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

• ClinicalTrials.gov Identifier: NCT04576156
• Recruitment Status: Recruiting
• First Posted: October 6, 2020
• Last Update Posted: June 1, 2023
• Sponsor: Geron Corporation
• Information provided by (Responsible Party): Geron Corporation

Tracking Information

• First Submitted Date: September 18, 2020
• First Posted Date: October 6, 2020
• Last Update Posted Date: June 1, 2023
• Actual Study Start Date: April 12, 2021
• Estimated Primary Completion Date: August 27, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 19, 2022)

Overall survival (OS) [ 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 (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.

Current Secondary Outcome Measures (submitted: August 19, 2022)

• 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).
• Assessment of Tmax [ Time Frame: Day 1 of all cycles (each cycle is 21 days) ]
  Time to reach the maximum observed plasma concentration
• Assessment of t1/2 [ Time Frame: Day 1 of all cycles (each cycle is 21 days) ]
  Elimination half-life.
• 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
• 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).

Original Secondary Outcome Measures (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: 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) Relapsed / Refractory (R/R) 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 relapsed/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: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Myelofibrosis

Intervention

• 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, chemotherapy or radiotherapy.

Study Arms

• 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.

  Participants on BAT who meet protocol-defined criteria for progressive disease may crossover to receive imetelstat treatment after sponsor's approval.

  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 Jul;18(22):2393-2402. doi: 10.2217/fon-2022-0235. Epub 2022 May 5.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 2, 2020): 320
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: August 27, 2025
• Estimated Primary Completion Date: August 27, 2025 (Final data collection date for primary outcome measure)

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

• 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:

    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 Myelofibrosis Symptom Assessment Form [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]).

  • (iii) Following maximum tolerated doses of JAK inhibitor therapy for ≥3 months duration, having documented relapsed disease defined as either

    1. Increase in spleen volume from time of best response by 25% measured by MRI or CT, or

    2. 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Tymara Berry, MD; 650-473-7793; myf3001-info@Geron.com

Contact: Denise Redding; myf3001-info@Geron.com

• Listed Location Countries: 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, Taiwan, Turkey, United Kingdom, United States
• Removed Location Countries: Switzerland

Administrative Information

• NCT Number: NCT04576156
• Other Study ID Numbers: 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: Not Provided
• Current Responsible Party: Geron Corporation
• Original Responsible Party: Same as current
• Current Study Sponsor: Geron Corporation
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Faye Feller; Geron Corporation

• PRS Account: Geron Corporation
• Verification Date: May 2023