A Study Comparing Imetelstat Versus Best Available Therapy for the Treatment of Intermediate-2 or High-risk Myelofibrosis (MF) Who Have Not Responded to Janus Kinase (JAK)-Inhibitor Treatment

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the overall survival of participants treated with imetelstat compared to best available therapy with intermediate-2 or high-risk Myelofibrosis (MF) who are relapsed/refractory to Janus Kinase (JAK)-Inhibitor treatment.

Detailed Description
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This is a multicenter study with 2 arms, and will include 3 phases: a) screening phase of up to 28 days before randomization during which participants will complete a 14-day washout period from all prior therapies including JAK-inhibitor treatment, and the participant's eligibility will be reviewed; b) treatment phase, from randomization until study treatment (imetelstat or BAT) discontinuation; and c) post treatment follow-up phase, that begins when the participant discontinues treatment, and will continue until death, lost to follow-up, withdrawal of consent, or study end, whichever occurs first. Participants will be randomized (2:1) into 2 Arms (Arm A will receive imetelstat and Arm B will receive BAT). Participants who meet progressive disease criteria and discontinue BAT, may crossover to receive imetelstat treatment after sponsor's approval.

Official Title
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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

Conditions
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Myelofibrosis

Intervention / Treatment
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* Drug: Imetelstat
* Drug: Best Available Therapy (BAT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of primary myelofibrosis according to the revised World Health Organization criteria or post-essential thrombocythemia-MF or post-polycythemia vera-MF according to the IWG-MRT criteria Dynamic International Prognostic Scoring System intermediate-2 or high-risk MF Relapsed/refractory to JAK-inhibitor treatment as defined in either inclusion (i), (ii) or (iii) and not eligible for allogeneic stem cell transplantation (ASCT) at screening: (i) Treatment with JAK-inhibitor for >= 6 months duration, including at least 2 months at an optimal dose as assessed by the investigator for that participant and at least one of the following: no decrease in spleen volume (< 10% by MRI or CT) from the start of treatment with JAK-inhibitor no decrease in spleen size (< 30% by palpation or length by imaging) from the start of treatment with JAK-inhibitor no decrease in symptoms (< 20% by Myelofibrosis Symptom Assessment Form [MFSAF] or myeloproliferative neoplasm SAF) from the start of treatment with JAK-inhibitor a score of at least 15 on TSS assessed using the MFSAF v4.0 during screening. (ii) Treatment with JAK-inhibitor treatment for>= 3 months duration with maximal doses (e.g., 20-25 mg twice daily ruxolitinib) for that participant and no decrease in spleen volume/size or symptoms as defined in inclusion criterion (i [a, b, or c]). (iii) Following maximum tolerated doses of JAK inhibitor therapy for ≥3 months duration, having documented relapsed disease defined as either Increase in spleen volume from time of best response by 25% measured by MRI or CT, or Increase in spleen size by palpation, CT, or ultrasound (b.i) For splenomegaly of 5-10 cm at the start of JAK inhibitor treatment, at least 100% increase in palpable spleen size from time of best response; (b.ii) For splenomegaly of > 10 cm at the start of JAK inhibitor treatment, at least 50% increase in palpable spleen size from time of best response; AND not a candidate for further JAK inhibitor at screening per investigator. Measurable splenomegaly demonstrated by a palpable spleen measuring >= 5 cm below the left costal margin or a spleen volume >= 450 cm^3 by MRI or CT Active symptoms of MF on the MFSAF v4.0 demonstrated by a symptom score of at least 5 points (on a 0 to 10 scale) Hematology laboratory test values within the protocol defined limits Biochemical laboratory test values must be within protocol defined limits Eastern Cooperative Oncology Group Performance Status score of 0, 1, or 2 Participants should follow protocol defined contraceptives procedures A woman of childbearing potential must have a negative serum or urine pregnancy test at screening Exclusion Criteria: Peripheral blood blast count of >= 10% or bone marrow blast count of >=10% Known allergies, hypersensitivity, or intolerance to imetelstat or its excipients Prior treatment with imetelstat Any chemotherapy or MF directed therapy, including investigational drug regardless of class or mechanism of action, immunomodulatory or immunosuppressive therapy, corticosteroids greater than 30 mg/day prednisone or equivalent, and JAK-inhibitor treatment less than equal to 14 days prior to randomization Diagnosis or treatment for malignancy other than MF except: Malignancy treated with curative intent and with no known active disease present for >= 3 years before randomization Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease Adequately treated cervical carcinoma in situ without evidence of disease Known history of human immunodeficiency virus or any uncontrolled active systemic infection requiring IV antibiotics Active systemic hepatitis infection requiring treatment (carriers of hepatitis virus are permitted to enter the study), or any known acute or chronic liver disease requiring treatment unless related to underlying hepatosplenomegaly due to MF Major surgery within 28 days prior to randomization Any life-threatening illness (e.g., coronavirus disease-2019), medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the participant's safety, interfere with the imetelstat metabolism, or put the study outcomes at undue risk

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Imetelstat<br>Participants will receive imetelstat at 9.4 mg/kg intravenous (IV) every 21 days (±3 days), until disease progression or unacceptable toxicity, treatment discontinuation or study end. | Drug: Imetelstat<br>* Imetelstat will be given intravenously at 9.4 mg/kg every 21 days, until disease progression or unacceptable toxicity, treatment discontinuation or study end.<br>* Other names: GRN163L;|
| Active Comparator: Best Available Therapy (BAT)<br>Participants will receive BAT (investigator-selected non-JAK-inhibitor treatment), until disease progression or unacceptable toxicity, treatment discontinuation or study end. Participants on BAT who meet protocol-defined criteria for progressive disease may crossover to receive imetelstat treatment after sponsor's approval. | Drug: Best Available Therapy (BAT)<br>* Non-JAK-inhibitor treatment will be given, which may include but is not limited to hydroxyurea, thalidomide or an analog of thalidomide, interferon, danazol, hypomethylating agents, chemotherapy or radiotherapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Overall survival is defined as the time interval from randomization date to date of death from any cause. | Baseline (Day 1) until End of Study (EOS) (approximately 3 years )] | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptom response rate | The proportion of participants achieving a ≥50% reduction in Total Symptom Score (TSS) measured at Week 24 compared to baseline | Baseline (Day 1), and at Week 24 | 
| Progression-free survival | Progression-free survival is defined as the time interval from randomization date to the first date of disease progression (worsening splenomegaly or leukemic transformation per 2013 International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria) or death from any cause, whichever occurs first. | Baseline (Day 1) until End of Study (EOS) (approximately 3 years) | 
| Spleen response rate | The proportion of participants who achieve a reduction in spleen volume of ≥ 35% from baseline at Week 24. | Baseline (Day 1), and at Week 24 | 
| Complete remission (CR), partial remission (PR), clinical improvement (CI), spleen response, symptoms response, and anemia response per modified 2013 IWG-MRT criteria | The proportion of participants achieving CR or PR, CI, spleen response, symptom response, and anemia response per modified 2013 IWG-MRT criteria. | Baseline (Day 1) until End of Treatment (approximately 3 years) | 
| Reduction in the degree of bone marrow fibrosis | Reduction in the degree of bone marrow fibrosis will be assessed. | Baseline (Day 1) until End of Treatment (approximately 3 years) | 
| Number of Participants with Adverse Events | Safety will be assessed based on the incidence and severity (according to the Common Terminology Criteria for Adverse Events) of treatment emergent adverse events from the time of randomization until 30 days after completion of treatment | Screening (Day -28 to -1) until End of Study (approximately 3 years) | 
| Assessment of Cmax | Maximum Observed Plasma Concentration (Cmax). | Day 1 of all cycles (each cycle is 21 days) | 
| Assessment of Tmax | Time to reach the maximum observed plasma concentration | Day 1 of all cycles (each cycle is 21 days) | 
| Assessment of t1/2 | Elimination half-life. | Day 1 of all cycles (each cycle is 21 days) | 
| Assessment of AUC | Area under the drug concentration-plasma time curve (AUC) from time zero to last measurable concentration | Day 1 of all cycles (each cycle is 21 days) | 
| European Organization for Research and Treatment of Cancer Quality-of-Life-Questionnaire-Core-30 (EORTC QLQ-C30) scores | Patient-reported outcomes including health-related quality of life, pain, and overall change in participant's health will be assessed using the EORTC QLQ-C30. The EORTC QLQ-C30 includes 30 items resulting in 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 Global Health Status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Scores are transformed to a 0 to 100 scale. Higher scores indicated worse outcome. | Baseline to End of Study (approximately 3 years) | 
| EuroQol-EQ-5D (EQ-5D-5L) questionnaire scores | EQ-5D-5L is a 5 item questionnaire that assesses 5 domains including mobility, self-care, usual activities, pain/discomfort and anxiety/depression plus a visual analog scale rating health today with anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). | Baseline to End of Study (approximately 3 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myeloproliferative neoplasms, Polycythemia, Thrombocythemia, Primary myelofibrosis, Janus Kinase-Inhibitor