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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

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ClinicalTrials.gov Identifier: NCT04576156
Recruitment Status : Recruiting
First Posted : October 6, 2020
Last Update Posted : May 18, 2022
Sponsor:
Information provided by (Responsible Party):
Geron Corporation

Tracking Information
First Submitted Date  ICMJE September 18, 2020
First Posted Date  ICMJE October 6, 2020
Last Update Posted Date May 18, 2022
Actual Study Start Date  ICMJE April 12, 2021
Estimated Primary Completion Date May 1, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 2, 2020)
Overall survival [ Time Frame: Baseline (Day 1) until End of Study (EOS) (approximately 3 years) ]
Overall survival is defined as the time interval from randomization date to date of death from any cause.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 30, 2021)
  • Symptom response rate [ Time Frame: Baseline (Day 1), and at Week 24 ]
    The proportion of participants achieving a ≥50% reduction in Total Symptom Score (TSS) measured at Week 24 compared to baseline
  • Progression-free survival [ Time Frame: Baseline (Day 1) until End of Study (EOS) (approximately 3 years) ]
    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.
  • Spleen response rate [ Time Frame: Baseline (Day 1), and at Week 24 ]
    The proportion of participants who achieve a reduction in spleen volume of ≥ 35% from baseline 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 [ Time Frame: Baseline (Day 1) until End of Treatment (approximately 3 years) ]
    The proportion of participants achieving CR or PR, CI, spleen response, symptom response, and anemia response per modified 2013 IWG-MRT criteria
  • Reduction in the degree of bone marrow fibrosis [ Time Frame: Baseline (Day 1) until End of Treatment (approximately 3 years) ]
    Reduction in the degree of bone marrow fibrosis will be assessed.
  • Number of Participants with Adverse Events [ Time Frame: Screening (Day -28 to -1) until End of Study (approximately 3 years) ]
    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
  • Assessment of Cmax [ Time Frame: Day 1 of all cycles (each cycle is 21 days) ]
    Maximum Observed Plasma Concentration (Cmax).
  • 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) ]
    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.
  • EuroQol-EQ-5D (EQ-5D-5L) questionnaire scores [ Time Frame: Baseline to End of Study (approximately 3 years) ]
    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).
  • Assessment of AUC [ Time Frame: Day 1 of all cycles (each cycle is 21 days) ]
    Area under the drug concentration-plasma time curve (AUC) from time zero to last measurable concentration
Original Secondary Outcome Measures  ICMJE
 (submitted: October 2, 2020)
  • Symptom response rate [ Time Frame: Baseline (Day 1), and at Week 24 ]
    The proportion of participants achieving a ≥50% reduction in Total Symptom Score (TSS) measured at Week 24 compared to baseline
  • Progression-free survival [ Time Frame: Baseline (Day 1) until End of Study (EOS) (approximately 3 years) ]
    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.
  • Spleen response rate [ Time Frame: Baseline (Day 1), and at Week 24 ]
    The proportion of participants who achieve a reduction in spleen volume of ≥ 35% from baseline at Week 24.
  • 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) ]
    The proportion of participants achieving CR or PR, CI, spleen response, symptom response, and anemia response per modified 2013 IWG-MRT criteria
  • Reduction in the degree of bone marrow fibrosis [ Time Frame: Baseline (Day 1) until End of Treatment (approximately 3 years) ]
    Reduction in the degree of bone marrow fibrosis will be assessed.
  • Number of Participants with Adverse Events [ Time Frame: Screening (Day -28 to -1) until End of Study (approximately 3 years) ]
    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
  • Assessment of Cmax [ Time Frame: Day 1 of all cycles (each cycle is 28 days) ]
    Maximum Observed Plasma Concentration (Cmax).
  • 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) ]
    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.
  • EuroQol-EQ-5D (EQ-5D-5L) questionnaire scores [ Time Frame: Baseline to End of Study (approximately 3 years) ]
    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).
  • Assessment of AUC [ Time Frame: Day 1 of all cycles (each cycle is 28 days) ]
    Area under the drug concentration-plasma time curve from time zero to last measurable concentration
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Myelofibrosis
Intervention  ICMJE
  • Drug: Imetelstat
    Imetelstat will be given intravenously at 9.4 mg/kg every 21 days, until disease progression or unacceptable toxicity, treatment discontinuation or study end.
    Other Name: GRN163L
  • Drug: Best Available Therapy (BAT)
    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, and chemotherapy.
Study Arms  ICMJE
  • Experimental: Imetelstat
    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.
    Intervention: Drug: Imetelstat
  • Active Comparator: Best Available Therapy (BAT)
    Participants will receive BAT (investigator-selected non-JAK-inhibitor treatment), until disease progression or unacceptable toxicity, treatment discontinuation or study end.
    Intervention: Drug: Best Available Therapy (BAT)
Publications * Mascarenhas J, Harrison CN, Kiladjian JJ, Komrokji RS, Koschmieder S, Vannucchi AM, Berry T, Redding D, Sherman L, Dougherty S, Peng L, Sun L, Huang F, Wan Y, Feller FM, Rizo A, Verstovsek S. Imetelstat in intermediate-2 or high-risk myelofibrosis refractory to JAK inhibitor: IMpactMF phase III study design. Future Oncol. 2022 May 5. doi: 10.2217/fon-2022-0235. [Epub ahead of print] Review.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 2, 2020)
320
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 1, 2024
Estimated Primary Completion Date May 1, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 or length by imaging) 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Faye Feller, MD 650-473-7745 myf3001-info@Geron.com
Contact: Souria Dougherty myf3001-info@Geron.com
Listed Location Countries  ICMJE Argentina,   Australia,   Austria,   Belgium,   Brazil,   Bulgaria,   Colombia,   Denmark,   France,   Georgia,   Germany,   Hungary,   India,   Israel,   Italy,   Korea, Republic of,   Malaysia,   Poland,   Portugal,   Russian Federation,   Singapore,   Spain,   Switzerland,   Taiwan,   Turkey,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04576156
Other Study ID Numbers  ICMJE MYF3001
2020-003288-24 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Geron Corporation
Study Sponsor  ICMJE Geron Corporation
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Faye Feller Geron Corporation
PRS Account Geron Corporation
Verification Date May 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP