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
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 289
- 试验地点
- 233
- 主要终点
- Phase 2: Percentage of Participants Without Any Red Blood Cell (RBC) Transfusion During Any Consecutive 8-Weeks Period (All Participants)
研究概览
简要总结
The purpose of this study is to evaluate the efficacy and safety of imetelstat sodium in transfusion-dependent participants with low or intermediate-1 risk myelodysplastic syndrome (MDS) that is relapsed/refractory to erythropoiesis-stimulating agent (ESA) treatment in Phase 2 study and to compare the efficacy, in terms of red blood cell (RBC) transfusion independence (TI), of imetelstat sodium to placebo in transfusion-dependent participants with low or intermediate-1 risk MDS that is relapsed/refractory to ESA treatment in Phase 3 study.
A separate Ventricular Repolarization Substudy (QTc Substudy) will evaluate the effect of imetelstat sodium on ventricular repolarization.
An Extension Phase has been included to allow continued treatment for those participants who are benefitting from imetelstat sodium and to continue to evaluate the long-term safety, overall survival (OS), and disease progression, including progression to acute myeloid leukemia (AML) in transfusion-dependent participants with low or immediate-1 risk MDS that is relapsed/refractory to ESA treatment.
详细描述
This is a Phase 2/3, multicenter study of imetelstat sodium in which 289 participants were enrolled.
- Phase 2 is an open-label, single-arm design to assess the efficacy and safety of imetelstat sodium. A total of 57 participants were enrolled in Phase 2, including the expansion cohort.
- Phase 3 is a double-blind, randomized design to compare the efficacy of imetelstat sodium with placebo. In the Phase 3 study, 178 participants were enrolled and randomized in a 2:1 ratio to receive either imetelstat sodium or placebo, respectively.
- In a separate Ventricular Repolarization (VR) Substudy (QTc Substudy), 54 participants were enrolled and randomized 2:1 to receive either imetelstat sodium or placebo. If after a minimum of 2 treatment cycles in the VR substudy, a participant has no significant change to packed red blood cell (pRBC) transfusion burden or evidence of clinical benefit per Investigator, after discussion with the Sponsor the participant may be unblinded. If the participant was on placebo treatment, he/she may be permitted to start treatment with imetelstat sodium.
The Extension Phase was initiated at the end of the Phase 3 study (24 months after the last participant was randomized in the Phase 3) and will continue until participants who entered Phase 3 study participated in the study for up to 5 years from the first dose of imetelstat sodium (including treatment and follow-up), or 3 years of post-treatment follow-up from the last dose of study treatment, whichever occurs later, or until death, withdrawal of consent, study termination, or until a participant is lost to follow-up. Participants ongoing on imetelstat sodium and considered to be benefiting from treatment per Investigator in the Phase 3 Study or Ventricular Repolarization Substudy, have the option to continue receiving imetelstat sodium in the Extension Phase. Participants in the follow-up phase for the Phase 3 study or Ventricular Repolarization Substudy have the option to continue the follow-up in the Extension Phase.
The Phase 2, Phase 3, and VR Substudy all consist of 3 phases: a Screening phase (up to 28 days); a treatment phase; and a post-treatment follow-up phase which will continue until death, lost to follow-up, withdrawal of consent, or the End of the Study (whichever occurs first). The Extension Phase of the study will consist of an extended treatment phase and an extended follow-up phase which will continue until death, lost to follow-up, withdrawal of consent, or the End of the Study (whichever occurs first).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Man or woman greater than or equal to (≥) 18 years of age
- •Diagnosis of myelodysplastic syndrome (MDS) according to World Health Organization (WHO) criteria confirmed by bone marrow aspirate and biopsy within 12 weeks prior to Cycle 1 Day 1 (C1D1) (Phase 2) or randomization (Phase 3). In Ventricular Repolarization Substudy, diagnosis of MDS or myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) according to WHO criteria confirmed by bone marrow aspirate and biopsy within 12 weeks prior to C1D1
- •International Prognostic Scoring System (IPSS) low Risk or intermediate-1 risk MDS
- •Red blood cell (RBC) transfusion dependent, defined as requiring at least 4 RBC units transfused over an 8-week period during the 16 weeks prior to Study Entry; pre-transfusion hemoglobin (Hb) should be less than or equal to (≤) 9.0 gram per deciliter (g/dL) to count towards the 4 units total
- •Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
排除标准
- •Participant has known allergies, hypersensitivity, or intolerance to imetelstat sodium or its excipients
- •Participant has received an investigational drug or used an invasive investigational medical device within 30 days prior to Study Entry or is currently enrolled in an investigational study
- •Prior treatment with imetelstat sodium
- •Have received corticosteroids greater than (>) 30 milligram per day (mg/day) prednisone or equivalent, or growth factor treatment within 4 weeks prior to study entry
- •Has received an erythropoiesis-stimulating agent (ESA) or any chemotherapy, immunomodulatory, or immunosuppressive therapy within 4 weeks prior to study entry (8 weeks for long-acting ESAs)
- •Phase 3: a) Prior treatment with a hypomethylating agent (example [eg], azacitidine, decitabine); b) Prior treatment with lenalidomide
- •Additional Exclusion Criteria for the Ventricular Repolarization Substudy:
- •Concurrent therapy with medications known to prolong the QT interval and have been associated with Torsade de pointes arrhythmia (TdP)
- •Cardiac function abnormalities on screening ECG as follows:
- •Resting heart rate outside of 50 to 100 beats per minute
- •QT interval by Fridericia's correction method (QTcF) >470 millisecond (msec) (or QTcF >490 msec in the presence of a right bundle branch block or ventricular conduction delay [QRS >119 msec]), determined by central assessment based on the average value of a triplicate set of ECGs
- •Diagnosed or suspected congenital long QT syndrome
- •Family history of sudden unexpected death from cardiac-related causes if indicative of a pathogenic mutation of cardiac ion channels
- •Family history of congenital long QT syndrome
- •History of Mobitz II second degree or third degree heart block
- •Implantable pacemaker or automatic implantable cardioverter defibrillator
- •Complete left bundle branch block
- •Chronic or persistent atrial arrhythmia including atrial fibrillation and atrial flutter
- •History or presence of clinically relevant heart rhythm disturbances including atrial, junctional, re-entry, and ventricular tachycardia
- •Unusual T-wave morphology (i.e., bifid T-wave) likely to interfere with QT measurements
- •History or evidence for any of the following: severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (example, pulmonary embolism, cerebrovascular accident including transient ischemic attacks) within 12 months prior to Cycle 1 Day 1, New York Heart Association (NYHA) Class II to IV heart disease
- •Presence of uncontrolled hypertension (persistent systolic blood pressure [BP] ≥160 mmHg or diastolic BP ≥100 mmHg). Participants with a history of hypertension are permitted, provided that BP is controlled to within these limits by anti-hypertensive treatment
- •Any skin condition likely to interfere with electrocardiographic electrode placement or adhesion
- •History of thoracic surgery likely to cause abnormality of the electrical conduction through thoracic tissues
研究组 & 干预措施
Extension Phase: Extended Follow-up
Participants randomized to the placebo arm in the Phase 3 study will enter the Extended Follow-up part of the Extension Phase and continue in follow up until death, lost to follow-up, withdrawal of consent, study termination, or whichever occurs first up to approximately 3 years.
干预措施: Placebo (Drug)
Phase 2: Imetelstat Sodium
Imetelstat sodium administered intravenously (IV), at a starting dose of 7.5 milligrams per kilogram (mg/kg), every 4 weeks (on a 28-day cycle) until death, lost to follow-up, withdrawal of consent, or study termination whichever occurs first. Dose escalation to 9.4 mg/kg was allowed before Protocol Amendment 2.
干预措施: Imetelstat Sodium (Drug)
Extension Phase: Imetelstat Sodium
Participants randomized to the imetelstat sodium arm in the Phase 3 and the VR QTc Substudy, based on the response will continue to receive imetelstat sodium IV, at the dose they were receiving in the Phase 3 or VR QTc Substudy, every 4 weeks (on a 28-day cycle) until death, lost to follow-up, withdrawal of consent, study termination, or up to 3 years whichever occurs first.
干预措施: Imetelstat Sodium (Drug)
Phase 3: Imetelstat Sodium
Imetelstat sodium administered IV, at a starting dose of 7.5 mg/kg, every 4 weeks (on a 28-day cycle) until death, lost to follow-up, withdrawal of consent, or study termination whichever occurs first.
干预措施: Imetelstat Sodium (Drug)
Phase 3: Placebo
Imetelstat sodium-matching placebo administered IV, every 4 weeks (on a 28-day cycle), until death, lost to follow-up, withdrawal of consent, or study termination whichever occurs first.
干预措施: Placebo (Drug)
QTc Substudy: Placebo
Imetelstat sodium-matching placebo administered IV, every 4 weeks (on a 28-day cycle), until death, lost to follow-up, withdrawal of consent, or study termination whichever occurs first. If after a minimum of 2 treatment cycles a participant has no significant change to pRBC transfusion burden or evidence of clinical benefit per Investigator, after discussion with the Sponsor the participant, he/she may be permitted to start treatment with imetelstat sodium.
干预措施: Placebo (Drug)
QTc Substudy: Imetelstat Sodium
Imetelstat sodium administered IV, at a starting dose of 7.5 mg/kg, every 4 weeks (on a 28-day cycle) until death, lost to follow-up, withdrawal of consent, or study termination whichever occurs first.
干预措施: Imetelstat Sodium (Drug)
结局指标
主要结局
Phase 2: Percentage of Participants Without Any Red Blood Cell (RBC) Transfusion During Any Consecutive 8-Weeks Period (All Participants)
时间窗: Up to 5 years in Phase 2
Percentage of participants without any RBC transfusion during any consecutive 8 weeks (56 days) starting from Study Day 1 until subsequent anti-cancer therapy if any were reported. Study Day 1 is defined as the day of the first dose for participants enrolled in Phase 2. The 95% confidence interval (CI) was calculated using Clopper-Pearson method. Percentages were rounded off to the nearest single decimal place.
Phase 2: Percentage of Participants Without Any RBC Transfusion During Any Consecutive 8-Weeks Period in Target Population
时间窗: Up to 5 years in Phase 2
Percentage of participants without any RBC transfusion during any consecutive 8 weeks (56 days) starting from Study Day 1 until subsequent anti-cancer therapy if any were reported. Study Day 1 is defined as the day of the first dose for participants enrolled in Phase 2. The 95% confidence interval (CI) was calculated using Clopper-Pearson method. Percentages were rounded off to the nearest single decimal place.
Phase 3: Percentage of Participants Without Any RBC Transfusion During Any Consecutive 8-Weeks Period
时间窗: Up to 3.7 years in Phase 3
Percentage of participants without any RBC transfusion during any consecutive 8 weeks (56 days) starting from Study Day 1 until subsequent anti-cancer therapy if any were reported. Study Day 1 is defined as the day of the first dose for participants enrolled in Phase 2. The 95% CI was calculated using Clopper-Pearson method. Percentages were rounded off to the nearest single decimal place.
次要结局
- Phase 2 and Phase 3: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Deaths(Adverse events: Up to 5 years in Phase 2 and up to 3.7 years in Phase 3; Deaths: Up to 6.6 years in Phase 2 and up to 4 years in Phase 3)
- Phase 2 and Phase 3: Percentage of Participants Without Any RBC Transfusion During Any Consecutive 24-Weeks Period(Up to 5 years in Phase 2 and up to 3.7 years in Phase 3)
- Phase 2 and Phase 3: Time to the 8-Weeks RBC Transfusion Independence (TI)(Up to 5 years in Phase 2 and up to 3.7 years in Phase 3)
- Phase 2 and Phase 3: Time to the 24-Weeks RBC TI(Up to 5 years in Phase 2 and up to 3.7 years in Phase 3)
- Phase 2 and Phase 3: Duration of RBC TI(Up to 5 years in Phase 2 and up to 3.7 years in Phase 3)
- Phase 2 and Phase 3: Percentage of Participants With Hematologic Improvement Including Erythroid Response (HI-E) as Per International Working Group (IWG) Response Criteria 2006(Up to 5 years in Phase 2 and up to 3.7 years in Phase 3)
- Phase 2: Percentage of Participants With Complete Remission (CR), Partial Remission (PR), or Marrow Complete Remission (mCR) as Per International Working Group (IWG) Response Criteria 2006 as Assessed by the Investigator(Up to 5 years in Phase 2)
- Phase 3: Percentage of Participants With CR, PR, or mCR as Per IWG Response Criteria 2006 as Assessed by the Independent Review Committee (IRC)(Up to 3.7 years in Phase 3)
- Phase 2 and Phase 3: Overall Survival (OS)(Up to 6.6 years in Phase 2 and up to 4 years in Phase 3)
- Phase 2 and Phase 3: Progression Free Survival (PFS)(Up to 6.6 years in Phase 2 and up to 4 years in Phase 3)
- Phase 2 and Phase 3: Time to Progression to Acute Myeloid Leukemia (AML)(Up to 6.6 years in Phase 2 and up to 4 years in Phase 3)
- Phase 2 and Phase 3: Amount of RBC Transfusions in the Best 8-week Interval(Up to 5 years in Phase 2 and up to 3.7 years in Phase 3)
- Phase 2 and Phase 3: Percent Change in RBC Transfusions Relative to Prior Transfusion Burden(Up to 5 years in Phase 2 and up to 3.7 years in Phase 3)
- Phase 2 and Phase 3: Percentage of Participants Who Received Any Myeloid Growth Factors(Up to 5 years in Phase 2 and up to 3.7 years in Phase 3)
- Phase 2 and Phase 3: Duration of Myeloid Growth Factors Administration(Up to 5 years in Phase 2 and up to 3.7 years in Phase 3)
- Phase 2 and Phase 3: Maximum Observed Plasma Concentration (Cmax)(Pre-dose on Cycle 1 Day 1 and pre-dose on Day 1 of every 3 cycles from Cycle 4 up to Cycle 66 in Phase 2 and Cycle 34 in Phase 3 (each cycle length= 28 days))
- Phase 2 and Phase 3: Area Under the Drug Concentration-Plasma Time Curve From Time Zero to Time 28 Days (AUC0-28d)(Cycle 1 (Days 1 to 28) (Cycle duration= 28 days))
- Phase 2 and Phase 3: Percentage of Participants With Anti-drug Antibodies (ADA) to Imetelstat Sodium(Pre-dose on Cycle 1 Day 1 and pre-dose on Day 1 of every 3 cycles from Cycle 4 up to Cycle 66 in Phase 2 and Cycle 34 in Phase 3 (each cycle length= 28 days))
- Phase 3: Medical Resource Utilization Assessed Based on Percentage of Participants With Outpatient Medical Encounters(Up to 3.7 years in Phase 3)
- Phase 3: Medical Resource Utilization Assessed Based on Duration of Hospitalization(Up to 3.7 years in Phase 3)
- QTc Substudy: Change From Baseline in QT Interval by Fridericia's Correction Method (ΔQTcF)(Baseline, Cycle 1, Day 1: 0.5, 1, 2, 4, 6, and 8 hours post-dose (cycle length= 28 days))