| Trial | Phase | Enrollment | Study Type | Start Date | Status |
|---|
| A Randomized Open-Label, Phase 3 Study to Evaluate Imetelstat (GRN163L) Versus Best Available Therapy (BAT) in Patients With Intermediate-2 or High-risk Myelofibrosis (MF) Relapsed / Refractory (R/R) to Janus Kinase (JAK) Inhibitor [NCT04576156] | Phase 3 | 320 participants (Anticipated) | Interventional | 2021-04-12 | Recruiting |
| A Phase II Clinical and Biologic Study of AMG 706 and Octreotide in Patients With Low-Grade Neuroendocrine Tumors [NCT00427349] | Phase 2 | 46 participants (Actual) | Interventional | 2008-11-07 | Completed |
| An Open-Label, Dose-Finding Study to Evaluate the Safety of AMG 706 Plus Panitumumab Plus Gemcitabine-Cisplatin in the Treatment of Subjects With Advanced Cancer [NCT00101907] | Phase 1 | 41 participants (Actual) | Interventional | 2004-12-31 | Terminated(stopped due to Study terminated per recommendation of Data Review Team) |
| A Phase 3, Multicenter, Randomized, Placebo-Controlled, Double-Blind Trial of AMG 706 in Combination With Paclitaxel and Carboplatin for Advanced Non-small Cell Lung Cancer. [NCT00460317] | Phase 3 | 1,450 participants (Actual) | Interventional | 2007-07-31 | Terminated(stopped due to Amgen discontinued the development of AMG706 because 20050201 did not meet its primary objective.) |
| An Open Label Treatment Extension Study of AMG 706 [NCT00360867] | Phase 2 | 94 participants (Actual) | Interventional | 2005-12-31 | Terminated(stopped due to Amgen decision) |
| A Randomized Phase II Study Of Imetelstat (GRN163L) In Combination With Paclitaxel (With Or Without Bevacizumab) in Patients With Locally Recurrent Or Metastatic Breast Cancer [NCT01256762] | Phase 2 | 166 participants (Actual) | Interventional | 2010-11-30 | Completed |
| A Randomized Phase II Study of Imetelstat as Maintenance Therapy After Initial Induction Chemotherapy for Advance Non-small Cell Lung Cancer(NSCLC) [NCT01137968] | Phase 2 | 116 participants (Actual) | Interventional | 2010-05-31 | 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 |
| An Open-label, Dose-finding Study to Evaluate the Safety and Pharmacokinetics (PK) of AMG 706 With Carboplatin/Paclitaxel, AMG 706 With Panitumumab and AMG 706 With Panitumumab and Carboplatin/Paclitaxel in the Treatment of Subjects With Advanced Non-Smal [NCT00094835] | Phase 1/Phase 2 | 51 participants (Actual) | Interventional | 2005-01-31 | Completed |
| A Phase 2, Multicenter, Open Label, Randomized Trial of AMG 706 or Bevacizumab in Combination With Paclitaxel and Carboplatin for Advanced Non-squamous Non-small Cell Lung Cancer [NCT00369070] | Phase 2 | 186 participants (Actual) | Interventional | 2007-01-31 | Terminated |
| Phase I/II Trial of Motesanib in Combination With Ixabepilone and Capecitabine in Women With Locally Recurrent or Metastatic Breast Cancer [NCT01349088] | Phase 1/Phase 2 | 0 participants (Actual) | Interventional | 2013-12-31 | Withdrawn |
| A Phase II Evaluation of AMG 706 (IND # 79,697) in the Treatment of Persistent or Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer [NCT00574951] | Phase 2 | 23 participants (Actual) | Interventional | 2007-12-31 | Terminated(stopped due to Study was stopped for severe toxicity causing concern for patients) |
| A Randomized, Single-Blind, Multicenter Phase 2 Study to Evaluate the Activity of 2 Dose Levels of Imetelstat in Subjects With Intermediate-2 or High-Risk Myelofibrosis (MF) Relapsed/Refractory to Janus Kinase (JAK) Inhibitor [NCT02426086] | Phase 2 | 107 participants (Actual) | Interventional | 2015-08-28 | Completed |
| A Phase I Study of GRN163L in Combination With Bortezomib and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma [NCT00718601] | Phase 1 | 40 participants (Anticipated) | Interventional | 2008-07-31 | Completed |
| A Global Phase 3, Randomized, Placebo Controlled, Double-Blind Trial of AMG 706 in Combination With Paclitaxel and Carboplatin for Advanced Non-Squamous Non-Small Cell Lung Cancer (Asian Phase 3 Study) [NCT02629848] | Phase 3 | 401 participants (Actual) | Interventional | 2012-07-31 | Terminated(stopped due to Sponsor decision to terminate the study because the study did not meet the primary endpoint.) |
| An Open-Label, Dose Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of AMG 386 With AMG 706, AMG 386 With Bevacizumab, AMG 386 With Sorafenib, and AMG 386 With Sunitinib in Adult Patients With Advanced Solid Tumors [NCT00861419] | Phase 1 | 88 participants (Anticipated) | Interventional | 2005-12-31 | Completed |
| An Open-label, Single Dose Study of the Mass Balance and Metabolic Disposition of Orally Administered [14C]-Labelled AMG 706 (Motesanib) Followed by Extended Treatment With Motesanib in Patients With Advanced Solid Tumors [NCT01386866] | Phase 1 | 4 participants (Actual) | Interventional | 2009-05-31 | Completed |
| A Pilot Study of Imetelstat Given Intravenously on Day 1 and 8 of a 21 Day Schedule Alone and With Standard 13-Cis-Retinoic Acid in Children With Recurrent and/or Refractory Neuroblastoma [NCT01916187] | Phase 1 | 0 participants (Actual) | Interventional | 2013-07-30 | Withdrawn(stopped due to drug company withdrew support following re-examination of benefit-risk assessment for the investigational use of imetelstat in this population) |
| A Phase II Study of Imetelstat (GRN163L, NSC# 754228) in Children With Relapsed or Refractory Solid Tumors [NCT02011126] | Phase 2 | 0 participants (Actual) | Interventional | 2014-06-30 | Withdrawn(stopped due to IND no longer available.) |
| A Phase 1 Sequential Cohort, Dose Escalation Trial to Determine the Safety, Tolerability, and Maximum Tolerated Dose of GRN163L in Patients With Refractory or Relapsed Multiple Myeloma [NCT00594126] | Phase 1 | 20 participants (Actual) | Interventional | 2007-11-30 | Completed |
| A Phase I Study of GRN163L in Combination With Paclitaxel and Carboplatin in Patients With Advanced or Metastatic Non-Small Cell Lung Cancer [NCT00510445] | Phase 1 | 27 participants (Actual) | Interventional | 2007-07-31 | Completed |
| A Phase II Trial to Evaluate the Activity of Imetelstat (GRN163L) in Patients With Essential Thrombocythemia or Polycythemia Vera Who Require Cytoreduction and Have Failed or Are Intolerant to Previous Therapy, or Who Refuse Standard Therapy [NCT01243073] | Phase 2 | 20 participants (Actual) | Interventional | 2010-12-31 | Completed |
| A Phase II Trial to Determine the Effect of Imetelstat (GRN163L) on Patients With Previously Treated Multiple Myeloma [NCT01242930] | Phase 2 | 13 participants (Actual) | Interventional | 2010-11-30 | Completed |
| 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 |
| An Open Label Study of AMG 706 in Subjects With Advanced Gastrointestinal Stromal Tumors (GISTs) Who Developed Progressive Disease or Relapsed While on Imatinib Mesylate [NCT00089960] | Phase 2 | 138 participants (Actual) | Interventional | 2004-10-31 | Completed |
| An Open-Label, Dose-Finding Study to Evaluate the Safety of AMG 706 Plus Panitumumab Plus Chemotherapy in the Treatment of Subjects With Metastatic Colorectal Cancer [NCT00101894] | Phase 1 | 119 participants (Actual) | Interventional | 2004-12-31 | 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 2, Open-label Study of AMG 706 to Treat Subjects With Locally Advanced or Metastatic Thyroid Cancer [NCT00121628] | Phase 2 | 184 participants (Actual) | Interventional | 2005-07-31 | Completed |
| Expanded Access Treatment With Imetelstat For Adult Participants With Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes (MDS) Who Are Transfusion-Dependent And Have Failed to Respond or Have Lost Response or Are Ineligible For Erythropoiesis-S [NCT05937568] | | 0 participants | Expanded Access | | Available |
| An Open-label Phase 2 Study of AMG 706 in Japanese Subjects With Advanced Gastrointestinal Stromal Tumors (GISTs) Who Developed Progressive Disease or Relapsed While on Imatinib Mesylate [NCT00254267] | Phase 2 | 35 participants (Actual) | Interventional | 2005-11-30 | Completed |
| A Phase Ib, Open-Label, Sequential, Dose-Finding, Study of AMG 706 in Combination With Gemcitabine to Treat Subjects With Solid Tumors [NCT00324597] | Phase 1 | 18 participants (Anticipated) | Interventional | 2005-10-31 | Active, not recruiting |
| A Phase I, Sequential Cohort, Dose Escalation Trial to Determine the Safety, Tolerability, and MTD of GRN163L in Patients With Refractory or Relapsed Solid Tumor Malignancies [NCT00310895] | Phase 1 | 85 participants (Anticipated) | Interventional | 2006-03-31 | Completed |
| An Open Label, Phase 1/1b Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of Imetelstat in Combination With Ruxolitinib in Patients With Myelofibrosis [NCT05371964] | Phase 1 | 41 participants (Anticipated) | Interventional | 2022-05-04 | Recruiting |
| A Randomized Phase 2 Trial of Double-Blind, Placebo Controlled AMG 706 in Combination With Paclitaxel, or Open-Label Bevacizumab in Combination With Paclitaxel, as First Line Therapy in Women With HER2 Negative Locally Recurrent or Metastatic Breast Cance [NCT00356681] | Phase 2 | 282 participants (Actual) | Interventional | 2006-12-31 | Terminated(stopped due to Sponsor decision to close study) |
| A Phase 1 Study of Imetelstat, a Telomerase Inhibitor, in Children With Refractory or Recurrent Solid Tumors and Lymphomas [NCT01568632] | Phase 1 | 0 participants (Actual) | Interventional | 2012-03-31 | Withdrawn |
| An Open-label, Dose-finding Study to Evaluate the Safety of AMG 706 in Combination With Paclitaxel or Docetaxel as Treatment for Locally Recurrent or Metastatic Breast Cancer [NCT00322400] | Phase 1 | 46 participants (Actual) | Interventional | 2006-03-31 | Completed |
| A Phase II Study Evaluating the Efficacy and Safety of Imetelstat in Patients With HR Myelodysplastic Syndromes or AML Failing HMA-based Therapy [NCT05583552] | Phase 2 | 46 participants (Anticipated) | Interventional | 2023-06-05 | Recruiting |
| A Pilot Open-Label Study of the Efficacy and Safety of Imetelstat (GRN163L) in Myelofibrosis and Other Myeloid Malignancies [NCT01731951] | Phase 2 | 80 participants (Actual) | Interventional | 2012-10-29 | Completed |
| A Phase 1 Study of Imetelstat, a Telomerase Inhibitor, in Children With Refractory or Recurrent Solid Tumors and Lymphomas [NCT01273090] | Phase 1 | 34 participants (Actual) | Interventional | 2011-05-31 | Completed |
| A Study to Evaluate Imetelstat (GRN163L) in Transfusion-Dependent Subjects With IPSS Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS) That is Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Treatment [NCT02598661] | Phase 2/Phase 3 | 289 participants (Actual) | Interventional | 2015-11-24 | Active, not recruiting |
| A Molecular Biology and Phase II Study of Imetelstat (GRN163L) in Children With Recurrent High-Grade Glioma, Ependymoma and Diffuse Intrinsic Pontine Glioma [NCT01836549] | Phase 2 | 43 participants (Actual) | Interventional | 2013-03-31 | Terminated(stopped due to Due to several intracranial hemorrhages and recommendation by the PBTC DSMB.) |
| [information is prepared from clinicaltrials.gov, extracted Sep-2024] |
Maximum Observed Plasma Concentration of Motesanib (Cmax) in Cycle 2
The maximal observed plasma concentration of motesanib in Cycle 2, after multiple doses. For the 75 mg BID cohorts, Cmax is reported for the first daily dose. (NCT00094835)
Timeframe: Cycle 2, Day 1 at predose, 15 and 30 min, and at 1, 2, 4, 6, 10 (QD cohorts only), and 24 hours post-dose.
| Intervention | ng/mL (Mean) |
|---|
| Paclitaxel/Carboplatin + Motesanib 50 mg QD | 148 |
| Paclitaxel/Carboplatin + Motesanib 125 mg QD | 748 |
| Paclitaxel/Carboplatin + Motesanib 75 mg BID | 390 |
| Panitumumab + Motesanib 50 mg QD | 265 |
| Panitumumab + Motesanib 125 mg QD | 672 |
| Panitumumab + Motesanib 75 mg BID | 242 |
| Panitumumab + Paclitaxel/Carboplatin + Motesanib 125 mg QD | 651 |
Area Under the Plasma Concentration-time Curve for Motesanib in Cycle 1
Area under the plasma concentration-time curve for motesanib in Cycle 1 calculated using the using the linear/log trapezoidal method. AUC from time zero to infinity (AUC0-inf) is reported for the 50 and 125 mg QD cohorts and AUC from time 0 to 24 hours post-dose (AUC0-24) is reported for the 75 mg BID cohort, where AUC0-24 is the sum of AUC0-12 for the first and second daily dose. (NCT00094835)
Timeframe: Cycle 1, Day 3 at predose, 15 and 30 minutes, and at 1, 2, 4, 6, 10 (QD cohorts only), and 24 hours post-dose.
| Intervention | μg*hr/mL (Mean) |
|---|
| Paclitaxel/Carboplatin + Motesanib 50 mg QD | 0.971 |
| Paclitaxel/Carboplatin + Motesanib 125 mg QD | 3.21 |
| Paclitaxel/Carboplatin + Motesanib 75 mg BID | 2.91 |
| Panitumumab + Motesanib 50 mg QD | 1.74 |
| Panitumumab + Motesanib 125 mg QD | 3.23 |
| Panitumumab + Motesanib 75 mg BID | 2.04 |
Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose for Motesanib in Cycle 2
Area under the plasma concentration-time curve from time 0 to 24 hours post-dose (AUC0-24) for motesanib in Cycle 2 calculated using the using the linear/log trapezoidal method. For the 75 mg BID cohort AUC0-24 is the sum of AUC0-12 for the first and second daily dose. (NCT00094835)
Timeframe: Cycle 2, Day 1 at predose, 15 and 30 minutes, and at 1, 2, 4, 6, 10 (QD cohorts only), and 24 hours post-dose.
| Intervention | μg*hr/mL (Mean) |
|---|
| Paclitaxel/Carboplatin + Motesanib 125 mg QD | 4.50 |
| Paclitaxel/Carboplatin + Motesanib 75 mg BID | 3.11 |
| Panitumumab + Motesanib 50 mg QD | 1.26 |
| Panitumumab + Motesanib 125 mg QD | 3.92 |
| Panitumumab + Paclitaxel/Carboplatin + Motesanib 125 mg QD | 3.16 |
Estimated Terminal-phase Half-life (t1/2,z) of Motesanib in Cycle 1
The terminal-phase elimination half-life (t1/2,z) of motesanib was calculated as ln(2)/λz. The terminal elimination rate constant (λz) was determined by linear regression of the natural logarithms of at least the last 3 measurable concentrations during the terminal phase. For the 75 mg BID cohorts, t1/2,z is reported for the first daily dose. (NCT00094835)
Timeframe: Cycle 1, Day 3 at predose, 15 and 30 min, and at 1, 2, 4, 6, 10 (QD cohorts only), and 24 hours postdose.
| Intervention | hours (Mean) |
|---|
| Paclitaxel/Carboplatin + Motesanib 50 mg QD | 7.34 |
| Paclitaxel/Carboplatin + Motesanib 125 mg QD | 5.33 |
| Paclitaxel/Carboplatin + Motesanib 75 mg BID | 5.77 |
| Panitumumab + Motesanib 50 mg QD | 6.47 |
| Panitumumab + Motesanib 125 mg QD | 7.57 |
| Panitumumab + Motesanib 75 mg BID | 8.28 |
Estimated Terminal-phase Half-life (t1/2,z) of Motesanib in Cycle 2
The terminal-phase elimination half-life (t1/2,z) of motesanib was calculated as ln(2)/λz. The terminal elimination rate constant (λz) was determined by linear regression of the natural logarithms of at least the last 3 measurable concentrations during the terminal phase. For the 75 mg BID cohorts, t1/2,z is reported for the first daily dose. (NCT00094835)
Timeframe: Cycle 2, Day 1 at predose, 15 and 30 min, and at 1, 2, 4, 6, 10 (QD cohorts only), and 24 hours post-dose.
| Intervention | hours (Mean) |
|---|
| Paclitaxel/Carboplatin + Motesanib 125 mg QD | 6.41 |
| Paclitaxel/Carboplatin + Motesanib 75 mg BID | 6.36 |
| Panitumumab + Motesanib 50 mg QD | 7.08 |
| Panitumumab + Motesanib 125 mg QD | 4.90 |
Maximum Observed Plasma Concentration of Motesanib (Cmax) in Cycle 1
The maximal observed plasma concentration of motesanib after a single dose dose in Cycle 1. For the 75 mg BID cohorts, Cmax is reported for the first daily dose. (NCT00094835)
Timeframe: Cycle 1, Day 3 at predose, 15 and 30 min, and at 1, 2, 4, 6, 10 (QD cohorts only), and 24 hours post-dose.
| Intervention | ng/mL (Mean) |
|---|
| Paclitaxel/Carboplatin + Motesanib 50 mg QD | 158 |
| Paclitaxel/Carboplatin + Motesanib 125 mg QD | 525 |
| Paclitaxel/Carboplatin + Motesanib 75 mg BID | 448 |
| Panitumumab + Motesanib 50 mg QD | 328 |
| Panitumumab + Motesanib 125 mg QD | 444 |
| Panitumumab + Motesanib 75 mg BID | 198 |
| Panitumumab + Paclitaxel/Carboplatin + Motesanib 125 mg QD | 360 |
Percentage of Participants With an Overall Objective Response
Confirmed objective tumor response defined as a complete response (CR) or partial response (PR) using modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. Tumor response was evaluated by computed tomography (CT) scan or magnetic resonance imaging (MRI). Responding disease (CR or PR) was confirmed no less than 4 weeks after the criteria for response were first met. A complete response defined as the disappearance of all target lesions and all non-target lesions, no new lesions and normalization of tumor marker level. Partial response defined as either the disappearance of all target lesions and the persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits, or, at least a 30% decrease in the sum of the longest diamer (LD) of target lesions, taking as reference the baseline sum LD and no new lesions and/or unequivocal progression of existing non-target lesions. (NCT00094835)
Timeframe: After 9 weeks of treatment (at the end of Cycle 3)
| Intervention | Percentage of participants (Number) |
|---|
| Paclitaxel/Carboplatin + Motesanib 50 mg QD | 33 |
| Paclitaxel/Carboplatin + Motesanib 125 mg QD | 18 |
| Paclitaxel/Carboplatin + Motesanib 75 mg BID | 0 |
| Panitumumab + Motesanib 50 mg QD | 0 |
| Panitumumab + Motesanib 125 mg QD | 0 |
| Panitumumab + Motesanib 75 mg BID | 0 |
| Panitumumab + Paclitaxel/Carboplatin + Motesanib 125 mg QD | 17 |
Time to Maximum Plasma Concentration of Motesanib (Tmax) for Cycle 1
The time after dosing that the maximal plasma concentration of motesanib was observed in Cycle 1. For the 75 mg BID cohorts, Tmax is reported for the first daily dose. (NCT00094835)
Timeframe: Cycle 1, Day 3 at predose, 15 and 30 minutes, and at 1, 2, 4, 6, 10 (QD cohorts only), and 24 hours post-dose.
| Intervention | hours (Median) |
|---|
| Paclitaxel/Carboplatin + Motesanib 50 mg QD | 0.75 |
| Paclitaxel/Carboplatin + Motesanib 125 mg QD | 1.0 |
| Paclitaxel/Carboplatin + Motesanib 75 mg BID | 0.75 |
| Panitumumab + Motesanib 50 mg QD | 1.5 |
| Panitumumab + Motesanib 125 mg QD | 1.0 |
| Panitumumab + Motesanib 75 mg BID | 0.58 |
| Panitumumab + Paclitaxel/Carboplatin + Motesanib 125 mg QD | 1.0 |
Time to Maximum Plasma Concentration of Motesanib (Tmax) in Cycle 2
The time after dosing that the maximal plasma concentration of motesanib was observed in Cycle 2. For the 75 mg BID cohorts, Tmax is reported for the first daily dose. (NCT00094835)
Timeframe: Cycle 2, Day 1 at predose, 15 and 30 min, and at 1, 2, 4, 6, 10 (QD cohorts only), and 24 hours post-dose.
| Intervention | hours (Median) |
|---|
| Paclitaxel/Carboplatin + Motesanib 50 mg QD | 1.5 |
| Paclitaxel/Carboplatin + Motesanib 125 mg QD | 1.0 |
| Paclitaxel/Carboplatin + Motesanib 75 mg BID | 0.63 |
| Panitumumab + Motesanib 50 mg QD | 1.0 |
| Panitumumab + Motesanib 125 mg QD | 0.75 |
| Panitumumab + Motesanib 75 mg BID | 1.0 |
| Panitumumab + Paclitaxel/Carboplatin + Motesanib 125 mg QD | 2.0 |
Trough Plasma Concentration at 24 Hours Post-dose (C24) for Motesanib in Cycle 1
The trough plasma concentration for motesanib at 24 hours postdose in Cycle 1. For the 75 BID cohort, C24 is the observed concentration at 24 hours (ie, after the second daily dose). (NCT00094835)
Timeframe: Cycle 1, Day 3, 24 hours post-dose
| Intervention | ng/mL (Mean) |
|---|
| Paclitaxel/Carboplatin + Motesanib 50 mg QD | 9.12 |
| Paclitaxel/Carboplatin + Motesanib 125 mg QD | 26.5 |
| Paclitaxel/Carboplatin + Motesanib 75 mg BID | 56.7 |
| Panitumumab + Motesanib 50 mg QD | 14.0 |
| Panitumumab + Motesanib 125 mg QD | 32.5 |
| Panitumumab + Motesanib 75 mg BID | 56.8 |
Trough Plasma Concentration at 24 Hours Post-dose (C24) for Motesanib in Cycle 2
The trough plasma concentration for motesanib at 24 hours postdose in Cycle 2. For the 75 BID cohort, C24 is the observed concentration at 24 hours (ie, after the second daily dose). (NCT00094835)
Timeframe: Cycle 2, Day 1, 24 hours post-dose
| Intervention | ng/mL (Mean) |
|---|
| Paclitaxel/Carboplatin + Motesanib 125 mg QD | 43.4 |
| Paclitaxel/Carboplatin + Motesanib 75 mg BID | 45.4 |
| Panitumumab + Motesanib 50 mg QD | 10.4 |
| Panitumumab + Motesanib 125 mg QD | 61.1 |
| Panitumumab + Paclitaxel/Carboplatin + Motesanib 125 mg QD | 45.1 |
AUC0-24
Area under the plasma concentration-time curve from time 0 to 24 hours postdose (AUC0-24) with AMG 706. AUC0-24 was estimated using the linear/log trapezoidal method. For the BID cohort, AUC0 24 was estimated as 2 times the AUC from time 0 to 12 hours post the first daily dose (AUC0-12) using the linear/log trapezoidal method. (NCT00101907)
Timeframe: Day 1, pre-dose and at 1, 3, 6,12 (BID cohort only) and 24 hours post-dose.
| Intervention | μg*hr/mL (Mean) |
|---|
| 50 mg QD AMG 706 + Panitumumab + Gem/Cis | 1.03 |
| 75 mg QD AMG 706 + Panitumumab + Gem/Cis | 1.31 |
| 100 mg QD AMG 706 + Panitumumab + Gem/Cis | 2.38 |
| 125 mg QD AMG 706 + Panitumumab + Gem/Cis | 2.82 |
| 75 mg BID AMG 706 + Panitumumab + Gem/Cis | 2.54 |
AUC0-inf
Area under the concentration-time curve from time 0 to infinite time (AUC0-inf) postdose with AMG 706. AUC0-inf was estimated using the linear/log trapezoidal method. AUC0-inf was not calculated for the BID cohort. (NCT00101907)
Timeframe: Day 1, pre-dose and at 1, 3, 6,12 (BID cohort only) and 24 hours post-dose.
| Intervention | μg*hr/mL (Mean) |
|---|
| 50 mg QD AMG 706 + Panitumumab + Gem/Cis | 1.12 |
| 75 mg QD AMG 706 + Panitumumab + Gem/Cis | 1.64 |
| 100 mg QD AMG 706 + Panitumumab + Gem/Cis | 2.59 |
| 125 mg QD AMG 706 + Panitumumab + Gem/Cis | 3.05 |
Cmax
The maximum observed plasma concentration after AMG 706 dosing (NCT00101907)
Timeframe: Day 1, pre-dose and at 1, 3, 6,12 (BID cohort only) and 24 hours post-dose.
| Intervention | ng/mL (Mean) |
|---|
| 50 mg QD AMG 706 + Panitumumab + Gem/Cis | 152 |
| 75 mg QD AMG 706 + Panitumumab + Gem/Cis | 186 |
| 100 mg QD AMG 706 + Panitumumab + Gem/Cis | 278 |
| 125 mg QD AMG 706 + Panitumumab + Gem/Cis | 458 |
| 75 mg BID AMG 706 + Panitumumab + Gem/Cis | 268 |
Number of Participants With an Objective Tumor Response
The number of participants with a confirmed objective tumor response, defined as a complete response (CR) or partial response (PR) throughout based on modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Any CR or PR was to be confirmed 4 to 6 weeks after the initial CR or PR. (NCT00101907)
Timeframe: From enrollment until date of last follow-up visit. The median follow-up time was 24 weeks, with a range of 3 to 73 weeks.
| Intervention | participants (Number) |
|---|
| Panitumumab + Gem/Cis | 2 |
| 50 mg QD AMG 706 + Panitumumab + Gem/Cis | 0 |
| 75 mg QD AMG 706 + Panitumumab + Gem/Cis | 1 |
| 100 mg QD AMG 706 + Panitumumab + Gem/Cis | 4 |
| 125 mg QD AMG 706 + Panitumumab + Gem/Cis | 2 |
| 75 mg BID AMG 706 + Panitumumab + Gem/Cis | 1 |
Participant Incidence of Adverse Events
The number of participants who experienced at least one treatment-emergent adverse event. Additional details regarding specfic adverse events are provided in the Adverse Event section of this posting. (NCT00101907)
Timeframe: From the first dose of any study treatment until 30 days after the last dose of study treatment, up to a maximum of 509 days.
| Intervention | Participants (Number) |
|---|
| Panitumumab + Gem/Cis | 8 |
| 50 mg QD AMG 706 + Panitumumab + Gem/Cis | 8 |
| 75 mg QD AMG 706 + Panitumumab + Gem/Cis | 6 |
| 100 mg QD AMG 706 + Panitumumab + Gem/Cis | 6 |
| 125 mg QD AMG 706 + Panitumumab + Gem/Cis | 11 |
| 75 mg BID AMG 706 + Panitumumab + Gem/Cis | 2 |
Tmax
Time after dosing when maximum plasma concentration was observed for AMG 706 (NCT00101907)
Timeframe: Day 1, pre-dose and at 1, 3, 6,12 (BID cohort only) and 24 hours post-dose.
| Intervention | hours (Median) |
|---|
| 50 mg QD AMG 706 + Panitumumab + Gem/Cis | 1.00 |
| 75 mg QD AMG 706 + Panitumumab + Gem/Cis | 1.00 |
| 100 mg QD AMG 706 + Panitumumab + Gem/Cis | 1.38 |
| 125 mg QD AMG 706 + Panitumumab + Gem/Cis | 1.00 |
| 75 mg BID AMG 706 + Panitumumab + Gem/Cis | 1.00 |
Objective Response Rate
Tumor response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. Objective response rate is defined as number of patients with complete response (CR) or partial response (PR) divided by the total number of analyzable patients. CR is defined as complete disappearance of all tumor lesions, and partial response is defined as at least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum longest diameter. (NCT00427349)
Timeframe: assessed every 8 weeks while on treatment, and frequency of tumor measurements during follow-up were determined by the treating physician, assessed up to 5 years
| Intervention | percentage of participants (Number) |
|---|
| AMG 706+Octreotide | 13.6 |
Overall Survival
Overall survival (OS) is defined as the time from registration until death (event), or censored at last date known alive. OS was estimated using the Kaplan-Meier method , with 95% confidence intervals calculated using Greenwood's formula (NCT00427349)
Timeframe: assessed every 3 months if patient is < 2 years from study entry, then every 6 months up to 5 years
| Intervention | months (Median) |
|---|
| AMG 706+Octreotide | 27.5 |
Four-month Progression-free Survival Rate
Four-month progression-free survival (PFS) rate is defined as number of patients who are still progression free at 4 months after study entry divided by number of eligible and treated patients enrolled to the study. Progression is evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s), or unequivocal progression of existing non-target lesions. (NCT00427349)
Timeframe: assessed every 4 weeks while on treatment and at three months post-treatment for participants treated for one cycle, up to month four
| Intervention | percentage of participants (Number) |
|---|
| AMG 706+Octreotide | 78.5 |
Duration of Overall Survival (OS)
Overall survival is defined as the duration of time from study entry to time of death or the date of last contact. (NCT00574951)
Timeframe: Every cycle during treatment, then every 3 months for the first 2 years, then every six months for the next three years and then annually for the next 5 years.
| Intervention | months (Median) |
|---|
| AMG 706 | 13.1 |
Incidence of Adverse Effects (Grade 3 or Higher) as Assessed by Common Terminology Criteria for Adverse Events Version 3.0
Number of participants with a maximum grade of 3 or higher during the treatment period. (NCT00574951)
Timeframe: Assessed every cycle while on treatment, 30 days after the last cycle of treatment
| Intervention | Participants (Count of Participants) |
|---|
| Cardiac | Gastrointestinal | Hepatobiliary | Metabolic | Muskuloskeletal | Other Neurological | Pain | Pulmonary | Death, Not CTC coded |
|---|
| AMG 706 | 2 | 5 | 1 | 4 | 1 | 4 | 1 | 1 | 1 |
Number of Patients With Objective Tumor Response Rate (Complete Response [CR] or Partial Response [PR]) Using RECIST Version 1.0
RECIST 1.0 defines complete response as the disappearance of all target lesions and non-target lesions and no evidence of new lesions documented by two disease assessments at least 4 weeks apart. Partial response is defined as at least a 30% decrease in the sum of longest dimensions (LD) of all target measurable lesions taking as reference the baseline sum of LD. There can be no unequivocal progression of non-target lesions and no new lesions. Documentation by two disease assessments at least 4 weeks apart is required. In the case where the ONLY target lesion is a solitary pelvic mass measured by physical exam, which is not radiographically measurable, a 50% decrease in the LD is required. These patients will have their response classified according to the definitions stated above. Complete and partial responses are included in the objective tumor response rate. (NCT00574951)
Timeframe: CT scan or MRI every other cycle for the first 6 months; then every 3 months thereafter; and at any other time if clinically indicated up to 5 years.
| Intervention | Participants (Count of Participants) |
|---|
| Partial response | Complete response |
|---|
| AMG 706 | 1 | 0 |
MDS Participants: Percentage of Participants With Overall Response (Hematologic Improvement [HI] or PR or CR) Per IWG Criteria
OR: HI/PR/CR per IWG. CR: BM:≤5% myeloblasts (all cell lines normal maturation), Peripheral blood:Hgb ≥11g/dL, PLTs ≥100x10^9/L, Neutrophils ≥1.0x10^9/L, Blasts 0%. PR: All CR criteria if abnormal before treatment except- BM blasts decreased ≥50% over pretreatment but still >5%, Cellularity, morphology not relevant. HI responses:1) Erythroid: Hgb increase ≥1.5 g/dL, Relevant reduction of red blood cell(RBC) units transfusions by absolute ≥4 RBC transfusions/8 week (wk) compared with pretreatment transfusion number in previous 8 wk. Only RBC transfusions given for Hgb of ≤9.0 g/dL.2)PLTs:Absolute increase ≥30x10^9/L starting >20x10^9/L PLTs; Increase from <20x10^9/L to >20x10^9/L and by ≥100%; 3)Neutrophil: ≥100% increase, absolute increase >0.5x10^9/L; 4)Progression/relapse after HI:≥1 of following:≥50% decrement from maximum response levels in granulocytes/PLTs, Reduction in Hgb ≥1.5 g/dL,Transfusion dependence. Data is reported separately for arm whose response was assessed per IWG. (NCT01731951)
Timeframe: Up to first 9 cycles of treatment (each cycle was of 28 days for Arm G)
| Intervention | percentage of participants (Number) |
|---|
| Arm G: Imetelstat 7.5 - 9.4 mg/kg (MDS/MPN or MDS With Spliceosome Mutations or Ring Sideroblasts) | 33.3 |
MDS Participants: Time to Response
Time to response was defined as the duration from study Day 1 to the earliest date that a response is first documented. Response was defined as HI, PR or CR per IWG criteria. Data for time to response is reported as per criteria of response assessment. (NCT01731951)
Timeframe: From study Day 1 to the earliest date that a response was first documented (Up to approximately 5.7 years)
| Intervention | months (Median) |
|---|
| Arm G: Imetelstat 7.5 - 9.4 mg/kg (MDS/MPN or MDS With Spliceosome Mutations or Ring Sideroblasts) | 3.7 |
MF and Blastic MF/AML Participants: Number of Participants With Transfusion Independence (CI by Anemia Response) Per IWG-MRT
Transfusion dependency was defined by a history of at least 2 units of red blood cell transfusions in the last month for a hemoglobin level of less than 85 g/L that was not associated with clinically overt bleeding. A participant who was transfusion dependent at baseline was considered transfusion independent if the participant met either of the following conditions: Received no more than 1 unit of red blood cell transfusions in a rolling time interval of 30 days or more, and had a hemoglobin level increase over baseline more than 2 g/dL if participant baseline hemoglobin level was less than 85 g/L and received no transfusion. Anemia response per IWG-MRT Criteria- Transfusion-independent participants: a ≥20 g/L increase in hemoglobin level. Transfusion-dependent participants: becoming transfusion-independent. Data is reported separately for arms assessed as per the IWG-MRT criteria. (NCT01731951)
Timeframe: Up to approximately 5.7 years
| Intervention | Participants (Count of Participants) |
|---|
| Arm A: Imetelstat 9.4 mg/kg (MF) | 1 |
| Arm B: Imetelstat 9.4 mg/kg as Induction + Maintenance (MF) | 0 |
| Arm D: Imetelstat 9.4 mg/kg (Blast-phase MF/Acute Myeloid Leukemia) | 0 |
| Arm E: Imetelstat 7.5 - 9.4 mg/kg (MF [With Spliceosome Mutation or Ring Sideroblasts]) | 0 |
| Arm F: Imetelstat 7.5 - 9.4 mg/kg (MF [Without Spliceosome Mutation and Ring Sideroblasts]) | 3 |
MF Participants: Duration of Response (DOR) Per IWG-MRT Criteria
DOR measured from time of initial response (CR/PR/CI) until documented PD or death whichever occurs first. If no PD/death occurs DOR is censored at last disease evaluation date for responders. CR:BM: <5%blasts; ≤Grade 1 MF, AND Peripheral blood:Hb≥100 g/L and = 5 cm below LCM) or increase in severity of anemia, thrombocytopenia or neutropenia. Data is reported separately for arms whose DOR was assessed per IWG-MRT. Kaplan-Meier method was used. (NCT01731951)
Timeframe: From time of initial response until documented disease progression or death whichever occurs first (Up to approximately 5.7 years)
| Intervention | months (Median) |
|---|
| Arm A: Imetelstat 9.4 mg/kg (MF) | 24.36 |
| Arm B: Imetelstat 9.4 mg/kg as Induction + Maintenance (MF) | NA |
| Arm F: Imetelstat 7.5 - 9.4 mg/kg (MF [Without Spliceosome Mutation and Ring Sideroblasts]) | 35.52 |
MF Participants: Percentage of Participants With Overall Response (OR) - (Clinical Improvement[CI] or Partial Remission[PR] or Complete Remission[CR]) Per International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Criteria
OR:CI/PR/CR per IWG-MRT. CR:Bone marrow (BM):<5% blasts;≤Grade 1 MF, AND Peripheral blood:Hemoglobin (Hb) ≥100 g/liter (g/L) and NCT01731951)
Timeframe: Up to first 9 cycles of treatment (each cycle was of 21 days for Arms A and B and 28 days for Arms E and F)
| Intervention | percentage of participants (Number) |
|---|
| Arm A: Imetelstat 9.4 mg/kg (MF) | 36.84 |
| Arm B: Imetelstat 9.4 mg/kg as Induction + Maintenance (MF) | 35.7 |
| Arm E: Imetelstat 7.5 - 9.4 mg/kg (MF [With Spliceosome Mutation or Ring Sideroblasts]) | 0 |
| Arm F: Imetelstat 7.5 - 9.4 mg/kg (MF [Without Spliceosome Mutation and Ring Sideroblasts]) | 33.3 |
MF Participants: Time to Response
Time to response was defined as the duration from study Day 1 to the earliest date that a response is first documented. The response CI/CR/PR was assessed by IWG-MRT criteria. (NCT01731951)
Timeframe: From study Day 1 to the earliest date that a response was first documented (Up to approximately 5.7 years)
| Intervention | months (Median) |
|---|
| Arm A: Imetelstat 9.4 mg/kg (MF) | 2.1 |
| Arm B: Imetelstat 9.4 mg/kg as Induction + Maintenance (MF) | 1.4 |
| Arm F: Imetelstat 7.5 - 9.4 mg/kg (MF [Without Spliceosome Mutation and Ring Sideroblasts]) | 2.9 |
Overall Survival (OS)
OS was defined as the as the interval from Study Day 1 to the date of death from any cause. Survival time of living participants was censored on the last date a participant is known to be alive or lost to follow-up. Overall Survival was estimated by Kaplan-Meier method. (NCT01731951)
Timeframe: From Study Day 1 to the date of death from any cause (Up to approximately 5.7 years)
| Intervention | months (Median) |
|---|
| Arm A: Imetelstat 9.4 mg/kg (MF) | 42.61 |
| Arm B: Imetelstat 9.4 mg/kg as Induction + Maintenance (MF) | 26.73 |
| Arm D: Imetelstat 9.4 mg/kg (Blast-phase MF/Acute Myeloid Leukemia) | 4.93 |
| Arm E: Imetelstat 7.5 - 9.4 mg/kg (MF [With Spliceosome Mutation or Ring Sideroblasts]) | 12.09 |
| Arm F: Imetelstat 7.5 - 9.4 mg/kg (MF [Without Spliceosome Mutation and Ring Sideroblasts]) | NA |
| Arm G: Imetelstat 7.5 - 9.4 mg/kg (MDS/MPN or MDS With Spliceosome Mutations or Ring Sideroblasts) | 28.42 |
Number of Participants With Spleen Response Per IWG-MRT Criteria
Spleen response per IWG-MRT criteria defined as baseline splenomegaly that is palpable at 5-10 cm, below the LCM, becomes not palpable, OR A baseline splenomegaly that is palpable at >10 cm, below the LCM, decreases by ≥50%. Baseline splenomegaly that is palpable at <5 cm, below the LCM, is not eligible for spleen response. Confirmation by Magnetic resonance imaging (MRI) or computerized tomography (CT) showing ≥35% spleen volume reduction is recommended (but not required). Spleen response was assessed only in participants with MF. (NCT01731951)
Timeframe: Up to approximately 5.7 years
| Intervention | Participants (Count of Participants) |
|---|
| Arm A: Imetelstat 9.4 mg/kg (MF) | 3 |
| Arm B: Imetelstat 9.4 mg/kg as Induction + Maintenance (MF) | 1 |
| Arm D: Imetelstat 9.4 mg/kg (Blast-phase MF/Acute Myeloid Leukemia) | 1 |
| Arm E: Imetelstat 7.5 - 9.4 mg/kg (MF [With Spliceosome Mutation or Ring Sideroblasts]) | 0 |
| Arm F: Imetelstat 7.5 - 9.4 mg/kg (MF [Without Spliceosome Mutation and Ring Sideroblasts]) | 2 |
Blastic MF/AML Participants: Percentage of Participants With Overall Response
For this pilot study, overall response was defined as achievement of a leukemic response (i.e. a clinically meaningful reduction in Blast cells). This was quantified as <5% peripheral blood and bone marrow blasts % that lasts for at least two months. Data is reported separately for this arm where response was assessed by this specific criterion. (NCT01731951)
Timeframe: Up to first 9 cycles of treatment (each cycle was of 28 days for Arm D)
| Intervention | percentage of participants (Number) |
|---|
| Arm D: Imetelstat 9.4 mg/kg (Blast-phase MF/Acute Myeloid Leukemia) | 0 |
MDS Participants: Duration of Response Per IWG Criteria
DOR: time of initial response (CR/PR/HI) until documented PD/death whichever occurs first. If no PD/death occurs DOR is censored at last disease evaluation date for responders. Data reported separately for arm assessed per IWG. Kaplan-Meier method was used. (NCT01731951)
Timeframe: From the time of initial response (CR/PR/HI) until documented disease progression or death whichever occurs first (Up to approximately 5.7 years)
| Intervention | months (Median) |
|---|
| Arm G: Imetelstat 7.5 - 9.4 mg/kg (MDS/MPN or MDS With Spliceosome Mutations or Ring Sideroblasts) | NA |
MDS Participants: Number of Participants With Transfusion Independence (HI by Erythroid Response) Per IWG Criteria
Transfusion dependency was defined by a history of at least 2 units of red blood cell transfusions in the last month for a hemoglobin level of less than 85 g/L that was not associated with clinically overt bleeding. A participant who was transfusion dependent at baseline was considered transfusion independent if the participant met either of the following conditions: Received no more than 1 unit of red blood cell transfusions in a rolling time interval of 30 days or more, and had a hemoglobin level increase over baseline more than 2 g/dL if participant baseline hemoglobin level was less than 85 g/L and received no transfusion. HI responses included: 1) Erythroid: Hgb increase ≥1.5 g/dL, Relevant reduction of RBC units transfusions by absolute number of >=4 RBC transfusions/8 week compared with pretreatment transfusion number in previous 8 week. Only RBC transfusions given for Hgb of ≤9.0 g/dL. Data is reported separately for arm assessed as per IWG criteria. (NCT01731951)
Timeframe: Up to approximately 5.7 years
| Intervention | Participants (Count of Participants) |
|---|
| Arm G: Imetelstat 7.5 - 9.4 mg/kg (MDS/MPN or MDS With Spliceosome Mutations or Ring Sideroblasts) | 3 |
Number of Participants With Telomerase Inhibition
This outcome measure is applicable only for the Molecular biology study arm. Telomerase inhibition was assessed in PBMCs and summarised as 'yes-inhibited' vs. 'no inhibition' (NCT01836549)
Timeframe: Up to 30 days
| Intervention | Participants (Count of Participants) |
|---|
| Molecular Biology Study | 5 |
Numver of Patients With Telomerase-positive Archival Tumors Who Demonstrate at Least 50% Reduction
This outcome measure is for the Molecular biology study only. The assessment was done to identify cases with at least 50% reduction in telomerase activity. (NCT01836549)
Timeframe: Up to 30 days
| Intervention | Participants (Count of Participants) |
|---|
| Molecular Biology Study | 1 |
Phase II: Stratum-specific Objective Response (CR+PR) Rate
"Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=50% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR sustained for at least 6 weeks.~For each stratum separately exact confidence interval estimates will be provided for the true, unknown rates of objective response. Estimated by cumulative incidence functions." (NCT01836549)
Timeframe: 6 months
| Intervention | Participants (Count of Participants) |
|---|
| Stratum-A | 0 |
| Stratum-B | 0 |
| Stratum-C | 0 |
| Stratum-D | 0 |
Stratum-specific Progression-free Survival (PFS) (Phase II)
Kaplan-Meier estimates of distributions of survival and PFS for all eligible subjects who received at least one dose of imetelstat will be provided separately. (NCT01836549)
Timeframe: Up to 2 years, from the date of initial treatment to the earliest date of disease progression, second malignancy or death for subjects who fail; and to the date of last contact for subjects who remain at risk for failure, assessed up to 3 years
| Intervention | days (Mean) |
|---|
| Stratum-A | 30 |
| Stratum-B | 54.2 |
| Stratum-C | 50.3 |
| Stratum-D | 52.6 |
Number of Patients With Telomerase Expression Data by Detection of hTERT mRNA and TERC RNA Levels by qRT-PCR and Telomerase Activity by TRAP in Archival Tumor Tissue and to Explore Association of Telomerase Positivity With Objective Response and PFS
This secondary objective is for Stratum-B and C only, which enroll HGG and ependymoma patients. We will describe the evidence of telomerase expression by detection of hTERT mRNA and TERC RNA levels by qRT-PCR and telomerase activity by TRAP in archival tumor tissue; Association of telomerase positivity with objective response and PFS will not be able to be conducted as the study was terminated early and there was no objective response. (NCT01836549)
Timeframe: Up to 30 days. Due to small number of patients evaluable for this objective, we can only provide number of patients with the targetted markers as no analysis with PFS is possible.
| Intervention | Participants (Count of Participants) |
|---|
| TRAP | TERT | TERC |
|---|
| Stratum-C | 3 | 3 | 3 |
Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC 0-24) of Imetelstat
(NCT02426086)
Timeframe: 0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days)
| Intervention | μg*hr/mL (Mean) |
|---|
| PK: Imetelstat 4.7 mg/kg | 171 |
| PK: Imetelstat 9.4 mg/kg | 501 |
Area Under the Plasma Concentration-Time Profile From Time Zero to Infinity (AUC0-inf) of Imetelstat
(NCT02426086)
Timeframe: 0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days)
| Intervention | μg*h/mL (Mean) |
|---|
| PK: Imetelstat 4.7 mg/kg | 193 |
| PK: Imetelstat 9.4 mg/kg | 524 |
Duration of Response (PR/CI/RWCI) as Per IWG-MRT Criteria
Duration of response (PR/CI/RWCI) is the duration from the date of initial documentation of a response to date of first documented evidence of PD or death, whichever occurs first. PR: BM: normocellular: <5% blasts ≤Grade 1 fibrosis/not meeting BM remission criteria; IMC in PB: <2%; Hb: 8.5 -<10 g/dL-ULN or 10 g/dL- ULN; neutrophils: 1*10^9/L-ULN; platelets: 50 -<100*10^9/L-ULN; spleen: ≥35% splenic volumetric reduction by MRI/not palpable; EMH: no non-hepato-splenic EMH; symptoms: >50% improvement in symptom score. CI: achievement of anemia, spleen or symptoms response without PD or increase in severity of anemia, thrombocytopenia, neutropenia. RWCI: Participants who met criteria for response but had worsening cytopenias. PD: Splenomegaly requires MRI showing ≥25% increase in spleen volume. (NCT02426086)
Timeframe: From date of initial documentation of a response to the date of first documented evidence of PD or death, whichever occurs first (approximately up to 2.3 years)
| Intervention | weeks (Median) |
|---|
| Imetelstat 4.7 mg/kg | 36.3 |
| Imetelstat 9.4 mg/kg | 38.3 |
Elimination Half-Life (t1/2) of Imetelstat
Elimination half-life (t 1/2) is associated with the terminal slope (lambda [z]) of the semi logarithmic drug concentration-time curve, calculated as 0.693/lambda(z). (NCT02426086)
Timeframe: 0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days)
| Intervention | hr (Mean) |
|---|
| PK: Imetelstat 4.7 mg/kg | 4.6 |
| PK: Imetelstat 9.4 mg/kg | 5.5 |
Maximum Observed Plasma Concentration (Cmax) of Imetelstat
(NCT02426086)
Timeframe: 0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days)
| Intervention | μg/mL (Mean) |
|---|
| PK: Imetelstat 4.7 mg/kg | 57.0 |
| PK: Imetelstat 9.4 mg/kg | 81.9 |
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
An AE is any untoward medical occurrence in a participant or clinical investigation participants administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. TEAEs were AEs with onset during or after the first dose of study drug, and within 30 days following the last dose of study drug. (NCT02426086)
Timeframe: Up to end of extension phase (approximately up to 4.2 years)
| Intervention | Participants (Count of Participants) |
|---|
| Imetelstat 4.7 mg/kg | 47 |
| Imetelstat 9.4 mg/kg | 59 |
Overall Survival
Overall Survival is measured from the date of Cycle 1, Day 1 to the date of the participants death. If the participant's was alive or the vital status was unknown, OS was censored at the date that the participant is last known to be alive. (NCT02426086)
Timeframe: Day 1 of Cycle 1 (each cycle was of 21 days), up to the date of the participant's death (approximately up to 4.1 years)
| Intervention | months (Median) |
|---|
| Imetelstat 4.7 mg/kg | 19.91 |
| Imetelstat 9.4 mg/kg | 28.09 |
Patient's Global Impression of Change (PGIC)
The PGIC was used to capture the participant's perspective of improvement or decline in MF symptoms over time. The PGIC had a 7-point response scale ranging from 1 to 7 where, (1=very much improved, 2= somewhat improved, 3= a little improved, 4=no change, 5= a little worse, 6= somewhat worse, 7=very much worse). (NCT02426086)
Timeframe: At the end of treatment, up to approximately 2.3 years
| Intervention | score on a scale (Mean) |
|---|
| Imetelstat 4.7 mg/kg | 4.82 |
| Imetelstat 9.4 mg/kg | 3.97 |
Percentage of Participants With Spleen Response Per Modified 2013 IWG-MRT Criteria
Spleen response per modified 2013 IWG-MRT criteria. Spleen response: a baseline splenomegaly that is palpable at 5-10 cm, below the left costal margin (LCM), becomes not palpable or a baseline splenomegaly that is palpable at >10 cm, below the LCM, decreases by ≥50%; A spleen response requires confirmation by MRI showing >35% spleen volume reduction (SVR). For response categories, benefit must last for >12 weeks to qualify as a response. Participants who achieved CI per modified IWG-MRT criteria considered as response with clinical improvement. Participants who met criteria for spleen response but had worsening cytopenias (and therefore did not meet criteria for clinical improvement) were considered to have a response without clinical improvement. The clinical improvement in IWG-MRT is defined as the achievement of anemia, spleen or symptoms response without progressive disease or increase in severity of anemia, thrombocytopenia, or neutropenia. (NCT02426086)
Timeframe: Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
| Intervention | percentage of participants (Number) |
|---|
| Spleen response with CI | Spleen response without CI |
|---|
| Imetelstat 4.7 mg/kg | 0 | 2.1 |
,| Imetelstat 9.4 mg/kg | 3.4 | 0 |
Percentage of Participants With Symptoms Response Per Modified 2013 IWG-MRT Criteria
Symptoms response per modified 2013 IWG-MRT criteria. Symptoms Response: a ≥50% reduction in the modified MFSAF v2.0 TSS. For response category, benefit must last for >12 weeks to qualify as a response. Participants who achieved CI per modified IWG-MRT criteria considered as response with clinical improvement. Participants who met criteria for symptom response but had worsening cytopenias (and therefore did not meet criteria for clinical improvement) were considered to have a response without clinical improvement. The clinical improvement in IWG-MRT is defined as the achievement of anemia, spleen or symptoms response without progressive disease or increase in severity of anemia, thrombocytopenia, or neutropenia. (NCT02426086)
Timeframe: Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
| Intervention | percentage of participants (Number) |
|---|
| Symptom response with CI | Symptom response without CI |
|---|
| Imetelstat 4.7 mg/kg | 14.6 | 4.2 |
,| Imetelstat 9.4 mg/kg | 22.0 | 8.5 |
Percentage of Participants With Clinical Response Per Modified 2013 IWG-MRT
Clinical response rate (CRR) was defined as percentage of participants who achieved CR, PR, or CI per modified 2013 IWG-MRT criteria. CR: bone marrow: normocellular <5% blasts, ≤Grade 1 fibrosis; immature myeloid cells in PB: <2%; Hb: 10 g/dL-ULN; neutrophils: 1*10^9/L-ULN; platelets: 100*10^9/L-ULN; spleen: not palpable and ≤350ml volume; EMH: no non-hepato-splenic EMH; symptoms: >70% improvement in symptom score per modified MFSAF v2.0 TSS. PR: bone marrow: normocellular: <5% blasts ≤ Grade 1 fibrosis or not meeting bone marrow remission criteria; Immature myeloid cells in PB: <2%; Hb: 8.5 -<10 g/dL-ULN or 10 g/dL-ULN; neutrophils: 1*10^9/L-ULN; platelets: 50 -<100*10^9/L-ULN; spleen: ≥35% splenic volumetric reduction by MRI or not palpable; EMH: no non-hepato-splenic EMH; symptoms: >50% improvement in symptom score per modified MFSAF v2.0 TSS. CI: achievement of anemia, spleen or symptoms response without PD or increase in severity of anemia, thrombocytopenia, or neutropenia. (NCT02426086)
Timeframe: Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
| Intervention | percentage of participants (Number) |
|---|
| Imetelstat 4.7 mg/kg | 16.7 |
| Imetelstat 9.4 mg/kg | 27.1 |
Percentage of Participants With Clinically Meaningful Improvement in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-30 (QLQ-C30): Global Health Status
EORTC QLQ-C30 is a questionnaire to assess quality of life of cancer patients. The EORTC QLQ-C30 included 30 items resulting in 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) which are based on 4-point scale (1= Not at all to 4= Very much); and 1 global health status scale based on 7-point scale (1= Very poor to 7= Excellent). All scales and items are averaged, transformed to 0-100 scale; higher score=better level of functioning. Clinically meaningful improvement defined as change greater than half of the standard deviation at baseline in QLQ-C30 Global Health Status. (NCT02426086)
Timeframe: Up to end of the treatment (approximately up to 2.3 years)
| Intervention | percentage of participants (Number) |
|---|
| Imetelstat 4.7 mg/kg | 22.2 |
| Imetelstat 9.4 mg/kg | 36.4 |
Percentage of Participants With Overall Response as Per Modified 2013 International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Criteria
Overall Response Rate: % of participants with complete remission (CR) or partial remission (PR) per modified IWG-MRT.CR: bone marrow: normocellular <5% blasts, ≤Grade 1 fibrosis; immature myeloid cells in peripheral blood (PB):<2%;hemoglobin (Hb):10 g/dL-upper limit of normal (ULN); neutrophils:1*10^9/L-ULN; platelets: 100*10^9/L-ULN; spleen:not palpable and ≤350ml volume; extramedullary hematopoiesis (EMH): no non-hepato-splenic EMH; symptoms: >70% improvement in symptom score per modified MFSAF v2.0 TSS. PR: bone marrow: normocellular: <5% blasts ≤ Grade 1 fibrosis or not meeting bone marrow remission criteria; Immature myeloid cells in PB: <2%; Hb: 8.5 -<10 g/dL-ULN or 10 g/dL-ULN; neutrophils: 1*10^9/L-ULN; platelets: 50 -<100*10^9/L-ULN; spleen: ≥35% splenic volumetric reduction by MRI or not palpable; EMH: no non-hepato-splenic EMH;symptoms: >50% improvement in symptom score per modified MFSAF v2.0 TSS. All response categories, benefit must last >12 weeks to qualify as response. (NCT02426086)
Timeframe: Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
| Intervention | percentage of participants (Number) |
|---|
| Imetelstat 4.7 mg/kg | 0 |
| Imetelstat 9.4 mg/kg | 1.7 |
Percentage of Participants With Spleen Response
Spleen response rate is defined as the percentage of participants who achieved ≥ 35% reduction in spleen volume at Week 24 from baseline performed by the IRC using magnetic resonance imaging (MRI). (NCT02426086)
Timeframe: Week 24
| Intervention | percentage of participants (Number) |
|---|
| Imetelstat 4.7 mg/kg | 0 |
| Imetelstat 9.4 mg/kg | 10.2 |
Percentage of Participants With Symptom Response
Symptom response rate is defined as percentage of participants who achieved ≥ 50% reduction in total symptom score (TSS) at Week 24 from baseline as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) version 2.0 diary. The MFSAF assessed following symptoms due to Myelofibrosis (MF): night sweats, itchiness, abdominal discomfort, pain under ribs on left side, feeling of fullness, bone or muscle pain and degree of inactivity. Each item is scored on a scale of 0 (absent) to 10 (worst imaginable) with higher scores indicating more severe symptoms and greater inactivity. The total score ranges from 0-70, where 0 indicates absent/as good as it can be and 70 indicates worst imaginable/as bad as it can be. (NCT02426086)
Timeframe: Week 24
| Intervention | percentage of participants (Number) |
|---|
| Imetelstat 4.7 mg/kg | 6.3 |
| Imetelstat 9.4 mg/kg | 32.2 |
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Imetelstat
(NCT02426086)
Timeframe: 0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days)
| Intervention | hr (Median) |
|---|
| PK: Imetelstat 4.7 mg/kg | 2.00 |
| PK: Imetelstat 9.4 mg/kg | 2.00 |
Total Systemic Clearance (CL) of Imetelstat
(NCT02426086)
Timeframe: 0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days)
| Intervention | L/hr/kg (Mean) |
|---|
| PK: Imetelstat 4.7 mg/kg | 0.0329 |
| PK: Imetelstat 9.4 mg/kg | 0.0252 |
Volume of Distribution (Vd) of Imetelstat
(NCT02426086)
Timeframe: 0 (before start of infusion), 1, 2, 3-5, 6-10, 12-16 and 18-24 hours post dose on Day 1 of Cycle 1 (each cycle was of 21 days)
| Intervention | L/kg (Mean) |
|---|
| PK: Imetelstat 4.7 mg/kg | 0.198 |
| PK: Imetelstat 9.4 mg/kg | 0.190 |
EuroQol 5 Dimension 5 Level (EQ-5D-5L): Utility Score and Visual Analog Scale (VAS)
EQ-5D-5L is a standardized health-related quality of life questionnaire developed by EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal. EQ-5D-5L consists of two components: a health state profile and VAS. EQ-5D health state profile comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. The 5D-5L systems are converted into a single index utility score between 0 to 1, where higher score indicates a better health state. EQ-5D-5L- VAS is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. (NCT02426086)
Timeframe: At the end of treatment, up to approximately 2.3 years
| Intervention | score on a scale (Mean) |
|---|
| EQ-5D-5L: Utility Score | EQ-5D-5L: VAS |
|---|
| Imetelstat 4.7 mg/kg | 0.498 | 51.28 |
,| Imetelstat 9.4 mg/kg | 0.626 | 47.73 |
Percentage of Participants With Clinical Improvement (CI) Per Modified 2013 IWG-MRT Criteria
CI per the modified 2013 IWG-MRT criteria defined as the achievement of anemia, spleen or symptoms response without progressive disease or increase in severity of anemia, thrombocytopenia, or neutropenia (Increase in severity of anemia constitutes the occurrence of new transfusion dependency or a ≥ 2.0 g/dL decrease in hemoglobin level from pretreatment baseline that lasts for at least 12 weeks. Increase in severity of thrombocytopenia or neutropenia is defined as a 2-grade decline, from pretreatment baseline, in platelet count or ANC, according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. In addition, assignment to CI requires a minimum platelet count of ≥ 25,000*10^9/L and ANC of ≥ 0.5*10^9/L.) For all response categories, benefit must last for >12 weeks to qualify as a response. (NCT02426086)
Timeframe: Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
| Intervention | percentage of participants (Number) |
|---|
| Imetelstat 4.7 mg/kg | 16.7 |
| Imetelstat 9.4 mg/kg | 25.4 |
Percentage of Participants With Anemia Response Per Modified 2013 IWG-MRT Criteria
"Anemia response per modified 2013 IWG-MRT criteria. Anemia response is defined as participants with baseline Hb <10 g/dL but not meeting strict criteria for transfusion dependency: a ≥ 2 g/dL increase in Hb; Transfusion dependent participants at baseline: becoming transfusion independent. Transfusion independence is defined as absence of any pRBC transfusions for at least 12 rolling weeks. For response categories, benefit must last for >12 weeks to qualify as a response. Participants who achieved CI per modified IWG-MRT criteria considered as response with clinical improvement. Participants who met criteria for anemia response but had worsening cytopenias (and therefore did not meet criteria for clinical improvement) were considered to have a response without clinical improvement. The clinical improvement in IWG-MRT is defined as the achievement of anemia, spleen or symptoms response without progressive disease or increase in severity of anemia, thrombocytopenia, or neutropenia." (NCT02426086)
Timeframe: Every 12 weeks up to Week 48 then every 24 weeks (approximately up to 2.3 years)
| Intervention | percentage of participants (Number) |
|---|
| Anemia response with CI | Anemia response without CI |
|---|
| Imetelstat 4.7 mg/kg | 4.2 | 0 |
,| Imetelstat 9.4 mg/kg | 6.8 | 1.7 |
Percentage of Participants With Clinically Meaningful Improvement in Brief Pain Inventory (BPI)
The BPI rates the intensity of pain on 4 items (right now, worst, least, and average), and the interference in 7 areas (general activity, mood, walking ability, normal work, relations, sleep, enjoyment of life). Minimum value = 0; maximum value = 10. Higher scores indicate greater symptom severity/worse outcomes. Clinically meaningful improvement in BPI defined as change greater than half of the standard deviation at baseline. (NCT02426086)
Timeframe: Up to end of treatment (approximately up to 2.3 years)
| Intervention | percentage of participants (Number) |
|---|
| Pain at its Worst: Improvement | Pain at its Least: Improvement | Pain on the Average: Improvement | Pain Right Now: Improvement | Relief Pain Treatments Provided: Improvement | Pain Interfered General Activity: Improvement | Pain Interfered with Mood: Improvement | Pain Interfered Walking Ability: Improvement | Pain Interfered with Normal Work: Improvement | Pain Interfered with Relations: Improvement | Pain Interfered with Sleep: Improvement | Pain Interfered Enjoyment of Life: Improvement |
|---|
| Imetelstat 4.7 mg/kg | 50.0 | 44.4 | 55.6 | 61.1 | 50.0 | 72.2 | 50.0 | 38.9 | 61.1 | 44.4 | 61.1 | 61.1 |
,| Imetelstat 9.4 mg/kg | 75.8 | 51.5 | 66.7 | 66.7 | 53.1 | 68.8 | 59.4 | 78.1 | 62.5 | 53.1 | 78.1 | 62.5 |