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

Study Overview
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Brief Summary
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The purpose of the study is to identify the recommended Part 2 dose (R2PD) of imetelstat 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 in combination with ruxolitinib in participants with MF in Part 2.

Official Title
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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

Conditions
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Myelofibrosis

Intervention / Treatment
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* Drug: Imetelstat
* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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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 only: 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 only: Candidate for ruxolitinib treatment as assessed by the investigator and has not previously been treated with a JAK inhibitor. 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, active symptoms of MF on the MFSAF v4.0. 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. 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, immunomodulatory or immunosuppressive therapy, corticosteroids >30 mg/day prednisone or equivalent ≤14 days prior to enrollment. Prior history of hematopoietic stem cell transplant. Prior history of partial or complete splenectomy. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Imetelstat + Ruxolitinib<br>Part 1: 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 therapy. Dose levels of imetelstat may include 4.7, 6, 7.5, 9.4mg, until a RP2D is established. Part 2: Janus kinase (JAK) inhibitor naïve participants will receive initial treatment with ruxolitinib for at least 12 weeks, including 4 weeks at a stable dose, followed by imetelstat treatment at the RP2D in combination with ruxolitinib. | Drug: Imetelstat<br>* Imetelstat sodium will be administered as intravenous (IV) every 28 days.<br>* Other names: GRN163L;Drug: Ruxolitinib<br>* Ruxolitinib will be administered, orally (PO), twice daily (BID) as the standard of care per local prescribing guidelines.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Part 2: Number of Participants With Treatment-emergent Adverse Event (AE) | 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. | 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 | 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. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 and 2: Pharmacokinetic Profile of Imetelstat and Ruxolitinib (Maximum Observed Plasma Concentration [Cmax] |  | From first dose of imetelstat treatment up to approximately 5 years | 
| Part 1 and 2: Pharmacokinetic Profile of Imetelstat and Ruxolitinib Area under the Plasma Concentration [AUC0-24] |  | From first dose of imetelstat treatment up to approximately 5 years | 
| Part 1 and 2: Pharmacokinetic Profile of Imetelstat and Ruxolitinib Terminal Disposition Half-life [T1/2] |  | From first dose of imetelstat treatment up to approximately 5 years | 
| Part 1 and 2: Pharmacokinetic Profile of Imetelstat and Ruxolitinib Time to Reach Maximum Plasma Concentration [Tmax]) |  | From first dose of imetelstat treatment up to approximately 5 years | 
| Part 1 and 2: Imetelstat and Ruxolitinib Exposure From Time Zero to Last Measurable Concentration (AUC0-t) |  | From first dose of imetelstat treatment up to approximately 5 years | 
| 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 | 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. | Week 24 | 
| Part 1 and 2: Spleen Response at 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). | Week 24 | 
| Part 1 and 2: Progression Free Survival (PFS) | The time interval from start of study treatment date to the first date of disease progression or death from any cause, whichever occurs first. | From start of study treatment date to the disease progression or death (up to approximately 5 years) | 
| Part 1 and 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 2: Time to Response | 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. | From first dose of study treatment to the earliest date that a response was first documented (Up to approximately 5 years) | 
| Part 1 and 2: Duration of Response (DOR) Per IWG-MRT Criteria | DOR measured from time of initial response (CR/PR/CI) until documented PD or death whichever occurs first. | From time of initial response to PD or death whichever occurs first (up to approximately 5 years) | 
| Part 1 and 2: Reduction of Bone Marrow Fibrosis | 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. | From first dose to end of the treatment (up to approximately 5 years) |