A Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of Imetelstat in Combination With Ruxolitinib in Participants With Myelofibrosis
- Conditions
- Myelofibrosis
- Interventions
- Registration Number
- NCT05371964
- Lead Sponsor
- Geron Corporation
- Brief Summary
The purpose of the study is to identify the recommended Part 2 dose (R2PD) of imetelstat sodium in combination with ruxolitinib in participants with myelofibrosis (MF) in Part 1, and to evaluate the safety and clinical activity of the R2PD of imetelstat sodium in combination with ruxolitinib or other Janus Kinase (JAK) inhibitors in participants with MF in Part 2.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 51
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Diagnosis of primary myelofibrosis (PMF) according to the revised World Health Organization (WHO) criteria or post-essential thrombocythemia-MF or post-polycythemia vera according to the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria.
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Dynamic International Prognostic Scoring System (DIPSS) intermediate-1, intermediate-2 or high-risk MF.
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Candidate for ruxolitinib treatment:
- Part 1 participants: On ruxolitinib treatment for at least 12 weeks with at least 4 consecutive weeks immediately prior to enrollment at a stable dose.
- Part 2 participants: Candidate for ruxolitinib treatment as assessed by the investigator and has not previously been treated with a JAK inhibitor (Cohort A) OR currently receiving JAK inhibitor treatment per standard of care for at least 12 weeks (maximum 48 weeks) with at least 4 consecutive weeks at a stable dose prior to enrollment (Cohort B).
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Clinical signs/symptoms of MF demonstrated by one of the following:
- Measurable splenomegaly demonstrated by either a palpable spleen measuring ≥5 cm below the left costal margin or a spleen volume ≥450 cm^3 by MRI or CT, AND
- active symptoms of MF on the MFSAF v4.0.
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Ineligible for or unwilling to undergo hematopoietic stem cell transplant at time of study entry.
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Hematology laboratory test values within protocol defined limits.
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Biochemical laboratory test values within protocol defined limits.
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Eastern Cooperative Oncology Group Performance Status score of 0, 1, or 2.
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Participants should follow protocol defined contraceptives procedures.
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A woman of childbearing potential must have a negative serum or urine pregnancy test at screening.
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Peripheral blood blast count of ≥10% or bone marrow blast count of ≥10%.
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Prior treatment with JAK inhibitor (except for participants being dosed optimized on ruxolitinib or other JAK inhibitor treatment prior to screening and enrollment in part 1 or Part 2 Cohort B).
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Known allergies, hypersensitivity, or intolerance to imetelstat or ruxolitinib or excipients.
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Prior treatment with imetelstat.
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Major surgery within 28 days prior to enrollment.
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Any investigational drug regardless of class or mechanism of action, hydroxyurea, chemotherapy, (except for ruxolitinib or other JAK inhibitor for participants being dose optimized on JAK inhibitor treatment prior to enrollment), immunomodulatory or immunosuppressive therapy, corticosteroids >30 mg/day prednisone or equivalent ≤14 days prior to enrollment.
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Prior history of hematopoietic stem cell transplant.
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Prior history of partial or complete splenectomy.
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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 enrollment.
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
- Adequately treated cervical carcinoma in situ without evidence of disease.
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Clinically significant cardiovascular disease.
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Known history of human immunodeficiency virus (HIV) or any uncontrolled active systemic infection requiring IV antibiotics.
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Active systemic hepatitis infection requiring treatment or any known acute or chronic liver disease unless related to MF. Carriers of hepatitis virus are permitted to enter the study.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Part 2: Imetelstat sodium + Ruxolitinib or other JAK inhibitor Pacritinib Cohort A: Janus Kinase (JAK) inhibitor naive participants will receive initial treatment with ruxolitinib on study for at least 12 weeks, including 4 consecutive weeks at a stable dose, prior to the addition of imetelstat sodium. Participants can begin imetelstat sodium treatment after sponsor review and approval and meet the following requirements: platelet value is ≥100 x 109/L for two consecutive measurements, at least 1 week apart, and the participant does not meet criteria for dose delay. Cohort B: Participants will receive treatment with ruxolitinib or other JAK inhibitor for 12 weeks (maximum 48 weeks) with at least 4 consecutive weeks at a stable dose prior to enrollment and will start combination treatment with imetelstat on study. Part 2: Imetelstat sodium + Ruxolitinib or other JAK inhibitor Momelotinib Cohort A: Janus Kinase (JAK) inhibitor naive participants will receive initial treatment with ruxolitinib on study for at least 12 weeks, including 4 consecutive weeks at a stable dose, prior to the addition of imetelstat sodium. Participants can begin imetelstat sodium treatment after sponsor review and approval and meet the following requirements: platelet value is ≥100 x 109/L for two consecutive measurements, at least 1 week apart, and the participant does not meet criteria for dose delay. Cohort B: Participants will receive treatment with ruxolitinib or other JAK inhibitor for 12 weeks (maximum 48 weeks) with at least 4 consecutive weeks at a stable dose prior to enrollment and will start combination treatment with imetelstat on study. Part 2: Imetelstat sodium + Ruxolitinib or other JAK inhibitor Fedratinib Cohort A: Janus Kinase (JAK) inhibitor naive participants will receive initial treatment with ruxolitinib on study for at least 12 weeks, including 4 consecutive weeks at a stable dose, prior to the addition of imetelstat sodium. Participants can begin imetelstat sodium treatment after sponsor review and approval and meet the following requirements: platelet value is ≥100 x 109/L for two consecutive measurements, at least 1 week apart, and the participant does not meet criteria for dose delay. Cohort B: Participants will receive treatment with ruxolitinib or other JAK inhibitor for 12 weeks (maximum 48 weeks) with at least 4 consecutive weeks at a stable dose prior to enrollment and will start combination treatment with imetelstat on study. Part 1: Imetelstat sodium + Ruxolitinib Imetelstat sodium Participants who have received ruxolitinib orally (PO) as part of standard of care (SOC) for at least 12 weeks prior to Screening will be enrolled. After enrollment, participants will initiate imetelstat sodium therapy. Dose levels of imetelstat sodium may include 4.7, 6, 7.5, 9.4mg, until a RP2D is established. Part 1: Imetelstat sodium + Ruxolitinib Ruxolitinib Participants who have received ruxolitinib orally (PO) as part of standard of care (SOC) for at least 12 weeks prior to Screening will be enrolled. After enrollment, participants will initiate imetelstat sodium therapy. Dose levels of imetelstat sodium may include 4.7, 6, 7.5, 9.4mg, until a RP2D is established. Part 2: Imetelstat sodium + Ruxolitinib or other JAK inhibitor Imetelstat sodium Cohort A: Janus Kinase (JAK) inhibitor naive participants will receive initial treatment with ruxolitinib on study for at least 12 weeks, including 4 consecutive weeks at a stable dose, prior to the addition of imetelstat sodium. Participants can begin imetelstat sodium treatment after sponsor review and approval and meet the following requirements: platelet value is ≥100 x 109/L for two consecutive measurements, at least 1 week apart, and the participant does not meet criteria for dose delay. Cohort B: Participants will receive treatment with ruxolitinib or other JAK inhibitor for 12 weeks (maximum 48 weeks) with at least 4 consecutive weeks at a stable dose prior to enrollment and will start combination treatment with imetelstat on study. Part 2: Imetelstat sodium + Ruxolitinib or other JAK inhibitor Ruxolitinib Cohort A: Janus Kinase (JAK) inhibitor naive participants will receive initial treatment with ruxolitinib on study for at least 12 weeks, including 4 consecutive weeks at a stable dose, prior to the addition of imetelstat sodium. Participants can begin imetelstat sodium treatment after sponsor review and approval and meet the following requirements: platelet value is ≥100 x 109/L for two consecutive measurements, at least 1 week apart, and the participant does not meet criteria for dose delay. Cohort B: Participants will receive treatment with ruxolitinib or other JAK inhibitor for 12 weeks (maximum 48 weeks) with at least 4 consecutive weeks at a stable dose prior to enrollment and will start combination treatment with imetelstat on study.
- Primary Outcome Measures
Name Time Method Part 2: Number of Participants With Treatment-emergent Adverse Event (AE) First dose of study treatment until 30 days after the last dose of study treatment (up to approximately 5 years) Safety will be assessed based on incidence and severity (according to Common Terminology Criteria for Adverse Events) of treatment emergent adverse events from the first dose of study treatment until 30 days after completion of treatment.
Part 2: Symptom Response Rate at Week 24 Week 24 Symptom response rate is defined as percentage of participants with \>50% reduction in the Total Symptom Score (TSS) measured by the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 e-diary at 24 week compared to baseline.
Part 1: Incidence, Type, and Severity of Adverse Events, Including Dose-limiting Toxicity (DLT) During the DLT Observation Period and/or Study Treatment 28 days after first dose
- Secondary Outcome Measures
Name Time Method Part 1 and Part 2: Percentage of Participants With Complete Remission (CR), Partial Remission (PR), Clinical Improvement (CI) Per the Modified 2013 International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Criteria. From first dose to end of the treatment (up to approximately 5 years) Part 1 and Part 2: Time to Response From first dose of study treatment to the earliest date that a response was first documented (Up to approximately 5 years) Time to response was defined as the duration from first dose of study treatment to the earliest date that a response is first documented. The response CI/CR/PR was assessed by IWG-MRT criteria.
Part 1 and Part 2: Duration of Response (DOR) Per IWG-MRT Criteria From time of initial response to PD or death whichever occurs first (up to approximately 5 years) DOR measured from time of initial response (CR/PR/CI) until documented PD or death whichever occurs first.
Part 1 and Part 2: Reduction of Bone Marrow Fibrosis From first dose to end of the treatment (up to approximately 5 years) Reduction of bone marrow fibrosis is defined as the percentage of participants with a post-baseline bone marrow fibrosis degree smaller than the baseline fibrosis degree prior to start of subsequent anticancer therapy.
Part 1: Pharmacokinetic Profile of Ruxolitinib (Maximum Observed Plasma Concentration [Cmax] From first dose of Ruxolitinib treatment up to approximately 5 years Part 1: Pharmacokinetic Profile of Ruxolitinib Time to Reach Maximum Plasma Concentration [Tmax]) From first dose of imetelstat treatment up to approximately 5 years Part 1 and Part 2: Pharmacokinetic Profile of Imetelstat Sodium Maximum Observed Plasma Concentration [Cmax] From first dose of imetelstat treatment up to approximately 5 years Part 1 and Part 2: Pharmacokinetic Profile of Imetelstat Time to Reach Maximum Plasma Concentration [Tmax]) From first dose of imetelstat treatment up to approximately 5 years Part 1 and Part 2: Percentage of Participants with Anti-imetelstat Antibodies From first dose of imetelstat treatment up to approximately 5 years Part 1: Symptom Response at Week 24 Baseline, Week 24 Symptom response rate is defined as percentage of participants with \>50% reduction in the TSS measured by the MFSAF v4.0 e-diary at 24 week compared to baseline.
Part 1 and Part 2: Absolute Change From Baseline in TSS at Week 24 Baseline, Week 24 Absolute change is defined as change in total symptom score from baseline to week 24 as measured by the MFSAF v4.0 e-diary.
Part 1 and Part 2: Average Absolute Change in TSS Over 24 weeks Baseline, Week 24 Average absolute change in TSS is defined as change in the average of absolute change in total symptom score from week 1(baseline) to week 24 as measured by the MFSAF v4.0 e-diary.
Part 1 and Part 2: Spleen Response at Week 24 Week 24 Spleen response is the proportion of participants who achieve a reduction in spleen volume of ≥35% from baseline confirmed by magnetic resonance imaging (MRI) or computed tomography (CT).
Part 1 and Part 2: Progression Free Survival (PFS) From start of study treatment date to the disease progression or death (up to approximately 5 years) The time interval from start of study treatment date to the first date of disease progression or death from any cause, whichever occurs first.
Trial Locations
- Locations (6)
Texas Oncology
🇺🇸Tyler, Texas, United States
City of Hope
🇺🇸Irvine, California, United States
University of Miami
🇺🇸Coral Gables, Florida, United States
H. Lee Moffitt Cancer Center and Research Institute, Inc.
🇺🇸Tampa, Florida, United States
Icahn School of Medicine at Mount Sinai
🇺🇸New York, New York, United States
Fred Hutchinson Cancer Center
🇺🇸Seattle, Washington, United States