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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

NCT04576156

Description:

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 refractory to Janus Kinase (JAK)-Inhibitor treatment.

Related Conditions:
  • Myelofibrosis
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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
  • Official Title: 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) Refractory to Janus Kinase (JAK)-Inhibitor

Clinical Trial IDs

  • ORG STUDY ID: MYF3001
  • SECONDARY ID: 2020-003288-24
  • NCT ID: NCT04576156

Conditions

  • Myelofibrosis

Interventions

DrugSynonymsArms
ImetelstatGRN163LImetelstat
Best Available Therapy (BAT)Best Available Therapy (BAT)

Purpose

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 refractory to Janus Kinase (JAK)-Inhibitor treatment.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
ImetelstatExperimentalParticipants 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.
  • Imetelstat
Best Available Therapy (BAT)Active ComparatorParticipants will receive BAT (investigator-selected non-JAK-inhibitor treatment), until disease progression or unacceptable toxicity, treatment discontinuation or study end.
  • Best Available Therapy (BAT)

Eligibility Criteria

        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

          -  Refractory to JAK-inhibitor treatment as defined in either inclusion (i) or (ii):

             (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 one of the
             following:

               1. no decrease in spleen volume (< 10% by MRI or CT) from the start of treatment
                  with JAK-inhibitor

               2. no decrease in spleen size (< 30% by palpation) from the start of treatment with
                  JAK-inhibitor

               3. no decrease in symptoms (< 20% by MFSAF or myeloproliferative neoplasm SAF) from
                  the start of treatment with JAK-inhibitor)

               4. 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])

          -  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 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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

Secondary Outcome Measures

Measure:Symptom response rate
Time Frame:Baseline (Day 1), and at Week 24
Safety Issue:
Description:The proportion of participants achieving a ≥50% reduction in Total Symptom Score (TSS) measured at Week 24 compared to baseline
Measure:Progression-free survival
Time Frame:Baseline (Day 1) until End of Study (EOS) (approximately 3 years)
Safety Issue:
Description: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.
Measure:Spleen response rate
Time Frame:Baseline (Day 1), and at Week 24
Safety Issue:
Description:The proportion of participants who achieve a reduction in spleen volume of ≥ 35% from baseline at Week 24.
Measure:Complete remission, PR, CI, spleen response, symptoms response, and anemia response per modified 2013 IWG-MRT criteria
Time Frame:Baseline (Day 1) until End of Treatment (approximately 3 years)
Safety Issue:
Description:The proportion of participants achieving CR or PR, CI, spleen response, symptom response, and anemia response per modified 2013 IWG-MRT criteria
Measure:Reduction in the degree of bone marrow fibrosis
Time Frame:Baseline (Day 1) until End of Treatment (approximately 3 years)
Safety Issue:
Description:Reduction in the degree of bone marrow fibrosis will be assessed.
Measure:Number of Participants with Adverse Events
Time Frame:Screening (Day -28 to -1) until End of Study (approximately 3 years)
Safety Issue:
Description: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
Measure:Assessment of Cmax
Time Frame:Day 1 of all cycles (each cycle is 28 days)
Safety Issue:
Description:Maximum Observed Plasma Concentration (Cmax).
Measure:European Organization for Research and Treatment of Cancer Quality-of-Life-Questionnaire-Core-30 (EORTC QLQ-C30) scores
Time Frame:Baseline to End of Study (approximately 3 years)
Safety Issue:
Description: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.
Measure:EuroQol-EQ-5D (EQ-5D-5L) questionnaire scores
Time Frame:Baseline to End of Study (approximately 3 years)
Safety Issue:
Description: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).
Measure:Assessment of AUC
Time Frame:Day 1 of all cycles (each cycle is 28 days)
Safety Issue:
Description:Area under the drug concentration-plasma time curve from time zero to last measurable concentration

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Geron Corporation

Trial Keywords

  • Myeloproliferative neoplasms
  • Polycythemia
  • Thrombocythemia
  • Primary myelofibrosis
  • Janus Kinase-Inhibitor

Last Updated

December 24, 2020