A Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of Imetelstat in Combination With Ruxolitinib in Participants With Myelofibrosis

Official title

An Open Label, Phase 1/1b Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of Imetelstat in Combination With Ruxolitinib in Patients With Myelofibrosis

Overview

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 preliminary clinical activity of the R2PD of imetelstat sodium in combination with ruxolitinib in participants with MF in Part 2.

Interventions

• Drug Imetelstat sodium
  Imetelstat sodium will be administered as intravenous (IV) every 28 days.
• Drug Ruxolitinib
  Ruxolitinib will be administered, orally (PO), twice daily (BID) in cohort B as the standard of care per local prescribing guidelines.

Primary outcome measures

• Part 1: Incidence, Type, and Severity of Adverse Events, Including Dose-limiting Toxicity (DLT) During the DLT Observation Period and/or Study Treatment [Time frame: 28 days after first dose]
• Part 2: Number of Participants With Treatment-emergent Adverse Event (AE) [Time frame: First dose of study treatment until 30 days after the last dose of study treatment (up to approximately 5 years)]
• Part 2: Symptom Response Rate at Week 24 [Time frame: Week 24]

Secondary outcome measures (12)

• Part 1: Pharmacokinetic Profile of Ruxolitinib (Maximum Observed Plasma Concentration [Cmax] [Time frame: From first dose of Ruxolitinib treatment up to approximately 5 years]
• Part 1: Pharmacokinetic Profile of Ruxolitinib Time to Reach Maximum Plasma Concentration [Tmax]) [Time frame: 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] [Time frame: 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]) [Time frame: From first dose of imetelstat treatment up to approximately 5 years]
• Part 1 and Part 2: Percentage of Participants with Anti-imetelstat Antibodies [Time frame: From first dose of imetelstat treatment up to approximately 5 years]
• Part 1: Symptom Response at Week 24 [Time frame: Baseline, Week 24]
• Part 1 and Part 2: Absolute Change From Baseline in TSS at Week 24 [Time frame: Baseline, Week 24]
• Part 1 and Part 2: Average Absolute Change in TSS Over 24 weeks [Time frame: Baseline, Week 24]
• Part 1 and Part 2: Spleen Response at Week 24 [Time frame: Week 24]
• Part 1 and Part 2: Progression Free Survival (PFS) [Time frame: From start of study treatment date to the disease progression or death (up to approximately 5 years)]
• 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. [Time frame: From first dose to end of the treatment (up to approximately 5 years)]
• Part 1 and Part 2: Time to Response [Time frame: From first dose of study treatment to the earliest date that a response was first documented (Up to approximately 5 years)]

Eligibility criteria

Inclusion criteria

• 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.
• Dynamic International Prognostic Scoring System (DIPSS) intermediate-1, intermediate-2 or high-risk MF.
• 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 ruxolitinib per standard of care for at least 12 weeks with at least 4 consecutive weeks at a stable dose prior to enrollment (Cohort B). Note that the study will no longer recruit participants into Cohort A.
• Active symptoms of MF on the MFSAF v4.0 demonstrated by:

• Part 1 participants only: At least 2 symptoms with a score ≥ 1
• Part 2 participants only: At least 2 symptoms with a score of ≥ 3, or a total score of at least 10.
• Ineligible for or unwilling to undergo hematopoietic stem cell transplant at time of study entry.
• Hematology laboratory test values within protocol defined limits.
• Biochemical laboratory test values 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%.
• Prior treatment with JAK inhibitor (except for participants being dosed optimized on ruxolitinib treatment prior to screening and enrollment in part 1 or Part 2 Cohort B).
• Known allergies, hypersensitivity, or intolerance to imetelstat or ruxolitinib or excipients.
• Prior treatment with imetelstat.
• Major surgery within 28 days prior to enrollment.
• Any investigational drug regardless of class or mechanism of action, hydroxyurea, chemotherapy, (except for ruxolitinib for participants being dose optimized prior to enrollment), immunomodulatory or immunosuppressive therapy, corticosteroids >30 mg/day prednisone or equivalent ≤14 days prior to enrollment.
• Prior history of hematopoietic stem cell transplant.
• 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.
• Clinically significant cardiovascular disease.
• Known history of human immunodeficiency virus (HIV) or any uncontrolled active systemic infection requiring IV antibiotics.
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 8 centers

• City of Hope — Duarte
• City of Hope — Irvine
• University of Miami — Coral Gables
• H. Lee Moffitt Cancer Center and Research Institute, Inc. — Tampa
• Icahn School of Medicine at Mount Sinai — New York
• Texas Oncology — Denison
• Texas Oncology — Tyler
• Fred Hutchinson Cancer Center — Seattle

Identifiers

NCT: NCT05371964 · MYF1001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗