pteridines and Benign Neoplasms studies

Research Excerpts

Excerpt	Relevance	Reference
"BI 2536 is a selective and potent small-molecule inhibitor of polo-like kinase 1."	6.75	Multicentric parallel phase II trial of the polo-like kinase 1 inhibitor BI 2536 in patients with advanced head and neck cancer, breast cancer, ovarian cancer, soft tissue sarcoma and melanoma. The first protocol of the European Organization for Research ( Aerts, C; Allgeier, A; Blay, JY; Bogaerts, J; Brain, E; De Greve, J; Fontaine, C; Fritsch, H; Hanft, G; Lacombe, D; Machiels, JP; Munzert, G; Rapion, J; Ray-Coquard, I; Schöffski, P; Sleijfer, S; Soria, JC; Wolter, P, 2010)
"These findings support the further exploration of volasertib for pediatric malignancies, particularly alveolar rhabdomyosarcoma, and its combination with mitotic spindle poison."	3.83	Polo-like Kinase Inhibitor Volasertib Exhibits Antitumor Activity and Synergy with Vincristine in Pediatric Malignancies. ( Abbou, S; Daudigeos-Dubus, E; Geoerger, B; Lanvers-Kaminsky, C; Laplace-Builhe, C; LE Dret, L; Molenaar, J; Vassal, G, 2016)
"This drug-drug interaction study determined whether the metabolism and distribution of the Polo-like kinase 1 inhibitor, volasertib, is affected by co-administration of the P-glycoprotein and cytochrome P-450 3A4 inhibitor, itraconazole."	2.94	Potential Drug-Drug Interactions with Combination Volasertib + Itraconazole: A Phase I, Fixed-sequence Study in Patients with Solid Tumors. ( Chizhikov, E; Fritsch, H; Lang, I; Liptai, B; Liu, D; Taube, T, 2020)
"To determine the maximum tolerated dose (MTD) of volasertib, a Polo-like kinase inhibitor, combined with afatinib, an oral irreversible ErbB family blocker, in patients with advanced solid tumors (NCT01206816; Study 1230."	2.80	A phase I study of volasertib combined with afatinib, in advanced solid tumors. ( De Smet, M; Herremans, C; Liu, D; Machiels, JP; Peeters, M; Pilz, K; Rottey, S; Specenier, P; Strelkowa, N; Surmont, V, 2015)
"Volasertib is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinases."	2.80	A phase I, dose-escalation study of volasertib combined with nintedanib in advanced solid tumors. ( Cascinu, S; Clementi, L; de Braud, F; De Pas, T; Liu, D; Pilz, K; Sikken, P; Spitaleri, G, 2015)
"These data support further development of volasertib and a harmonised dosing for Asian and Caucasian patients."	2.79	A phase I study of two dosing schedules of volasertib (BI 6727), an intravenous polo-like kinase inhibitor, in patients with advanced solid malignancies. ( Cheng, AL; Fritsch, H; Hsu, CH; Huang, DC; Lin, CC; Lu, YS; Su, WC; Su, WP; Taube, T; Voss, F; Yang, JC; Yeh, KH; Yen, CJ, 2014)
"Volasertib (BI 6727) is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase (Plk)."	2.77	A phase I, dose-escalation study of the novel Polo-like kinase inhibitor volasertib (BI 6727) in patients with advanced solid tumours. ( Awada, A; Bartholomeus, S; Dumez, H; Fritsch, H; Gil, T; Glomb, P; Munzert, G; Schöffski, P; Taton, M; Wolter, P, 2012)
"BI 2536 is a selective and potent small-molecule inhibitor of polo-like kinase 1."	2.75	Multicentric parallel phase II trial of the polo-like kinase 1 inhibitor BI 2536 in patients with advanced head and neck cancer, breast cancer, ovarian cancer, soft tissue sarcoma and melanoma. The first protocol of the European Organization for Research ( Aerts, C; Allgeier, A; Blay, JY; Bogaerts, J; Brain, E; De Greve, J; Fontaine, C; Fritsch, H; Hanft, G; Lacombe, D; Machiels, JP; Munzert, G; Rapion, J; Ray-Coquard, I; Schöffski, P; Sleijfer, S; Soria, JC; Wolter, P, 2010)
" The MTD for the second dosing schedule was not determined; a 225-mg dose was well tolerated."	2.75	An open-label, phase I study of the polo-like kinase-1 inhibitor, BI 2536, in patients with advanced solid tumors. ( Al-Batran, SE; Fritsch, H; Hochhaus, A; Hofheinz, RD; Jäger, E; Munzert, G; Reichardt, VL; Trommeshauser, D, 2010)
"BI 2536 is a novel, potent, and highly specific inhibitor of polo-like kinase 1 (Plk1), which has an essential role in the regulation of mitotic progression."	2.73	Phase I dose escalation and pharmacokinetic study of BI 2536, a novel Polo-like kinase 1 inhibitor, in patients with advanced solid tumors. ( Frost, A; Hedbom, S; Hoesl, CE; Kaiser, R; Mross, K; Munzert, G; Rentschler, J; Rouyrre, N; Steinbild, S; Trommeshauser, D, 2008)
"Plk1, which has been validated as a cancer target, came into the focus of many pharmaceutical companies for the development of small-molecule inhibitors as anticancer agents."	2.53	The role of Plk3 in oncogenesis. ( Becker, S; Helmke, C; Strebhardt, K, 2016)
"Volasertib has shown promising activity in various cancer cell lines and xenograft models of human cancer."	2.52	Discovery and development of the Polo-like kinase inhibitor volasertib in cancer therapy. ( Gjertsen, BT; Schöffski, P, 2015)
"Significant advances in cancer treatment have resulted from the targeted cancer therapy by understanding the process of malignant transformation."	2.49	Current clinical trials with polo-like kinase 1 inhibitors in solid tumors. ( Yim, H, 2013)
"Pteridines are a class of potential cancer biomarkers."	2.47	Metabolic profiling of pteridines for determination of potential biomarkers in cancer diseases. ( Bujak, R; Daghir, E; Kośliński, P; Markuszewski, MJ, 2011)
"About 80% of human tumors, of various origins, express high levels of PLK transcripts."	2.45	Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology. ( Schöffski, P, 2009)
"In haematologic neoplasias correlations of neopterin values to clinical features, to tumour staging, and to laboratory data were apparent."	2.36	Pteridines in the assessment of neoplasia. ( Hausen, A; Wachter, H, 1982)
"In solid tumors, cancer cells have devised multiple approaches to survival and proliferate in response to glucose starvation that is often observed in solid tumor microenvironments."	1.72	P90 ribosomal S6 kinase confers cancer cell survival by mediating checkpoint kinase 1 degradation in response to glucose stress. ( Cui, D; Gong, L; Ma, Y; Pan, H; Wang, L; Wang, Y; Xiong, X; Yang, F; Zhang, M; Zhao, Y, 2022)
"Volasertib is a potent inhibitor of Plk1 that inhibits the proliferation of multiple human cancer cell lines by promoting cell cycle arrest at nanomolar concentrations."	1.42	Human ATP-Binding Cassette Transporter ABCB1 Confers Resistance to Volasertib (BI 6727), a Selective Inhibitor of Polo-like Kinase 1. ( Hsiao, SH; Hsieh, CH; Hsu, SC; Huang, CW; Huang, YH; Li, YQ; Luo, SY; Su, CY; Wu, CP, 2015)
"Concomitant inhibition of multiple cancer-driving kinases is an established strategy to improve the durability of clinical responses to targeted therapies."	1.40	Dual kinase-bromodomain inhibitors for rationally designed polypharmacology. ( Ciceri, P; Fedorov, O; Filippakopoulos, P; Hunt, JP; Knapp, S; Lasater, EA; Martin, S; Müller, S; O'Mahony, A; Pallares, G; Picaud, S; Shah, NP; Treiber, DK; Wells, C; Wodicka, LM, 2014)
"In treated tumors, cells arrest in prometaphase, accumulate phosphohistone H3, and contain aberrant mitotic spindles."	1.34	BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. ( Adolf, GR; Baum, A; Garin-Chesa, P; Grauert, M; Gürtler, U; Hoffmann, M; Kraut, N; Krssák, M; Lénárt, P; Lieb, S; Peters, JM; Petronczki, M; Quant, J; Rettig, WJ; Steegmaier, M, 2007)
"In patients with tumors of the genitourinary tract or with hemopoietic neoplasms, urinary neopterin levels were correlated with the tumor burden and became normal when remission was achieved."	1.27	Urinary neopterin in the diagnosis and follow-up of neoplasia: a biochemical parameter to detect cell-mediated immune response. ( Fuchs, D; Hausen, A; Huber, C; Reibnegger, G; Wachter, H, 1984)
"In testicular cancer patients receiving adjuvant chemotherapy, a significant increase in serum (p less than 0."	1.27	Neopterin as tumour marker serum and urinary neopterin concentrations in malignant diseases. ( Hofbauer, J; Kratzik, C; Kuzmits, R; Legenstein, E; Ludwig, H; Szekeresz, T, 1986)
"Marked increases during extended cancer and especially during leukemias corroborated the view that P-AGPM may be identical with abnormal orosomucoid."	1.26	Blood levels of a pteridine-binding alpha 1-acid glycoprotein in cancer patients. ( Fink, M; Maier, K; Wilmanns, W; Ziegler, I, 1982)

Research

Studies (64)

Authors

Clinical Trials (6)

Trial Overview

Trial Outcomes

Area Under the Plasma Concentration-time Curve Over the Time Interval From 0 to Infinity (AUC0-∞) of Volasertib and Its Metabolite CD 10899

Timeframe	Studies, this research(%)	All Research%
pre-1990	22 (34.38)	18.7374
1990's	0 (0.00)	18.2507
2000's	10 (15.63)	29.6817
2010's	27 (42.19)	24.3611
2020's	5 (7.81)	2.80

Authors	Studies
Ma, Y	3
Cui, D	1
Wang, L	1
Wang, Y	1
Yang, F	1
Pan, H	1
Gong, L	1
Zhang, M	1
Xiong, X	1
Zhao, Y	1
Lang, I	1
Liu, D	4
Fritsch, H	5
Taube, T	3
Chizhikov, E	1
Liptai, B	1
El-Kalyoubi, S	1
Agili, F	1
Shin, SB	1
Kim, CH	1
Jang, HR	1
Yim, H	2
Al-Qahtani, QH	1
Moghrabi, WN	1
Al-Yahya, S	1
Al-Haj, L	1
Al-Saif, M	1
Mahmoud, L	1
Al-Mohanna, F	1
Al-Souhibani, N	1
Alaiya, A	1
Hitti, E	1
Khabar, KSA	1
Larocca, C	1
Cohen, JR	1
Fernando, RI	1
Huang, B	1
Hamilton, DH	1
Palena, C	1
Krause, M	1
Kummer, B	1
Deparade, A	1
Eicheler, W	1
Pfitzmann, D	1
Yaromina, A	1
Kunz-Schughart, LA	1
Baumann, M	1
Burton, C	1
Ciceri, P	1
Müller, S	1
O'Mahony, A	1
Fedorov, O	1
Filippakopoulos, P	1
Hunt, JP	1
Lasater, EA	1
Pallares, G	1
Picaud, S	1
Wells, C	1
Martin, S	1
Wodicka, LM	1
Shah, NP	1
Treiber, DK	1
Knapp, S	1
Lin, CC	1
Su, WC	1
Yen, CJ	1
Hsu, CH	1
Su, WP	1
Yeh, KH	1
Lu, YS	1
Cheng, AL	1
Huang, DC	1
Voss, F	1
Yang, JC	1
Rajasekaran, R	1
Aruna, P	1
Koteeswaran, D	1
Baludavid, M	1
Ganesan, S	1
Gjertsen, BT	1
Schöffski, P	5
Raab, M	1
Krämer, A	1
Hehlgans, S	1
Sanhaji, M	1
Kurunci-Csacsko, E	1
Dötsch, C	1
Bug, G	1
Ottmann, O	1
Becker, S	2
Pachl, F	1
Kuster, B	1
Strebhardt, K	2
Awada, A	2
Dumez, H	2
Aftimos, PG	1
Costermans, J	1
Bartholomeus, S	2
Forceville, K	1
Berghmans, T	1
Meeus, MA	1
Cescutti, J	1
Munzert, G	5
Pilz, K	3
Helmke, C	1
Machiels, JP	2
Peeters, M	2
Herremans, C	1
Surmont, V	1
Specenier, P	2
De Smet, M	1
Strelkowa, N	1
Rottey, S	1
de Braud, F	1
Cascinu, S	1
Spitaleri, G	1
Clementi, L	1
Sikken, P	1
De Pas, T	1
Wu, CP	1
Hsieh, CH	1
Hsiao, SH	1
Luo, SY	1
Su, CY	1
Li, YQ	1
Huang, YH	1
Huang, CW	1
Hsu, SC	1
Nokihara, H	1
Yamada, Y	1
Fujiwara, Y	1
Yamamoto, N	1
Wakui, H	1
Nakamichi, S	1
Kitazono, S	1
Inoue, K	1
Harada, A	1
Takeuchi, Y	1
Tamura, T	1
Abbou, S	1
Lanvers-Kaminsky, C	1
Daudigeos-Dubus, E	1
LE Dret, L	1
Laplace-Builhe, C	1
Molenaar, J	1
Vassal, G	1
Geoerger, B	1
Van den Bossche, J	1
Lardon, F	1
Deschoolmeester, V	1
De Pauw, I	1
Vermorken, JB	1
Pauwels, P	1
Wouters, A	1
NORRIS, ER	1
MAJNARICH, JJ	1
Mross, K	1
Frost, A	1
Steinbild, S	1
Hedbom, S	1
Rentschler, J	1
Kaiser, R	1
Rouyrre, N	1
Trommeshauser, D	2
Hoesl, CE	1
Sur, S	1
Pagliarini, R	1
Bunz, F	1
Rago, C	1
Diaz, LA	1
Kinzler, KW	1
Vogelstein, B	1
Papadopoulos, N	1
Wäsch, R	1
Hasskarl, J	1
Schnerch, D	1
Lübbert, M	1
Blay, JY	1
De Greve, J	1
Brain, E	1
Soria, JC	1
Sleijfer, S	1
Wolter, P	2
Ray-Coquard, I	1
Fontaine, C	1
Hanft, G	1
Aerts, C	1
Rapion, J	1
Allgeier, A	1
Bogaerts, J	1
Lacombe, D	1
Hofheinz, RD	1
Al-Batran, SE	1
Hochhaus, A	1
Jäger, E	1
Reichardt, VL	1
Liu, KK	1
Bagrodia, S	1
Bailey, S	1
Cheng, H	1
Chen, H	1
Gao, L	1
Greasley, S	1
Hoffman, JE	1
Hu, Q	1
Johnson, TO	1
Knighton, D	1
Liu, Z	1
Marx, MA	1
Nambu, MD	1
Ninkovic, S	1
Pascual, B	1
Rafidi, K	1
Rodgers, CM	1
Smith, GL	1
Sun, S	1
Wang, H	1
Yang, A	1
Yuan, J	1
Zou, A	1
Gamagedara, S	1
Gibbons, S	1
Eckerdt, F	1
Kośliński, P	1
Bujak, R	1
Daghir, E	1
Markuszewski, MJ	1
Gil, T	1
Taton, M	1
Glomb, P	1
Chang, YC	1
Wu, CH	1
Yen, TC	1
Ouyang, P	1
Garuti, L	1
Roberti, M	1
Bottegoni, G	1
Patarca, R	1
Akhurst, RJ	1
Steegmaier, M	1
Hoffmann, M	1
Baum, A	1
Lénárt, P	1
Petronczki, M	1
Krssák, M	1
Gürtler, U	1
Garin-Chesa, P	1
Lieb, S	1
Quant, J	1
Grauert, M	1
Adolf, GR	1
Kraut, N	1
Peters, JM	1
Rettig, WJ	1
Plyte, S	1
Musacchio, A	1
Kothe, M	1
Kohls, D	1
Low, S	1
Coli, R	1
Rennie, GR	1
Feru, F	1
Kuhn, C	1
Ding, YH	1
Fuchs, D	3
Hausen, A	4
Huber, C	2
Reibnegger, G	2
Wachter, H	5
Niederwieser, D	1
Stea, B	1
Smith, RA	1
Matsumoto, J	1
Ishikawa, T	1
Masahito, P	1
Takayama, S	1
Dhondt, JL	3
Farriaux, JP	3
Ziegler, I	3
Maier, K	2
Fink, M	2
Wilmanns, W	1
Bellhasene, Z	1
Largilliere, C	1
Bonneterre, J	1
Rokos, H	1
Rokos, K	1
Frisius, H	1
Kirstaedter, HJ	1
Ebels, I	1
Murr, C	1
Widner, B	1
Wirleitner, B	1
Grassmayr, K	1
Kokolis, N	1
Dinovo, EC	1
Lynn, JK	1
McIntosh, ME	1
Johnson, M	1
Bauer, C	1
Kuzmits, R	1
Ludwig, H	1
Legenstein, E	1
Szekeresz, T	1
Kratzik, C	1
Hofbauer, J	1
Hayte, JM	1
Nichol, CA	1
Smith, GK	1
Duch, DS	1
Goldberg, M	1
Gassner, F	1
Merkenschlager, M	1
Zeitler, HJ	1
Andondonskaja-Renz, B	1
Bichler, A	1
Hetzel, H	1

Trial	Phase	Enrollment	Study Type	Start Date	Status
An Open-label Fixed Sequence Trial to Investigate the Potential Drug-drug Interaction of Intravenous Volasertib Co-administered With a P-gp and CYP3A4 Inhibitor (Itraconazole p.o.) in Patients With Various Solid Tumours[NCT01772563]	Phase 1	28 participants (Actual)	Interventional	2013-02-04	Completed
A Phase I Dose Escalation Trial of BI 6727 in Combination With Cisplatin or Carboplatin in Patients With Advanced or Metastatic Solid Tumors[NCT00969761]	Phase 1	61 participants (Actual)	Interventional	2009-08-31	Completed
An Open Label Phase I Dose Escalation Trial of Intravenous BI 6727 in Combination With Oral BIBW 2992 in Patients With Advanced Solid Tumours With Repeated Administration in Patients With Clinical Benefit[NCT01206816]	Phase 1	57 participants (Actual)	Interventional	2010-10-04	Completed
An Open-label Phase I Study of Once Every Three Weeks Intravenous Treatment With BI 6727 in Japanese Patients With Advanced Solid Tumours[NCT01348347]	Phase 1	15 participants (Actual)	Interventional	2011-04-25	Completed
Multicenter Parallel Phase II Trial of BI 2536 Administered as One Hour IV Infusion Every 3 Weeks in Defined Cohorts of Patients With Various Solid Tumors. A New Drug Screening Program of the EORTC Network of Core Institutions (NOCI)[NCT00526149]	Phase 2	76 participants (Actual)	Interventional	2007-07-31	Completed
A Phase 1 Dose Escalation Study of Hepatic Intra-Arterial Administration of TKM 080301 (Lipid Nanoparticles Containing siRNA Against the PLK1 Gene Product) in Patients With Colorectal, Pancreas, Gastric, Breast, Ovarian and Esophageal Cancers With Hepatic[NCT01437007]	Phase 1	1 participants (Actual)	Interventional	2011-08-26	Completed
[information is prepared from clinicaltrials.gov, extracted Sep-2024]

Area under the plasma concentration-time curve over the time interval from 0 to infinity (AUC0-∞) of volasertib and its metabolite CD 10899 is reported. (NCT01772563)
Timeframe: 30 minutes before volasertib administration and 1 hour (h), 1.75h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 72h, 168h, 336h, 504 h after volasertib administration on Day 1 of Cycle 1 (Volasertib+ Itraconazole) and of Cycle 2 (Volasertib).

Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to the Last Quantifiable Drug Plasma Concentration After Dose Administration (AUC0-tz) of Volasertib and Its Metabolite CD 10899

Intervention	nanogramhour/milliliter (ngh/mL) (Geometric Mean)
	volasertib	CD 10899
Volasertib (Cycle 2)	7610	1310
Volasertib+ Itraconazole (Cycle 1)	7360	1020

Area under the plasma concentration-time curve over the time interval from zero to the last quantifiable drug plasma concentration after dose administration (AUC0-tz) of volasertib and its metabolite CD 10899 is reported. (NCT01772563)
Timeframe: 30 minutes before volasertib administration and 1 hour (h), 1.75h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 72h, 168h, 336h, 504 h after volasertib administration on Day 1 of Cycle 1 (Volasertib+ Itraconazole) and of Cycle 2 (Volasertib).

Maximum Measured Concentration of Volasertib and Its Metabolite CD 10899 in Plasma (Cmax)

Intervention	nanogramhour/milliliter (ngh/mL) (Geometric Mean)
	volasertib	CD 10899
Volasertib (Cycle 2)	7140	1130
Volasertib+ Itraconazole (Cycle 1)	6690	855

Maximum measured concentration of the analyte (volasertib and its metabolite CD 10899) in plasma (Cmax) is reported. (NCT01772563)
Timeframe: 30 minutes before volasertib administration and 1 hour (h), 1.75h, 4h, 6h, 8h, 12h, 24, 36h, 48h, 72h, 168h, 336h, 504 h after volasertib administration on Day 1 of Cycle 1 (Volasertib+ Itraconazole) and of Cycle 2 (Volasertib).

Apparent Volume of Distribution at Steady State Following Intravascular Administration (Vss)

Intervention	nanogram/milliliter (ng/mL) (Geometric Mean)
	volasertib	CD 10899
Volasertib (Cycle 2)	414	7.10
Volasertib+ Itraconazole (Cycle 1)	328	4.51

Apparent volume of distribution at steady state following intravascular administration (Vss) of Volasertib in combination with cisplatin or carboplatin during treatment cycle 1. (NCT00969761)
Timeframe: 1 hour (h) 35 minutes (min) before start of volasertib infusion and 1h, 2h, 8h, 24h, 48h, 168h and 336h after start of volasertib infusion

Change From Baseline in Neutrophils

Intervention	Litres (Geometric Mean)
V100+Cis60	6580
V100+Cis75	11100
V200+Cis75	5570
V300+Cis75	7140
V300+Cis100	5880
V350+Cis75	7270
V100+Car4	8810
V100+Car5	9960
V200+Car5	8950
V300+Car5	8270
V300+Car6	7440
V350+Car5	3640

Change from baseline in neutrophils with the maximum value on treatment (NCT00969761)
Timeframe: Baseline and from first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days

Change From Baseline in Platelets

Intervention	10^9 cells /L (Mean)
V100+Cis60	7.6
V100+Cis75	3.3
V200+Cis75	3.4
V300+Cis75	3.0
V300+Cis100	6.0
V350+Cis75	5.2
V100+Car4	2.1
V100+Car5	6.8
V200+Car5	3.6
V300+Car5	5.9
V300+Car6	5.5
V350+Car5	4.7

Change from baseline in platelets with the maximum value on treatment (NCT00969761)
Timeframe: Baseline and from first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days

Change From Baseline in Pulse Rate

Intervention	10^9 cells /L (Mean)
V100+Cis60	57
V100+Cis75	65
V200+Cis75	96
V300+Cis75	71
V300+Cis100	67
V350+Cis75	89
V100+Car4	186
V100+Car5	50
V200+Car5	49
V300+Car5	39
V300+Car6	73
V350+Car5	104

Change from baseline in pulse rate at last value on treatment (NCT00969761)
Timeframe: Baseline and from first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days

Disease Control Rate

Intervention	bpm (Mean)
V100+Cis60	10.0
V100+Cis75	23.3
V200+Cis75	6.7
V300+Cis75	-11.7
V300+Cis100	10.3
V350+Cis75	5.2
V100+Car4	3.7
V100+Car5	0.7
V200+Car5	12.0
V300+Car5	5.7
V300+Car6	14.4
V350+Car5	-21.7

Percentage of participants with confirmed disease control, defined as the proportion of patients with a best overall response of at least stable disease (SD), determined based on RECIST V1.0 criteria. (NCT00969761)
Timeframe: From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days

Duration of Disease Control

Intervention	Percentage of participants (Number)
V100+Cis60	66.7
V100+Cis75	100.0
V200+Cis75	33.3
V300+Cis75	66.7
V300+Cis100	25.0
V350+Cis75	33.3
V100+Car4	33.3
V100+Car5	33.3
V200+Car5	0.0
V300+Car5	50.0
V300+Car6	15.4
V350+Car5	33.3

Duration of Disease control was defined as the time from the start of study treatment to the time of disease progression or death, whichever occurred first. (NCT00969761)
Timeframe: From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days

Duration of Objective Response

Intervention	Days (Median)
V100+Cis60	196.5
V100+Cis75	309.0
V200+Cis75	264.0
V300+Cis75	268.0
V300+Cis100	155.0
V350+Cis75	103.5
V100+Car4	135.0
V100+Car5	229.0
V300+Car5	234.0
V300+Car6	190.5
V350+Car5	126.0

"Duration of objective response was defined as the time from first documented confirmed complete response (CR) or partial response (PR) to first evidence of progressive disease (PD) or death from any cause, whichever occurred first, determined based on RECIST V1.0 criteria.~Tumour response was documented using appropriate techniques" (NCT00969761)
Timeframe: From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days

Frequency of Participants (%) With Possible Clinically Significant Abnormalities for Neutrophils

Intervention	Days (Median)
V100+Cis75	298
V300+Cis75	359
V300+Car5	282
V300+Car6	207

Frequency of participants (%) with possible clinically significant abnormalities for neutrophils: : defined as neutrophils >=CTCAE grade 2 (CTCAE v3.0), with worsening from baseline. The CTCAE scale measures the severity of adverse events which goes from 1 (mild AE) to 5 (death related AE). (NCT00969761)
Timeframe: From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days

Frequency of Participants (%) With Possible Clinically Significant Abnormalities for Platelets

Intervention	Percentage of participants (Number)
V100+Cis60	33.0
V100+Cis75	100.0
V200+Cis75	0.0
V300+Cis75	66.7
V300+Cis100	75.0
V350+Cis75	50.0
V100+Car4	33.3
V100+Car5	33.3
V200+Car5	33.3
V300+Car5	83.3
V300+Car6	76.9
V350+Car5	100.0

"Frequency of participants (%) with possible clinically significant abnormalities for platelets : defined as platelets >=CTCAE grade 2 (based on CTCAE v3.0), with worsening from baseline.~The CTCAE scale measures the severity of adverse events which goes from 1 (mild AE) to 5 (death related AE)." (NCT00969761)
Timeframe: From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days

Maximum Tolerated Dose

Intervention	Percentage of participants (Number)
V100+Cis60	0.0
V100+Cis75	0.0
V200+Cis75	0.0
V300+Cis75	33.0
V300+Cis100	41.7
V350+Cis75	83.3
V100+Car4	0.0
V100+Car5	33.3
V200+Car5	0.0
V300+Car5	83.3
V300+Car6	76.9
V350+Car5	100.0

"The maximum tolerated dose (MTD) was defined as the highest dose studied for which the incidence of DLT was less than 33% (i.e. 1/6 patients) during the first cycle, for Volasertib in combination with cisplatin or carboplatin.~0=not maximum tolerated dose, 1=was maximum tolerated dose." (NCT00969761)
Timeframe: 3 weeks

Objective Response Rate

Intervention	Units on a scale (Number)
V100+Cis60	0
V100+Cis75	0
V200+Cis75	0
V300+Cis75	0
V300+Cis100	1
V350+Cis75	0
V100+Car4	0
V100+Car5	0
V200+Car5	0
V300+Car5	0
V300+Car6	1
V350+Car5	0

"Objective response was defined as the proportion of participants having at least a best response of complete response (CR) or partial response (PR) determined based on RECIST criteria, version 1.0 (V1.0).~Tumour response was documented using appropriate techniques" (NCT00969761)
Timeframe: From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days

Percentage of Participants With Dose Limiting Toxicities

Intervention	Percentage of participants (Number)
V100+Cis60	0.0
V100+Cis75	33.3
V200+Cis75	0.0
V300+Cis75	33.3
V300+Cis100	0.0
V350+Cis75	0.0
V100+Car4	0.0
V100+Car5	0.0
V200+Car5	0.0
V300+Car5	16.7
V300+Car6	7.7
V350+Car5	0.0

Percentage of participants with dose limiting toxicities (DLTs) during the first treatment cycle. (NCT00969761)
Timeframe: 3 weeks

Percentage of Participants With Serious Adverse Events

Intervention	Percentage of participants (Number)
V100+Cis60	0.0
V100+Cis75	0.0
V200+Cis75	0.0
V300+Cis75	0.0
V300+Cis100	25.0
V350+Cis75	33.3
V100+Car4	0.0
V100+Car5	0.0
V200+Car5	0.0
V300+Car5	16.7
V300+Car6	16.7
V350+Car5	66.7

Percentage of participants with serious adverse events (AEs) (NCT00969761)
Timeframe: From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days

Percentage of Participants With Significant Adverse Events

Intervention	Percentage of participants (Number)
V100+Cis60	66.7
V100+Cis75	33.3
V200+Cis75	0.0
V300+Cis75	33.3
V300+Cis100	50.0
V350+Cis75	50.0
V100+Car4	33.3
V100+Car5	0.0
V200+Car5	33.3
V300+Car5	16.7
V300+Car6	46.2
V350+Car5	66.7

"Percentage of participants with significant adverse events (AEs): dose limiting toxicity (DLT) was defined as significant AE.~DLTs (i.e. significant AEs) per protocol were:~drug related CTCAE grade 3 or 4 non haematological toxicity (except vomiting or diarrhoea responding to supportive treatment and ototoxicity)~drug related CTCAE grade 4 neutropenia for seven or more days and / or complicated by infection~drug related CTCAE Grade 4 thrombocytopenia~drug related febrile neutropenia grade 3 (ANC<1000/mm³ and fever≥ 38.5°C)" (NCT00969761)
Timeframe: From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days

Progression-free Survival

Intervention	Percentage of participants (Number)
V100+Cis60	0.0
V100+Cis75	0.0
V200+Cis75	0.0
V300+Cis75	66.7
V300+Cis100	25.0
V350+Cis75	33.3
V100+Car4	0.0
V100+Car5	0.0
V200+Car5	0.0
V300+Car5	16.7
V300+Car6	15.4
V350+Car5	0.0

Progression-free survival based on RECIST V1.0 criteria was defined as the time from start of treatment to the date of evidence of progressive disease (PD) or death from any cause, whichever occurred first. (NCT00969761)
Timeframe: From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days

Total Plasma Clearance After Intravascular Administration (CL)

Intervention	Days (Median)
V100+Cis60	123.0
V100+Cis75	309.0
V200+Cis75	37.0
V300+Cis75	100.0
V300+Cis100	49.5
V350+Cis75	69.5
V100+Car4	80.0
V100+Car5	64.0
V200+Car5	40.0
V300+Car5	71.0
V300+Car6	43.0
V350+Car5	39.0

Total plasma clearance after intravascular administration (CL) of Volasertib in combination with cisplatin or carboplatin during treatment cycle 1. (NCT00969761)
Timeframe: 1 hour (h) 35 minutes (min) before start of volasertib infusion and 1h, 2h, 8h, 24h, 48h, 168h and 336h after start of volasertib infusion

Worst CTCAE Grade on Treatment for Neutrophils

Intervention	mL/min (Geometric Mean)
V100+Cis60	852
V100+Cis75	1130
V200+Cis75	1090
V300+Cis75	1050
V300+Cis100	971
V350+Cis75	1010
V100+Car4	1110
V100+Car5	812
V200+Car5	881
V300+Car5	808
V300+Car6	974
V350+Car5	546

Worst Common terminology criteria for adverse events (CTCAE) grade on treatment for neutrophils (CTC version 3). The CTCAE scale measures the severity of adverse events which goes from 1 (mild AE) to 5 (death related AE). (NCT00969761)
Timeframe: From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days

Worst CTCAE Grade on Treatment for Platelets

Intervention	Units on a scale (Number)
V100+Cis60	2
V100+Cis75	3
V200+Cis75	0
V300+Cis75	4
V300+Cis100	4
V350+Cis75	4
V100+Car4	3
V100+Car5	3
V200+Car5	2
V300+Car5	4
V300+Car6	4
V350+Car5	4

Worst Common terminology criteria for adverse events (CTCAE) grade on treatment for platelets (CTC version 3). The CTCAE scale measures the severity of adverse events which goes from 1 (mild AE) to 5 (death related AE). (NCT00969761)
Timeframe: From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days

Best Overall Response

Intervention	Units on a scale (Number)
V100+Cis60	1
V100+Cis75	1
V200+Cis75	1
V300+Cis75	2
V300+Cis100	3
V350+Cis75	3
V100+Car4	1
V100+Car5	3
V200+Car5	1
V300+Car5	4
V300+Car6	4
V350+Car5	4

Best overall response was defined as the best response obtained since the start of study treatment until disease progression, determined based on RECIST V1.0 criteria. (NCT00969761)
Timeframe: From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days

Frequency of Participants With Transitions Relative to the Baseline CTC Grade for Neutrophils Based on Last Value on Treatment

Intervention	Percentage of participants (Number)
	Complete response	Partial response	Stable disease	Progressive disease	Non evaluable	No post-baseline tumour assessment
V100+Car4	0.0	0.0	33.3	66.7	0.0	0.0
V100+Car5	0.0	0.0	33.3	66.7	0.0	0.0
V100+Cis60	0.0	0.0	66.7	33.3	0.0	0.0
V100+Cis75	0.0	33.3	66.7	0.0	0.0	0.0
V200+Car5	0.0	0.0	0.0	100.0	0.0	0.0
V200+Cis75	0.0	0.0	33.3	33.3	0.0	33.3
V300+Car5	0.0	16.7	33.3	33.3	16.7	0.0
V300+Car6	0.0	7.7	7.7	61.5	0.0	23.1
V300+Cis100	0.0	0.0	25.0	58.3	0.0	16.7
V300+Cis75	0.0	33.3	33.3	33.3	0.0	0.0
V350+Car5	0.0	0.0	33.3	33.3	0.0	33.3
V350+Cis75	0.0	0.0	33.3	50.0	0.0	16.7

"Percentage of participants with transitions relative to the baseline CTC grade (version 3) for neutrophils based on last value on treatment.~Common terminology criteria for adverse events (CTCAE) grade on treatment for neutrophils (CTC version 3). The CTCAE scale measures the severity of adverse events which goes from 1 (mild AE) to 5 (death related AE)" (NCT00969761)
Timeframe: From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days

Frequency of Participants With Transitions Relative to the Baseline CTC Grade for Neutrophils Based on Worst Value on Treatment

Intervention	Percentage of participants (Number)
	Baseline=0, last value=0	Baseline=0, last value=1	Baseline=0, last value=3	Baseline=1, last value=1	Baseline=0, last value=2	Baseline=0, last value=4	Baseline=1, last value=0
V100+Car4	100.0	0.0	0.0	0.0	0.0	0.0	0.0
V100+Car5	100.0	0.0	0.0	0.0	0.0	0.0	0.0
V100+Cis60	100.0	0.0	0.0	0.0	0.0	0.0	0.0
V100+Cis75	66.7	33.3	0.0	0.0	0.0	0.0	0.0
V200+Car5	100.0	0.0	0.0	0.0	0.0	0.0	0.0
V200+Cis75	100.0	0.0	0.0	0.0	0.0	0.0	0.0
V300+Car5	83.3	0.0	0.0	0.0	16.7	0.0	0.0
V300+Car6	69.2	30.8	0.0	0.0	0.0	0.0	0.0
V300+Cis100	91.7	0.0	8.3	0.0	0.0	0.0	0.0
V300+Cis75	66.7	0.0	0.0	33.3	0.0	0.0	0.0
V350+Car5	100.0	0.0	0.0	0.0	0.0	0.0	0.0
V350+Cis75	66.7	0.0	0.0	0.0	0.0	0.0	33.3

"Percentage of participants with transitions relative to the baseline CTC grade (version 3) for neutrophils based on worst value on treatment.~Worst Common terminology criteria for adverse events (CTCAE) grade on treatment for neutrophils (CTC version 3). The CTCAE scale measures the severity of adverse events which goes from 1 (mild AE) to 5 (death related AE)" (NCT00969761)
Timeframe: From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days

Frequency of Participants With Transitions Relative to the Baseline CTC Grade for Platelets Based on Last Value on Treatment

Intervention	Percentage of participants (Number)
	Baseline=0, worst value=0	Baseline=0, worst value=1	Baseline=0, worst value=2	Baseline=0, worst value=3	Baseline=0, worst value=4	Baseline=1, worst value=3	Baseline=1, worst value=4
V100+Car4	66.7	0.0	0.0	33.3	0.0	0.0	0.0
V100+Car5	66.7	0.0	0.0	33.3	0.0	0.0	0.0
V100+Cis60	33.3	33.3	33.3	0.0	0.0	0.0	0.0
V100+Cis75	0.0	0.0	33.3	66.7	0.0	0.0	0.0
V200+Car5	66.7	0.0	33.3	0.0	0.0	0.0	0.0
V200+Cis75	100.0	0.0	0.0	0.0	0.0	0.0	0.0
V300+Car5	16.7	0.0	16.7	16.7	50.0	0.0	0.0
V300+Car6	7.7	15.4	15.4	53.8	7.7	0.0	0.0
V300+Cis100	16.7	8.3	25.0	16.7	33.3	0.0	0.0
V300+Cis75	0.0	33.3	0.0	0.0	33.3	0.0	33.3
V350+Car5	0.0	0.0	0.0	66.7	33.3	0.0	0.0
V350+Cis75	16.7	33.3	0.0	0.0	16.7	16.7	16.7

"Percentage of participants with transitions relative to the baseline CTC grade (version 3) for platelets based on last value on treatment.~Common terminology criteria for adverse events (CTCAE) grade on treatment for platelets (CTC version 3). The CTCAE scale measures the severity of adverse events which goes from 1 (mild AE) to 5 (death related AE)." (NCT00969761)
Timeframe: From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days

Frequency of Participants With Transitions Relative to the Baseline CTC Grade for Platelets Based on Worst Value on Treatment

Intervention	Percentage of participants (Number)
	Baseline=0, last value=0	Baseline=0, last value=1	Baseline=1, last value=0	Baseline=0, last value=2	Baseline=0, last value=3	Baseline=1, last value=1
V100+Car4	100.0	0.0	0.0	0.0	0.0	0.0
V100+Car5	66.7	33.3	0.0	0.0	0.0	0.0
V100+Cis60	33.3	33.3	33.3	0.0	0.0	0.0
V100+Cis75	66.7	33.3	0.0	0.0	0.0	0.0
V200+Car5	66.7	33.3	0.0	0.0	0.0	0.0
V200+Cis75	100.0	0.0	0.0	0.0	0.0	0.0
V300+Car5	83.3	0.0	0.0	0.0	0.0	16.7
V300+Car6	84.6	7.7	0.0	7.7	0.0	0.0
V300+Cis100	83.3	16.7	0.0	0.0	0.0	0.0
V300+Cis75	100.0	0.0	0.0	0.0	0.0	0.0
V350+Car5	100.0	0.0	0.0	0.0	0.0	0.0
V350+Cis75	100.0	0.0	0.0	0.0	0.0	0.0

"Percentage of participants with transitions relative to the baseline CTC grade (version 3) for platelets based on worst value on treatment.~Worst Common terminology criteria for adverse events (CTCAE) grade on treatment for platelets (CTC version 3). The CTCAE scale measures the severity of adverse events which goes from 1 (mild AE) to 5 (death related AE)." (NCT00969761)
Timeframe: From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days

Incidence and Intensity of Adverse Events According to CTCAE Version 3.0

Intervention	Percentage of participants (Number)
	Baseline=0, worst value=0	Baseline=0, worst value=1	Baseline=0, worst value=2	Baseline=0, worst value=3	Baseline=1, worst value=1	Baseline=0, worst value=4	Baseline=1, worst value=4	Baseline=1, worst value=0
V100+Car4	66.7	33.3	0.0	0.0	0.0	0.0	0.0	0.0
V100+Car5	33.3	33.3	0.0	33.3	0.0	0.0	0.0	0.0
V100+Cis60	33.3	33.3	0.0	0.0	0.0	0.0	0.0	33.3
V100+Cis75	66.7	33.3	0.0	0.0	0.0	0.0	0.0	0.0
V200+Car5	33.3	66.7	0.0	0.0	0.0	0.0	0.0	0.0
V200+Cis75	66.7	33.3	0.0	0.0	0.0	0.0	0.0	0.0
V300+Car5	16.7	0.0	33.3	33.3	0.0	0.0	16.7	0.0
V300+Car6	7.7	15.4	15.4	38.5	0.0	23.1	0.0	0.0
V300+Cis100	25.0	33.3	8.3	33.3	0.0	0.0	0.0	0.0
V300+Cis75	0.0	66.7	33.3	0.0	0.0	0.0	0.0	0.0
V350+Car5	0.0	0.0	33.3	0.0	0.0	66.7	0.0	0.0
V350+Cis75	16.7	0.0	66.7	16.7	0.0	0.0	0.0	0.0

Incidence and intensity of adverse events according to common terminology criteria for adverse events (CTCAE) version 3.0 (NCT00969761)
Timeframe: From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days

Number of Participants With Dose Limiting Toxicities (DLT)

Intervention	Percentage of participants (Number)
	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
V100+Car4	33.3	0.0	66.7	0.0	0.0
V100+Car5	0.0	33.3	66.7	0.0	0.0
V100+Cis60	0.0	0.0	100.0	0.0	0.0
V100+Cis75	0.0	0.0	100.0	0.0	0.0
V200+Car5	0.0	66.7	33.3	0.0	0.0
V200+Cis75	0.0	66.7	33.3	0.0	0.0
V300+Car5	0.0	0.0	50.0	50.0	0.0
V300+Car6	0.0	0.0	61.5	23.1	15.4
V300+Cis100	8.3	8.3	41.7	41.7	0.0
V300+Cis75	0.0	33.3	0.0	66.7	0.0
V350+Car5	0.0	0.0	33.3	66.7	0.0
V350+Cis75	0.0	16.7	50.0	33.3	0.0

MTD was defined on the basis of DLTs occuring during Cycle 1 of the dose escalation part in each of the 2 treatment schedules. DLTs were defined as drug related based on Common Terminology Criteria for AE's (CTCAE) Grade(G) :1) G4 neutropenia (ANC, including bands, <500/mm³) for more than 7 days, 2) G3 or 4 neutropenia associated with fever >38.5° C (febrile neutropenia),3) Neutropenic infection G ≥3, 4) G4 thrombocytopenia or G3 thrombocytopenia associated with bleeding requiring whole blood transfusion.5) Non-haematological G ≥3 toxicity excluding: (a) untreated G3 diarrhoea, (b) untreated G3 nausea and/or vomiting, (c) untreated G3 rash. 6) G2 increase in AST and/or ALT in conjunction with an elevated bilirubin level of G ≥2, 7) G2 nausea and/or vomiting despite optimal supportive/antiemetic treatment for at least 7consecutive days. 8) G2 diarrhoea for 2 or more consecutive days despite antidiarrhoeal medication/hydration, 9) Decrease in left ventricular function G ≥2. (NCT01206816)
Timeframe: 22 Days

Number of Patients With Drug-related Adverse Events According to Common Terminology Criteria for Adverse Events (CTCAE) Criteria v 3.0

Intervention	participants (Number)
Volasertib150 mg+Afatinib 30 mg (Schedule A)	0
Volasertib 225 mg+Afatinib 30 mg (Schedule A)	0
Volasertib 300 mg+Afatinib 30 mg (Schedule A)	3
Volasertib 300 mg+Afatinib 40 mg (Schedule A)	2
Volasertib 300 mg+Afatinib 50 mg (Schedule B)	0
Volasertib 300 mg+Afatinib 70 mg (Schedule B)	5
Volasertib 300 mg+Afatinib 90 mg (Schedule B)	2

Number of patients with investigator defined drug-related adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) criteria v 3.0 (NCT01206816)
Timeframe: After the first drug administration until 28 days after the last drug administration, up to 413 days.

Maximum Tolerable Dose (MTD) of Two Combination Therapy of Volasertib and Afatinib.

Intervention	participants (Number)
Volasertib150 mg+Afatinib 30 mg (Schedule A)	3
Volasertib 225 mg+Afatinib 30 mg (Schedule A)	3
Volasertib 300 mg+Afatinib 30 mg (Schedule A)	18
Volasertib 300 mg+Afatinib 40 mg (Schedule A)	3
Volasertib 300 mg+Afatinib 50 mg (Schedule B)	3
Volasertib 300 mg+Afatinib 70 mg (Schedule B)	19
Volasertib 300 mg+Afatinib 90 mg (Schedule B)	6

"Maximum Tolerable Dose (MTD) was determined by dose escalation for volasertib and afatinib. The 3 + 3 design with de-escalation for both the Schedules A and B. Patients were sequentially allocated to the dose cohorts. Apart from allocation to the treatment schedules, escalation and/or de-escalation to determine the MTD occurred independently within the 2 dose schedules. Cohorts of 3 patients were to be treated at the starting dose levels according to the treatment schedule. Before entering patients at a higher dose level, all patients at the previous dose level combination had to complete at least the initial cycle of 21 days." (NCT01206816)
Timeframe: MTD was assessed during the first cycle of combination of Volasertib and Afatinib therapy (22 days)

Number of Patients With Best Overall Response.

Intervention	mg (Number)
	Volasertib	Afatinib
Volasertib in Combination With Afatinib (Schedule A)	300	30
Volasertib in Combination With Afatinib (Schedule B)	300	70

"Best overall response based on response evaluation criteria in solid tumors (RECIST) version 1.1. Best overall response is defined as complete response, partial response, stable disease, progressive disease or not evaluable.~As Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by using appropriate radiology techniques: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; progression, 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; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression." (NCT01206816)
Timeframe: Tumor assessment was performed at screening and at the end of every 3 treatment cycle (ie every 9 weeks of treatment).

Number of Patients With Disease Control

Intervention	participants (Number)
	Complete response	Partial response	Stable disease	Progressive disease	Not evaluable	Unknown
Volasertib 225 mg+Afatinib 30 mg (Schedule A)	0	0	0	3	0	0
Volasertib 300 mg+Afatinib 30 mg (Schedule A)	0	1	8	8	1	2
Volasertib 300 mg+Afatinib 40 mg (Schedule A)	0	0	0	3	0	0
Volasertib 300 mg+Afatinib 50 mg (Schedule B)	0	0	1	2	0	0
Volasertib 300 mg+Afatinib 70 mg (Schedule B)	0	0	5	10	0	4
Volasertib 300 mg+Afatinib 90 mg (Schedule B)	0	0	2	4	0	0
Volasertib150 mg+Afatinib 30 mg (Schedule A)	0	1	0	2	0	0

"Disease control based on response evaluation criteria in solid tumors (RECIST) version 1.1. Patients who had a best overall tumour response of complete response (CR), partial response (PR) or stable disease (SD) were assessed to show disease control.~As Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by using appropriate radiology techniques: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression." (NCT01206816)
Timeframe: Tumor assessment was performed at screening and at the end of every 3 treatment cycle (ie every 9 weeks of treatment).

Number of Patients With Objective Response (OR)

Intervention	participants (Number)
	YES	NO	Unknown
Volasertib 225 mg+Afatinib 30 mg (Schedule A)	0	3	0
Volasertib 300 mg+Afatinib 30 mg (Schedule A)	9	9	2
Volasertib 300 mg+Afatinib 40 mg (Schedule A)	0	3	0
Volasertib 300 mg+Afatinib 50 mg (Schedule B)	1	2	0
Volasertib 300 mg+Afatinib 70 mg (Schedule B)	5	10	4
Volasertib 300 mg+Afatinib 90 mg (Schedule B)	2	4	0
Volasertib150 mg+Afatinib 30 mg (Schedule A)	1	2	0

"Objective tumor response based on response evaluation criteria in solid tumors (RECIST) version 1.1. OR is defined as complete response (CR) or partial response (PR).~As Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by using appropriate radiology techniques: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions." (NCT01206816)
Timeframe: Tumor assessment was performed at screening and at the end of every 3 treatment cycle (ie every 9 weeks of treatment).

Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-infinity) of Volasertib (BI 6727)

Intervention	participants (Number)
	Yes	No	Unknown
Volasertib 225 mg+Afatinib 30 mg (Schedule A)	0	3	0
Volasertib 300 mg+Afatinib 30 mg (Schedule A)	1	17	2
Volasertib 300 mg+Afatinib 40 mg (Schedule A)	0	3	0
Volasertib 300 mg+Afatinib 50 mg (Schedule B)	0	3	0
Volasertib 300 mg+Afatinib 70 mg (Schedule B)	0	15	4
Volasertib 300 mg+Afatinib 90 mg (Schedule B)	0	6	0
Volasertib150 mg+Afatinib 30 mg (Schedule A)	1	2	0

Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-infinity) of Volasertib (BI 6727). (NCT01348347)
Timeframe: PK plasma samples were taken at: 5 minutes predose, 1hour, 2hours (h), 3h, 4h, 8h, 24h, 48h, 72h, 96h, 168h and 336h of course1.

Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 up to the Last Quantifiable Data Point (AUC0-tz) of Volasertib (BI 6727)

Intervention	ng*h/mL (Geometric Mean)
Volasertib 200 mg Cohort	4350
Volasertib 300 mg Cohort	5300
Volasertib 350 mg Cohort	7260

Area under the concentration-time curve of the analyte in plasma over the time interval from 0 up to the last quantifiable data point (AUC0-tz) of Volasertib (BI 6727). (NCT01348347)
Timeframe: PK plasma samples were taken at: 5 minutes predose, 1hour, 2hours (h), 3h, 4h, 8h, 24h, 48h, 72h, 96h, 168h and 336h of course1.

Cmax of Volasertib (BI 6727)

Intervention	ng*h/mL (Geometric Mean)
Volasertib 200 mg Cohort	4000
Volasertib 300 mg Cohort	5100
Volasertib 350 mg Cohort	6900

Maximum concentration of an analyte in plasma (NCT01348347)
Timeframe: Pharmacokinetic (PK) plasma samples were taken at: 5 minutes predose, 1hour, 2hours (h), 3h, 4h, 8h, 24h, 48h, 72h, 96h, 168h and 336h of course1.

Maximum Tolerated Dose (MTD) of Volasertib

Intervention	ng/mL (Geometric Mean)
Volasertib 200 mg Cohort	398
Volasertib 300 mg Cohort	501
Volasertib 350 mg Cohort	615

Maximum tolerated dose (MTD) of volasertib was the highest dose tested at which DLT was developed in not more than 1 of 6 patients in the course 1. (NCT01348347)
Timeframe: 21 days

Number of Participants With Dose Limiting Toxicities (DLTs) in Process for the Determination of the Maximum Tolerated Dose (MTD).

Intervention	mg (Number)
Volasertib Cohort	300

"The following drug-related adverse events (AE) were defined as DLT;~Haematological toxicities: CTCAE(Common Terminology Criteria for Adverse Events) grade 4 neutropenia persisted for 7 or more days, CTCAE grade 4 thrombocytopenia or CTCAE grade 3 thrombocytopenia requiring blood transfusion.~Non-haematological toxicities: CTCAE grade ≥3 non-haematological toxicities. The following toxicity with neutropenia was defined as DLT.- CTCAE grade 3 febrile neutropenia persisted for over 2 days, Clinically significant laboratory abnormalities of CTCAE grade ≥3 persisted for over 3 days. The following laboratory abnormalities should be defined as DLT. - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT): >5.0 × ULN persisted for 7 days or longer - Creatinine: >3.0 × upper limit of normal(ULN) (if the creatinine abnormality was observed even once) - Persistent electrolyte abnormality assessed by the investigator." (NCT01348347)
Timeframe: 21 days

Disease Control Rate According to RECIST v1.1

Intervention	Participants (Number)
Volasertib 200 mg Cohort	0
Volasertib 300 mg Cohort	0
Volasertib 350 mg Cohort	2

Disease control rate according to RECIST v1.1 - Unconfirmed disease control. The patients with complete response (CR), partial response (PR) or stable disease (SD). (NCT01348347)
Timeframe: 6 months

Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1

Intervention	Participants (Number)
	No	Yes
Volasertib 200 mg Cohort	0	3
Volasertib 300 mg Cohort	1	5
Volasertib 350 mg Cohort	2	4

Objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1: Unconfirmed objective response. The patients with complete response (CR) or partial response (PR). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by magnetic resonance imaging (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. (NCT01348347)
Timeframe: 6 months

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Phase I dose escalation and pharmacokinetic study of BI 2536, a novel Polo-like kinase 1 inhibitor, in patients with advanced solid tumors. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2008, Dec-01, Volume: 26, Issue:34 Topics: Adult; Aged; Antineoplastic Agents; Cell Cycle Proteins; Dose-Response Relationship, Drug; Enzyme In	2008
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pteridines and Benign Neoplasms