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, and 10 h post-dose on Cycle 1 Day 1 and Day 15; pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 h post dose on Cycle 3 Day 1

Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of MSC1936369B: : Regimen 2 (Without Food Effect)

Intervention	hour*ng/mL (Geometric Mean)
	C1D1	C1D15	C3D1
MSC1936369B 45 mg	527.6	674.1	696.0
MSC1936369B 60 mg	742.3	1004.2	700.8
MSC1936369B 75 mg	939.9	978.4	1285.7

Area under the plasma concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1

Intervention	hour*ng/mL (Geometric Mean)
	C1D1	C1D15
MSC1936369B 14 mg	188.4	161.5
MSC1936369B 45 mg	808.0	906.3

Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of MSC1936369B: Regimen 1

Intervention	hour*ng/mL (Geometric Mean)
	C1D1	C1D15	C3D1
MSC1936369B 1 mg	1.9	4.3	0.5
MSC1936369B 120 mg	2287.0	1862.3	2053.6
MSC1936369B 150 mg	2216.5	2086.6	2171.2
MSC1936369B 195 mg	3415.6	3436.8	2484.5
MSC1936369B 2 mg	8.2	22.2	10.2
MSC1936369B 255 mg	4041.3	5765.9	4906.3
MSC1936369B 28 mg	625.7	621.2	306.2
MSC1936369B 3.5 mg	6.7	13.8	26.2
MSC1936369B 5 mg	67.9	79.3	40.5
MSC1936369B 68 mg	861.1	1553.9	1394.7
MSC1936369B 7 mg	74.4	67.8	46.1
MSC1936369B 94 mg	1484.6	1826.2	1299.3

Intervention	hournanogram per milliliter (hng/mL) (Geometric Mean)
	C1D1	C1D12
MSC1936369B 68 mg	1624.8	1900.3

Intervention	hournanogram per milliliter (hng/mL) (Geometric Mean)
	C1D1	C1D12	C3D1
MSC1936369B 1.5 mg	5.2	6.0	2.7
MSC1936369B 120 mg	2292.4	1682.4	2064.1
MSC1936369B 14 mg	213.9	182.0	113.2
MSC1936369B 2.5 mg	18.5	26.0	21.0
MSC1936369B 28 mg	531.3	691.9	334.9
MSC1936369B 3.5 mg	22.7	35.9	23.0
MSC1936369B 45 mg	889.0	880.0	666.3
MSC1936369B 1 mg	4.6	7.0	6.9
MSC1936369B 7 mg	52.7	83.6	45.2
MSC1936369B 94 mg	1748.1	1991.4	876.7

Area under the plasma concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule. Summarized data over Day 1 and Day 2 was reported. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12 and 24 hours post-dose on Cycle 1 Day 1 and Day 2

Intervention	hour*ng/mL (Geometric Mean)
	Fasted	Fed
MSC1936369B 150 mg	3286	5072.9
MSC1936369B 90 mg	1509.6	1458.3

Intervention	hour*ng/mL (Geometric Mean)
	C1D1	C1D15	C3D1
MSC1936369B 60 mg	1229.3	1532.4	1392.3
MSC1936369B 90 mg	1544.9	1428.8	1122.5

Area under the plasma concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, and 10 h post-dose on Cycle 1 Day 1 and Day 15; pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 h post dose on Cycle 3 Day 1

Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 1

Intervention	hour*ng/mL (Geometric Mean)
	C1D1	C1D15	C3D1
MSC1936369B 45 mg	407.2	589.3	450.0
MSC1936369B 60 mg	681.4	838.8	577.0
MSC1936369B 75 mg	791.1	710.3	1005.0

Pharmacokinetic (PK) parameter Cmax was obtained directly from the concentration versus time curve. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours (h) post-dose on Cycle 1(C1) Day 1 (D1), Cycle 1 Day 12 (D12) and Cycle 3 (C3) Day 1

Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 1

Intervention	nanogram per milliliter (ng/mL) (Geometric Mean)
	C1D1	C1D12
MSC1936369B 68 mg	357.39	413.58

Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 2 (With Food Effect)

Intervention	nanogram per milliliter (ng/mL) (Geometric Mean)
	C1D1	C1D12	C3D1
MSC1936369B 1 mg	2.02	2.92	2.00
MSC1936369B 1.5 mg	3.20	2.69	2.90
MSC1936369B 120 mg	428.85	425.26	652.70
MSC1936369B 14 mg	62.32	54.47	51.30
MSC1936369B 2.5 mg	4.21	6.29	5.60
MSC1936369B 28 mg	126.21	150.67	84.70
MSC1936369B 3.5 mg	6.69	9.75	8.06
MSC1936369B 45 mg	212.96	175.94	167.75
MSC1936369B 7 mg	12.60	21.93	10.90
MSC1936369B 94 mg	325.99	602.12	282.44

Cmax was obtained directly from the concentration versus time curve. Summarized data over Day 1 and Day 2 was reported. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12 and 24 hours post-dose on Cycle 1 Day 1 and Day 2

Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 2 (Without Food Effect)

Intervention	ng/mL (Geometric Mean)
	Fasted	Fed
MSC1936369B 150 mg	1158.00	370.70
MSC1936369B 90 mg	321.14	305.94

Cmax was obtained directly from the concentration versus time curve. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1

Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 2 (Without Food Effect)

Intervention	ng/mL (Geometric Mean)
	C1D1	C1D15
MSC1936369B 14 mg	39.19	34.87
MSC1936369B 45 mg	321.85	286.88

Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 3 Once Daily

Intervention	ng/mL (Geometric Mean)
	C1D1	C1D15	C3D1
MSC1936369B 120 mg	605.11	492.81	568.49
MSC1936369B 150 mg	539.02	450.29	795.86
MSC1936369B 195 mg	680.87	629.85	773.14
MSC1936369B 2 mg	2.87	7.77	4.30
MSC1936369B 255 mg	990.92	1535.60	2344.91
MSC1936369B 28 mg	187.98	131.71	96.60
MSC1936369B 3.5 mg	4.55	4.21	6.56
MSC1936369B 1 mg	1.65	2.28	1.25
MSC1936369B 5 mg	17.26	18.78	14.81
MSC1936369B 68 mg	306.63	539.17	710.94
MSC1936369B 7 mg	30.90	18.47	16.10
MSC1936369B 94 mg	373.59	432.46	532.80

Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 3 Twice Daily

Cmax was obtained directly from the concentration versus time curve. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, and 10 h post-dose on Cycle 1 Day 1 and Day 15; pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 h post dose on Cycle 3 Day 1

Number of Subjects With Clinical Benefit (Complete Response [CR], Partial Response [PR] or Stable Disease [SD}) and Progressive Disease (PD) Based on the Best Overall Response (BOR)

Number of subjects with clinical benefit (CR, PR, or SD) and PD according to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0) was reported. CR: defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: defined as at least a 30% decrease in sum of longest diameter of target lesions, taking as reference the baseline sum of longest diameter. PD:defined as at least a 20% increase in sum of longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study) or unequivocal progression of existing non-target lesions. SD: defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of longest diameter while on study. (NCT00982865)
Timeframe: Baseline until disease progression (assessed up to end of treatment [253 weeks])

Number of Subjects With Clinical Significant Laboratory Abnormalities and Vital Signs Reported as Treatment Emergent Adverse Events

Any clinically significant changes in laboratory evaluations and vital signs were recorded as treatment emergent adverse events. The clinical laboratory parameters that were assessed included: Hematological parameters, Blood chemistry parameters, Urinalysis and the vital signs that were assessed included: Blood pressure, Heart rate, Temperature and Weight. SAF analysis was used. (NCT00982865)
Timeframe: Baseline up to 253 weeks

Number of Subjects With Treatment-Emergent Adverse Events (TEAE), Serious TEAEs, TEAEs Leading to Discontinuation

AE was defined as any untoward medical occurrence which does not necessarily have a causal relationship with this the study drug. An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-emergent are events between first dose of study drug and up to 253 weeks. TEAEs include both Serious TEAEs and non-serious TEAEs. (NCT00982865)
Timeframe: Baseline up to 253 weeks

Phosphorylated Extra-Cellular Signal-Regulated Kinase (pERK) Fold Change in Peripheral Blood Monocyte Cells (PBMC) and Tot ERK Fold Change in Peripheral Blood Monocyte Cells (PBMC)

(NCT00982865)
Timeframe: Pre-dose on C1D1, C1D2, C1D5, C1D8; 2, 4, 8 h post-dose on C1D1; pre-dose, 2, 8, 24 h post-dose on C1D12-15; pre-dose, 2, 4 h post-dose on C1D3

Phosphorylated Extra-Cellular Signal-Regulated Kinase (pERK) Fold Change in Peripheral Blood Monocyte Cells (PBMC) and Tot ERK Fold Change in Peripheral Blood Monocyte Cells (PBMC)

(NCT00982865)
Timeframe: Pre-dose on C1D1, C1D2, C1D5, C1D8; 2, 4, 8 h post-dose on C1D1; pre-dose, 2, 8, 24 h post-dose on C1D12-15; pre-dose, 2, 4 h post-dose on C1D3

Phosphorylated Extra-Cellular Signal-Regulated Kinase (pERK) Fold Change in Peripheral Blood Monocyte Cells (PBMC) and Tot ERK Fold Change in Peripheral Blood Monocyte Cells (PBMC)

(NCT00982865)
Timeframe: Pre-dose on C1D1, C1D2, C1D5, C1D8; 2, 4, 8 h post-dose on C1D1; pre-dose, 2, 8, 24 h post-dose on C1D12-15; pre-dose, 2, 4 h post-dose on C1D3

Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 1

Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 12 and Cycle 3 Day 1

Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 1

Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 2 (With Food Effect)

Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve. Summarized data over Day 1 and Day 2 was reported. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12 and 24 hours post-dose on Cycle 1 Day 1 and Day 2

Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 2 (Without Food Effect)

Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 3 Once Daily

Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 3 Twice Daily

Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, and 10 h post-dose on Cycle 1 Day 1 and Day 15; pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 h post dose on Cycle 3 Day 1

Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 1

Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent body clearance of the drug from plasma, CL= Dose/AUC0-inf. As AUCextra was >20% of AUC0-inf, CL/f derived from λz was regarded as implausible & not calculated for arms MSC1936369B 1mg, 1.5mg, 2.5 mg. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 12 and Cycle 3 Day 1

Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 1

Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 2 (With Food Effect)

Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent body clearance of the drug from plasma, CL= Dose/AUC0-inf. Summarized data over Day 1 and Day 2 was reported. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12 and 24 hours post-dose on Cycle 1 Day 1 and Day 2

Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 2 (Without Food Effect)

Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent body clearance of the drug from plasma, CL= Dose/AUC0-inf. As AUCextra was >20% of AUC0-inf, CL/f derived from λz was regarded as implausible & not calculated for arms MSC1936369B 1mg, 2mg, 3.5 mg. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1

Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 2 (Without Food Effect)

Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent body clearance of the drug from plasma, CL= Dose/AUC0-inf. As AUCextra was >20% of AUC0-inf, CL/f derived from λz was regarded as implausible & not calculated for arms MSC1936369B 1mg, 2mg, 3.5 mg. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1

Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 2 (Without Food Effect)

Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent body clearance of the drug from plasma, CL= Dose/AUC0-inf. As AUCextra was >20% of AUC0-inf, CL/f derived from λz was regarded as implausible & not calculated for arms MSC1936369B 1mg, 2mg, 3.5 mg. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1

Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 3 Once Daily

Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 3 Twice Daily

Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent body clearance of the drug from plasma, CL= Dose/AUC0-inf. (NCT00982865)
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, and 10 h post-dose on Cycle 1 Day 1 and Day 15; pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 h post dose on Cycle 3 Day 1

Apparent Terminal Elimination Rate Constant (λz) of Total [14C] Radioactivity

λz of total [14C] radioactivity was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve. (NCT01713036)
Timeframe: Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8

Apparent Terminal Half-life (t1/2) of Total [14C] Radioactivity

(NCT01713036)
Timeframe: Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8

Apparent Volume of Distribution of Total [14C] Radioactivity During the Terminal Phase Following Oral Administration (Vz/f)

Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed. Vz/f of total radioactivity during the terminal phase was calculated by dividing the dose with the product of area under the plasma concentration time curve and apparent terminal rate constant (dose/AUC0inf*λz). (NCT01713036)
Timeframe: Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8

Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of [14C]-Pimasertib Following IV Administration on Day 1

(NCT01713036)
Timeframe: Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post [14C] intravenous pimasertib dose on Day 1

Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib Following Oral Administration on Day 1

(NCT01713036)
Timeframe: Pre-dose, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1

Area Under the Plasma Concentration Time Curve From Time Zero to the Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Total [14C] Radioactivity

Area under the plasma concentration time curve from time zero to the last sampling time at which the concentration is at or above the lower limit of quantification was calculated by using mixed log linear trapezoidal rule. Unit of assessment was hour*nanogram equivalent per milliliter (hr*ng eq/mL). (NCT01713036)
Timeframe: Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8

Area Under the Plasma Concentration Time Curve From Time Zero to the Last Sampling Time Point (AUC0-t) of [14C]-Pimasertib Following Intravenous (IV) Administration on Day 1

(NCT01713036)
Timeframe: Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post [14C] intravenous pimasertib dose on Day 1

Area Under the Plasma Concentration Time Curve From Time Zero to the Last Sampling Time Point (AUC0-t) of Pimasertib Following Oral Administration on Day 1

(NCT01713036)
Timeframe: Pre-dose, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1

Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Total [14C] Radioactivity

Area under the concentration time curve (AUC) from time zero to infinity (AUC0-inf) was calculated from AUC0-t + AUCextra, where AUCextra = Clast calc/λz. Clast calc was the calculated plasma concentration at the last sampling time point at which plasma concentration was at or above the lower limit of quantification was measured and λz represents apparent terminal elimination rate constant. (NCT01713036)
Timeframe: Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8

Blood/ Plasma Concentration Ratios of Total [14C] Radioactivity

Fraction Unbound of [14C] Pimasertib

Fraction of unbound drug (fu) is defined as the ratio of unbound drug concentration to the total drug concentration multiplied by 100. (NCT01713036)
Timeframe: 1.5 hour post [14C]-labeled pimasertib dose on Day 8

Maximum Observed Plasma Concentration (Cmax) of Intravenous [14C] Pimasertib

(NCT01713036)
Timeframe: Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post [14C] intravenous pimasertib dose on Day 1

Maximum Observed Plasma Concentration (Cmax) of Total [14C] Radioactivity

Unit of assessment was nanogram equivalent per milliliter (ng eq/mL). (NCT01713036)
Timeframe: Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8

Maximum Observed Plasma Concentration (Cmax) of Unlabeled Pimasertib

(NCT01713036)
Timeframe: Pre-dose 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1

Oral Bioavailability of Pimasertib After Single Oral Dose of Unlabeled Pimasertib and Intravenous (IV) Single Tracer Dose of [14C] Pimasertib

Oral bioavailability (F) was calculated using the formula=AUC0-inf oral/dose oral) / (AUC0-inf iv/dose iv) * 100%, where AUC0-inf is the area under the concentration time curve (AUC) from time zero to infinity. (NCT01713036)
Timeframe: Pre-dose, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1; Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post [14C] labeled pimasertib dose on Day 1

The Volume of Distribution of the Central or Plasma Compartment (Vc) of Intravenous [14C] Pimasertib

The volume of distribution of the central or plasma compartment (Vc) was calculated using the formula=Dose/C0 (NCT01713036)
Timeframe: Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post intravenous [14C] pimasertib dose on Day 1

Time to Reach Maximum Plasma Concentration (Tmax) of Total [14C] Radioactivity

(NCT01713036)
Timeframe: Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8

Total Body Clearance of Total [14C] Radioactivity From Plasma Following Oral Administration (CL/f)

Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/f was influenced by the fraction absorbed. Apparent body clearance of total radioactivity from plasma was calculated by dividing the dose with area under the plasma concentration time curve from zero to infinity (Dose/AUC0inf). (NCT01713036)
Timeframe: Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8

Apparent Terminal Elimination Rate Constant (λz) of M445 and M554

The λz of M445 and M554 was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve. (NCT01713036)
Timeframe: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8

Apparent Terminal Elimination Rate Constant (λz) of Unlabeled Pimasertib and Intravenous [14C] Pimasertib

Apparent terminal elimination rate constant (λz) was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve. (NCT01713036)
Timeframe: Pre-dose, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1; Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post intravenous [14C] labeled pimasertib dose on Day 1

Apparent Terminal Half-life (t1/2) of M445 and M554

(NCT01713036)
Timeframe: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8

Apparent Volume of Distribution During the Terminal Phase Following Oral Administration (Vz/f) and the Apparent Volume of Distribution During the Terminal Phase Following Intravenous Administration (Vz) of [14C] Pimasertib

The apparent volume of distribution during the terminal phase following oral administration (Vz/f) and the apparent volume of distribution during the terminal phase following intravenous administration was calculated by using the formula=Dose/( AUC0-inf* λz). (NCT01713036)
Timeframe: Pre-dose, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1; Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post [14C] labeled pimasertib dose on Day 1

Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of M445 and M554

AUC from time 0 to infinity (AUC0-inf), was calculated from AUC0-t + AUCextra, where AUCextra = Clast calc/lambda z (λz). Clast calc was the calculated plasma concentration at the last sampling time point at which plasma concentration was at or above the lower limit of quantification was measured and λz represents apparent terminal elimination rate constant. (NCT01713036)
Timeframe: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8

Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time (AUC0-t) of M445 and M554

Area under the plasma concentration-time curve from time zero to the last sampling time (AUC0-t) at which the concentration is at or above the lower limit of quantification. (NCT01713036)
Timeframe: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8

Mass Balance: Amount of Total Radioactivity Recovered Into the Urine and Feces From Time Zero to the Last Sampling Time Point (Ae0-t)

Recovery of total [14C]-radioactivity was determined in excreta, i.e., urine and feces at each sampling period subsequent to oral administration of [14C]-pimasertib on Day 8. Cumulative recovery of total [14C]-radioactivity in terms of percentage of dose recovered in urine and feces and total percentage of dose recovered was reported for the outcome measure. (NCT01713036)
Timeframe: Urine: 0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours post [14C]-labeled pimasertib dose on Day 8; Feces: 0-12, 12-24, 24-48, 48-72, 72-96, 96-120, 120-144, and 144-168 hours post [14C]-labeled pimasertib dose on Day 8

Maximum Observed Plasma Concentration (Cmax) of M445 and M554

Maximum observed plasma concentration (Cmax) for the metabolites M445 and M554 was calculated. (NCT01713036)
Timeframe: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8

Number of Metabolites Identified Overall and as Major

Identification and profiling of the metabolites was done. The total number of metabolites and the number of metabolites identified as major were reported. (NCT01713036)
Timeframe: Pre-dose 1.0, 2.0, 4.0, 10 and 24 hours post [14C]-labeled Pimasertib dose on Day 8

Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug administration until 30+/-2 days after the last dose of study drug administration that were absent before treatment or that worsened relative to pre treatment state. (NCT01713036)
Timeframe: Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months

Part B: Number of Subjects Who Experienced Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD)

Anti tumor activity defined as CR, PR, or stable disease and PD based on the investigator tumor evaluations performed every 2 cycles in accordance with Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. CR =Disappearance of all target lesions except lymph nodes (LN); LN must have a decrease in the short axis to less than (<)10 millimeter (mm); PR = 30% decrease in sum of diameters of target lesions taking as reference the baseline sum diameters; Progressed Disease (PD) = 20% increase in sum of diameters of target lesions; the appearance of >=1 new lesions; SD= Neither shrinkage to qualify for PR nor increase to qualify for PD taking the smallest sum diameters on study as reference. For non-target lesions a CR = Disappearance of all non-target lesions and all LN must be non-pathological in size <10 mm; Non-CR/Non PD: persistence of one or more non-target lesions; PD = unequivocal progression of existing non-target lesions or appearance of new ones. (NCT01713036)
Timeframe: From the screening every 2 cycles until end of the treatment, assessed up to 18 months

Plasma Concentrations of [14C] Pimasertib

(NCT01713036)
Timeframe: Pre-dose 1.0, 2.0, 4.0, 10 and 24 hours post [14C]-labeled Pimasertib dose on Day 8

Plasma Concentrations of Pimasertib Metabolites

Plasma concentration of the Pimasertib metabolite M445 and M554 were presented for the outcome measure. (NCT01713036)
Timeframe: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8

Time to Reach Maximum Plasma Concentration (Tmax) of M445 and M554

Time to reach maximum plasma concentration (Tmax) for the metabolites M445 and M554 was calculated. (NCT01713036)
Timeframe: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8

Time to Reach Maximum Plasma Concentration (Tmax) of Unlabeled Pimasertib and Intravenous [14C] Pimasertib

(NCT01713036)
Timeframe: Pre-dose 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1; Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post intravenous [14C] labeled pimasertib dose on Day 1

Total Body Clearance of Unlabeled Pimasertib (CL/f) and Intravenous [14C] Pimasertib (CL)

The total body clearance of drug from plasma following oral administration (Cl/f) and the total body clearance of drug from plasma following intravenous administration was calculated by dividing the Dose with area under the plasma concentration time curve from time zero to infinity (AUC0 inf)=Dose/AUC0- inf. (NCT01713036)
Timeframe: Pre-dose, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1; Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post intravenous [14C] labeled pimasertib dose on Day 1

Number of Subjects With Dose Limiting Toxicities (DLTs)

DLT was defined as any of the following toxicities graded as per National Cancer Institute (NCI) common terminology criteria for adverse events (NCI CTCAE v4.0) encountered within cycle 1 of treatment at any dose level and judged not to be related to the underlying disease or concomitant medications. A treatment emergent adverse event (TEAE) of potential clinical significance such that further dose escalation would expose subjects to unacceptable risk; any Grade >=3 non-hematological toxicity except Grade 3 asymptomatic increases in liver function tests, diarrhea, nausea or vomiting with duration <= 48 hours and alopecia; Grade 4 neutropenia of >5 days duration or febrile neutropenia of >1 day duration; Grade 3 thrombocytopenia with bleeding or Grade 4 thrombocytopenia; any treatment interruption >2 weeks due to adverse events; any severe, impairing daily functions or life-threatening, complication or abnormality not defined in NCI-CTCAE that is attributable to the therapy. (NCT01378377)
Timeframe: Up to 21 Days (within Cycle 1)

Number of Subjects With Treatment-emergent Adverse Events (TEAEs)

An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. The TEAEs were those events that occur between first dose of trial treatment and up to 30 days after last dose of the trial treatment that were absent before treatment or that worsened relative to pretreatment state. (NCT01378377)
Timeframe: From the start of the trial treatment until data cut-off date (23 February 2012)

Apparent Clearance From Plasma Following Oral Administration (CL/f) of Pimasertib

Clearance (CL) of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. The CL obtained after oral dose (CL/F) was influenced by the fraction of the dose absorbed (bioavailability). Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. (NCT01378377)
Timeframe: DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1

Apparent Clearance From Plasma Following Oral Administration (CL/f) of Pimasertib

Apparent Terminal Half-life (t1/2) of Pimasertib

The t1/2 was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. (NCT01378377)
Timeframe: DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1

Apparent Terminal Half-life (t1/2) of Pimasertib

Apparent Terminal Half-life (t1/2) of Temsirolimus

The t1/2 was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. (NCT01378377)
Timeframe: DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1

Apparent Terminal Half-life (t1/2) of Temsirolimus

The t1/2 was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. (NCT01378377)
Timeframe: DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1

Apparent Volume of Distribution (Vz/F) of Pimasertib

Volume of distribution (Vz) was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. The Vz after oral dose (Vz/F) was influenced by the fraction absorbed. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. (NCT01378377)
Timeframe: DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1

Apparent Volume of Distribution (Vz/F) of Pimasertib

Area Under Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Temsirolimus

The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. (NCT01378377)
Timeframe: DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1

Area Under Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Temsirolimus

Area Under the Concentration Time Curve During a Dosing Interval (AUCtau) and Area Under the Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib

The AUCtau was defined as the area under the concentration curve divided by the dosing interval. AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. (NCT01378377)
Timeframe: DDI cohorts: Days 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1 for AUCtau; DDI cohorts: Day 1 of Cycle 1 AUC0-inf

Area Under the Concentration Time Curve During a Dosing Interval (AUCtau) and Area Under the Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib

Maximum Plasma Concentration (Cmax) of Pimasertib

Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. (NCT01378377)
Timeframe: Drug-drug interaction (DDI) cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1

Maximum Plasma Concentration (Cmax) of Pimasertib

Maximum Plasma Concentration (Cmax) of Temsirolimus

Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. (NCT01378377)
Timeframe: DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 8

Maximum Plasma Concentration (Cmax) of Temsirolimus

Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. (NCT01378377)
Timeframe: DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 8

Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib

Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. (NCT01378377)
Timeframe: DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1

Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib

Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. (NCT01378377)
Timeframe: DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1

Time to Reach Maximum Plasma Concentration (Tmax) of Temsirolimus

Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. (NCT01378377)
Timeframe: DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1

Time to Reach Maximum Plasma Concentration (Tmax) of Temsirolimus

Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. (NCT01378377)
Timeframe: DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1

Total Body Clearance From Plasma Following Intravenous Administration (CL) of Temsirolimus

The clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. (NCT01378377)
Timeframe: DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1

Total Body Clearance From Plasma Following Intravenous Administration (CL) of Temsirolimus

Volume of Distribution (Vz) of Temsirolimus

The Vz was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. (NCT01378377)
Timeframe: DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1

Volume of Distribution (Vz) of Temsirolimus

Geometric Mean for Exposure Area Under the Curve (AUC) 0-12

Geometric mean exposure for sorafenib. (NCT00090545)
Timeframe: 0, 0.25, 0.50, 1, 2, 4, 6, 8, 12, and 24 hours post-dose

Maximum Observed Plasma Concentration (Cmax) of BAY 43-9006 (Sorafenib)

Plasma concentration-time profile for sorafenib. (NCT00090545)
Timeframe: 0, 0.25, 0.50, 1, 2, 4, 6, 8, 12, AND 24 hours post dose

Median Overall Survival

Time from treatment start date until date of death or date last known alive. (NCT00090545)
Timeframe: Time from treatment start date until date of death or date last known alive, approximately 18.3 months.

Number of Participants With Adverse Events

Here is the number of participants with adverse events. For the detailed list of adverse events, see the adverse event module. (NCT00090545)
Timeframe: Date treatment consent signed to date off study, approximately 49 months.

Progression Free Survival

Determine whether BAY 43-9006 when used to treat metastatic prostate cancer is associated with having 50% of Patients Progression Free at 4 Months by clinical, radiographic, and prostatic specific antigen (PSA)criteria. (NCT00090545)
Timeframe: 4 months

Time to Maximum Observed Plasma Concentration (Tmax) of BAY 43-9006 (Sorafenib)

Time to maximum concentration for sorafenib. (NCT00090545)
Timeframe: 0, 0.25, 0.50, 1, 2, 4, 6, 8, 12, and 24 hours post-dose

Overall Response Evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST)

Overall response was evaluated by the RECIST. Complete Response (CR) is the disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. (NCT00090545)
Timeframe: Every 2 cycles (1 cycle = 28 days)

Overall Response Rate

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR). (NCT00810394)
Timeframe: At least 3 months

Percentage of Patients Tolerating Re-escalated Dose of Sorafenib for 28 Days Without Dose Interruption or De-escalation for Toxicity

Overall percentage of patients tolerating a dose escalation to 600 mg twice daily for 28 days plus the percentage tolerating a re-escalation to 400 mg twice daily in Cycle 3. (NCT00810394)
Timeframe: At least 3 months

Time to Disease Progression

Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. (NCT00810394)
Timeframe: Up to 2 years

Median Time Course to Development of Worst Grade (Grade 3) HFSR as Assessed by CTCAE v4.03 Criteria When Treated With a Combination of Regorafenib and Perindopril

Median time course for participants to develop worst grade 3 HFSR toxicity is defined as the time (days) from start date of study drug to date of first documented grade 3 HFSR toxicity and will be calculated only for patients who had a HFSR toxicity grade 3. (NCT02651415)
Timeframe: p to Safety Follow-Up Visit (30 days +/- 7 days after permanently stopping study treatment)

Median Time to Progression Free Survival (PFS)

Median time (in months) to PFS. PFS is defined as the time from start date of study drugs to the date of first documented disease progression (radiological or clinical) or death due to any cause, if death occurs before progression is documented. PFS will be evaluated based on RECIST v1.1 criteria, 20% progression or any new lesion. (NCT02651415)
Timeframe: From start date of study drugs to the date of first documented disease progression or death due to any cause.

Number of Participants That Have Any Grade HFSR Toxicity

"The trial will measure the toxicities of HFSR in participants receiving both perindopril and regorafenib using the CTCAE v4.03 criteria.~The toxicity of HFSR will be expressed based on the number of participants in the study (N=10) who are experiencing HFSR of all grades." (NCT02651415)
Timeframe: Up to Safety Follow-Up Visit (30 days +/- 7 days after permanently stopping study treatment)

Number of Participants With Maximal Severity of HFSR as Assessed by CTCAE v4.03 Criteria When Treated With a Combination of Regorafenib and Perindopril

The number of participants that experienced an HFSR of grade 3 or above as assessed by CTCAE v4.03 criteria when treated with a combination of regorafenib and perindopril. (NCT02651415)
Timeframe: Up to Safety Follow-Up Visit (30 days +/- 7 days after permanently stopping study treatment)

The Number of Participants That Experienced All Grade Toxicities as Assessed by CTCAE v4.03 Criteria When Treated With a Combination of Regorafenib and Perindopril

All grades of adverse events (including HFSR) will be evaluated using CTCAE v4.03, at baseline and at D1 of each cycle while they are on the study drug and during the 30-day follow-up period (Post therapy). (NCT02651415)
Timeframe: At baseline and at D1 of each cycle while on the study drug and during the 30-day follow-up period

The Number of Participants That Experienced Any Grade of Hypertension as Assessed by CTCAE v4.03 Criteria When Treated With a Combination of Regorafenib and Perindopril

All grades of hypertension will be evaluated using CTCAE v4.03, weekly for the first six weeks while they are on the study drug, then every second week and during the 30-day follow-up period (Post therapy). (NCT02651415)
Timeframe: Weekly for the first six weeks while on the study drug, then every second week and during the 30-day follow-up period

Intervention	Subjects (Number)
	CR	PR	SD	PD
MSC1936369B Regimen 1	0	0	19	20
MSC1936369B Regimen 2 and Regimen 2 Food Effect	0	4	34	33
MSC1936369B Regimen 3 Once Daily (QD)	0	2	9	4
MSC1936369B Regimen 3 Twice Daily	1	6	14	12

Intervention	Subjects (Number)
	Haemoglobin decreased	Anaemia	Lymphopenia	Thrombocytopenia	Platelet count decreased	Neutropenia	Leukopenia	Pancytopenia	Hyponatraemia	Hypokalaemia	Hyperkalaemia	Hypocalcaemia	Hypercalcaemia	Hypomagnesaemia	Hypophosphataemia	Hepatic enzyme increased	Hepatic function abnormal	Alanine aminotransferase increased	Aspartate aminotransferase increased	Blood alkaline phosphatase increased	Hyperbilirubinaemia	Blood lactate dehydrogenase increased	Blood creatine phosphokinase increased	Blood creatinine increased	Blood 25-hydroxycholecalciferol decreased	Vitamin D decreased	Blood parathyroid hormone increased	Hyperglycaemia	C-reactive protein increased	Proteinuria	Hyperthyroidism	Hypoalbuminaemia	Weight increased	Weight decreased	Hyperthermia	Hypertension	Hypotension	Heart rate increased	Tachycardia	Blood potassium increased
MSC1936369B Regimen 1	1	10	3	3	0	0	0	0	0	4	1	2	0	2	0	0	0	0	1	1	1	1	1	0	1	0	1	0	0	0	0	3	0	6	1	7	3	1	3	1
MSC1936369B Regimen 2 (Without Food Effect + With Food Effect)	2	23	7	6	1	4	0	0	1	10	0	7	3	3	2	1	1	1	1	0	1	0	2	1	1	1	1	1	1	0	0	4	3	8	5	5	1	0	0	0
MSC1936369B Regimen 3 Once Daily (QD)	0	3	0	2	0	0	1	0	0	2	0	0	0	2	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	1	0	0	0	4	0	1	2	0	2	0
MSC1936369B Regimen 3 Twice Daily	0	3	0	1	0	1	0	1	1	2	0	1	0	0	0	0	0	2	2	1	0	1	5	0	0	0	0	0	0	1	1	2	3	2	1	4	0	0	0	0

Intervention	Subjects (Number)
	TEAEs	Serious TEAEs	TEAEs leading to discontinuation
MSC1936369B Regimen 1	47	23	13
MSC1936369B Regimen 2 (Without Food Effect + With Food Effect)	82	45	22
MSC1936369B Regimen 3 Once Daily (QD)	15	8	2
MSC1936369B Regimen 3 Twice Daily	34	21	6

Intervention	fold change (Mean)
	C1D1, Pre-dose (pERK)	C1D1, 2 h post-dose (pERK)	C1D1, 8 h post-dose (pERK)	C1D2, Pre-dose (pERK)	C1D8, Pre-dose (pERK)	C1D12-15, Pre-dose (pERK)	C1D12-15, 2 h Post-dose (pERK)	C1D12-15, 8 h Post-dose (pERK)	C1D12-15, 24 h Post-dose (pERK)	C1D1, Pre-dose (Tot ERK)	C1D1, 2 h post-dose (Tot ERK)	C1D1, 8 h post-dose (Tot ERK)	C1D2, Pre-dose (Tot ERK)	C1D8, Pre-dose (Tot ERK)	C1D12-15, Pre-dose (Tot ERK)	C1D12-15, 2 h Post-dose (Tot ERK)	C1D12-15, 8 h Post-dose (Tot ERK)	C1D12-15, 24 h Post-dose (Tot ERK)
MSC1936369B Regimen 3 Once Daily	4.121	1.178	1.878	3.081	2.541	3.241	1.471	1.902	2.598	1.02	1.078	1.078	1.013	0.944	1.333	1.335	1.044	1.048
MSC1936369B Regimen 3 Twice Daily	3.629	1.249	1.821	2.069	2.235	2.16	1.315	1.98	2.043	1.086	1.079	1.098	1.108	1.049	1.047	1.059	1.026	1.068

Intervention	fold change (Mean)
	C1D1, Pre-dose (pERK)	C1D1, 2 h post-dose (pERK)	C1D1, 4 h post-dose (pERK)	C1D1, 8 h post-dose (pERK)	C1D2, Pre-dose (pERK)	C1D8, Pre-dose (pERK)	C1D12-15, Pre-dose (pERK)	C1D12-15, 2 h Post-dose (pERK)	C1D12-15, 8 h Post-dose (pERK)	C1D12-15, 24 h Post-dose (pERK)	C3D1, Pre-dose (pERK)	C3D1, 2 h Post-dose (pERK)	C3D1, 4 h Post-dose (pERK)	C1D1, Pre-dose (Tot ERK)	C1D1, 2 h post-dose (Tot ERK)	C1D1, 4 h post-dose (Tot ERK)	C1D1, 8 h post-dose (Tot ERK)	C1D2, Pre-dose (Tot ERK)	C1D8, Pre-dose (Tot ERK)	C1D12-15, Pre-dose (Tot ERK)	C1D12-15, 2 h Post-dose (Tot ERK)	C1D12-15, 8 h Post-dose (Tot ERK)	C1D12-15, 24 h Post-dose (Tot ERK)	C3D1, Pre-dose (Tot ERK)	C3D1, 2 h Post-dose (Tot ERK)	C3D1, 4 h Post-dose (Tot ERK)
MSC1936369B Regimen 2 (Without Food Effect + With Food Effect)	3.937	1.305	3.422	1.454	2.411	2.868	3.265	1.293	1.653	2.476	3.716	1.288	2.688	1.075	1.069	1.012	1.095	1.13	1.108	1.118	1.125	1.041	1.045	1.138	1.251	1.052

Intervention	Hours (h) (Median)
	Fasted	Fed
MSC1936369B 150 mg	1.000	6.000
MSC1936369B 90 mg	1.600	2.033

Intervention	Liter per hour (Geometric Mean)
	Fasted	Fed
MSC1936369B 150 mg	44.85	26.62
MSC1936369B 90 mg	56.94	60.17

Intervention	per hour (Geometric Mean)
	Unlabeled pimasertib	Intravenous [14C] pimasertib
Pimasertib	0.1096	0.1994

Intervention	subjects (Number)
	TEAEs	Serious TEAEs	TEAEs leading to death	TEAEs leading to discontinuation
Pimasertib	6	2	1	3

Intervention	subjects (Number)
	Stable disease	Progressive disease	Confirmed Response	Partial Response	Non evaluable
Pimasertib	3	1	0	0	1

Intervention	nanogram equivalent per milliliter (Mean)
	Predose	Hour 1	Hour 2.0	Hour 4.0	Hour 10.0	Hour 24.0
Pimasertib	0.0	695.2	691.2	379.3	165.6	46.62

Intervention	Nanogram equivalent per milliliter (Mean)
	M445 (Predose)(n=6)	M445 (Hour 1.0)(n=6)	M445 (Hour 2.0)(n=6)	M445 (Hour 4.0)(n=6)	M445 (Hour 10.0)(n=5)	M445 (Hour 24.0)(n=3)	M554(Predose)(n=6)	M554(Hour 1.0)(n=6)	M554 (Hour 2.0)(n=6)	M554 (Hour 4.0)(n=6)	M554 (Hour 10.0) (n=5)	M554 (Hour 24.0) (n=3)
Pimasertib	0.0	285.2	262.2	85.05	28.58	0.0	0.0	87.53	167.6	169.1	108.8	51.33

Intervention	hours (Median)
	Unlabeled pimasertib	[14C] intravenous pimasertib
Pimasertib	0.75	0.5

Intervention	subjects (Number)
Pimasertib 45 mg+Temsirolimus 12.5 mg	0
Pimasertib 45 mg+Temsirolimus 25 mg	7
Pimasertib 75 mg+Temsirolimus 25 mg	2

Intervention	liter/hour (Median)
	Non-DDI: Day 8
Pimasertib 45 mg+Temsirolimus 25 mg (Non-DDI)	64.31
Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI)	53.6

Intervention	liter/hour (Median)
	DDI: Day 1	DDI: Day 9
Pimasertib 45 mg+Temsirolimus 12.5 mg (DDI)	81.25	71.99
Pimasertib 45 mg+Temsirolimus 25 mg (DDI)	54.36	55.9

Intervention	hour (Median)
	Non-DDI: Day 8
Pimasertib 45 mg+Temsirolimus 25 mg (Non-DDI)	7.746
Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI)	5.712

Intervention	hour (Median)
	Non-DDI: Day 8
Pimasertib 45 mg+Temsirolimus 25 mg (Non-DDI)	29.08
Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI)	10.42

Intervention	hour (Median)
	DDI: Day 9	DDI: Day 16
Pimasertib 45 mg+Temsirolimus 12.5 mg (DDI)	25.57	20.62
Pimasertib 45 mg+Temsirolimus 25 mg (DDI)	13.2	19.14

Intervention	liter (Median)
	Non-DDI: Day 8
Pimasertib 45 mg+Temsirolimus 25 mg (Non-DDI)	760.6
Pimasertib 75 mg+Temsirolimus (TEM) 25 mg (Non-DDI)	416.5

niacinamide and Neoplasms

Research Excerpts

Research

Studies (374)

Authors

Clinical Trials (31)

Trial Overview

Trial Outcomes

Number of Subjects Experienced Any Dose-Limiting Toxicity (DLT) Over the First Cycle - Day 1 to 21

Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) Leading to Death

Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 1

Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 1

Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 2 (With Food Effect)

Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 2 (Without Food Effect)

Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 2 (Without Food Effect)

Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 2 (Without Food Effect)

Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 3 Once Daily

Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 3 Twice Daily

Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 2 (With Food Effect)

Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 2 (Without Food Effect)

Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 2 (Without Food Effect)

Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 2 (Without Food Effect)

Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 3 Once Daily

Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 3 Twice Daily

Apparent Volume of Distribution Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 1

Apparent Volume of Distribution Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 1

Area Under the Concentration Time Curve Extrapolated From Last Observation to Infinity Given as Percentage of AUC 0-∞ (AUC Extra): Regimen 1

Area Under the Concentration Time Curve Extrapolated From Last Observation to Infinity Given as Percentage of AUC 0-∞ (AUC Extra): Regimen 1

Area Under the Concentration Time Curve Extrapolated From Last Observation to Infinity Given as Percentage of AUC 0-∞ (AUC Extra): Regimen 2 (With Food Effect)

Area Under the Concentration Time Curve Extrapolated From Last Observation to Infinity Given as Percentage of AUC 0-∞ (AUC Extra): Regimen 2 (Without Food Effect)

Area Under the Concentration Time Curve Extrapolated From Last Observation to Infinity Given as Percentage of AUC 0-∞ (AUC Extra): Regimen 2 (Without Food Effect)

Area Under the Concentration Time Curve Extrapolated From Last Observation to Infinity Given as Percentage of AUC 0-∞ (AUC Extra): Regimen 2 (Without Food Effect)

Area Under the Concentration Time Curve Extrapolated From Last Observation to Infinity Given as Percentage of AUC 0-∞ (AUC Extra): Regimen 3 Once Daily

Area Under the Concentration Time Curve Extrapolated From Last Observation to Infinity Given as Percentage of AUC 0-∞ (AUC Extra): Regimen 3 Twice Daily

Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B : Regimen 1

Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B : Regimen 1

Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B: Regimen 2 (With Food Effect)

Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B: Regimen 2 (Without Food Effect)

Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B: Regimen 2 (Without Food Effect)

Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B: Regimen 2 (Without Food Effect)

Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B: Regimen 3 Once Daily

Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B: Regimen 3 Twice Daily

Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of MSC1936369B: : Regimen 2 (Without Food Effect)

Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of MSC1936369B: : Regimen 2 (Without Food Effect)

Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of MSC1936369B: Regimen 1

Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of MSC1936369B: Regimen 1

Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of MSC1936369B: Regimen 2 (With Food Effect)

Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of MSC1936369B: Regimen 3 Once Daily

Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of MSC1936369B: Regimen 3 Twice Daily

Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 1

Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 1

Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 2 (With Food Effect)

Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 2 (Without Food Effect)

Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 2 (Without Food Effect)

Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 3 Once Daily

Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 3 Twice Daily

Number of Subjects With Clinical Benefit (Complete Response [CR], Partial Response [PR] or Stable Disease [SD}) and Progressive Disease (PD) Based on the Best Overall Response (BOR)

Number of Subjects With Clinical Significant Laboratory Abnormalities and Vital Signs Reported as Treatment Emergent Adverse Events

Number of Subjects With Treatment-Emergent Adverse Events (TEAE), Serious TEAEs, TEAEs Leading to Discontinuation

Phosphorylated Extra-Cellular Signal-Regulated Kinase (pERK) Fold Change in Peripheral Blood Monocyte Cells (PBMC) and Tot ERK Fold Change in Peripheral Blood Monocyte Cells (PBMC)

Phosphorylated Extra-Cellular Signal-Regulated Kinase (pERK) Fold Change in Peripheral Blood Monocyte Cells (PBMC) and Tot ERK Fold Change in Peripheral Blood Monocyte Cells (PBMC)

Phosphorylated Extra-Cellular Signal-Regulated Kinase (pERK) Fold Change in Peripheral Blood Monocyte Cells (PBMC) and Tot ERK Fold Change in Peripheral Blood Monocyte Cells (PBMC)

Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 1

Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 1

Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 2 (With Food Effect)

Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 2 (Without Food Effect)

Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 2 (Without Food Effect)

Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 3 Once Daily

Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 3 Twice Daily

Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 1

Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 1

Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 2 (With Food Effect)

Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 2 (Without Food Effect)

Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 2 (Without Food Effect)

Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 2 (Without Food Effect)

Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 3 Once Daily

Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 3 Twice Daily

Apparent Terminal Elimination Rate Constant (λz) of Total [14C] Radioactivity

Apparent Terminal Half-life (t1/2) of Total [14C] Radioactivity

Apparent Volume of Distribution of Total [14C] Radioactivity During the Terminal Phase Following Oral Administration (Vz/f)

Intervention	hour*nanogram/milliliter (Median)
	Non-DDI: Day 8
Pimasertib 45 mg+Temsirolimus 25 mg (Non-DDI)	4026
Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI)	2194

Intervention	hour*nanogram/milliliter (Median)
	Non-DDI: AUCtau: Day 8
Pimasertib 45 mg+Temsirolimus 25 mg (Non-DDI)	706
Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI)	1402

Intervention	hour*nanogram/milliliter (Median)
	DDI: AUCtau: Day 9	DDI: AUC0-inf: Day 1
Pimasertib 45 mg+Temsirolimus 12.5 mg (DDI)	628	573.2
Pimasertib 45 mg+Temsirolimus 25 mg (DDI)	805	828.6

Intervention	nanogram/milliliter (Median)
	Non-DDI: Day 8
Pimasertib 45 mg+Temsirolimus 25 mg (Non-DDI)	197.6
Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI)	308.1

Intervention	nanogram/milliliter (Median)
	Non-DDI: Day 8
Pimasertib 45 mg+Temsirolimus 25 mg (Non-DDI)	489.9
Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI)	480.9

Intervention	liter/hour (Median)
	Non-DDI: Day 8
Pimasertib 45 mg+Temsirolimus 25 mg (Non-DDI)	6.284
Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI)	11.39

Intervention	liter (Median)
	Non-DDI: Day 8
Pimasertib 45 mg+Temsirolimus 25 mg (Non-DDI)	309.7
Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI)	172.9

Intervention	mg/L.h (Geometric Mean)
First Stage - Disease Progression	9.76
Second Stage - Increased Accrual	18.63

Intervention	mg/L (Mean)
First Stage - Disease Progression	1.28
Second Stage - Increased Accrual	2.57

Intervention	Months (Median)
First Stage - Disease Progression	18
Second Stage - Increased Accrual	18.3