Clinical trial NCT05371964: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Myelofibrosis
Lead sponsor: Geron Corporation
Sponsor class: INDUSTRY
First posted: 2022-05-12
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


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:

  1. 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.
  2. 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).
* Clinical signs/symptoms of MF demonstrated by one of the following:

  1. 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
  2. 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 (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).
* 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 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.
* 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.

Primary outcomes:
measure: Part 1: Incidence, Type, and Severity of Adverse Events, Including Dose-limiting Toxicity (DLT) During the DLT Observation Period and/or Study Treatment
timeFrame: 28 days after first dose
measure: Part 2: Number of Participants With Treatment-emergent Adverse Event (AE)
timeFrame: First dose of study treatment until 30 days after the last dose of study treatment (up to approximately 5 years)
measure: Part 2: Symptom Response Rate at Week 24
timeFrame: Week 24
Secondary outcomes:
measure: Part 1: Pharmacokinetic Profile of Ruxolitinib (Maximum Observed Plasma Concentration [Cmax]
timeFrame: From first dose of Ruxolitinib treatment up to approximately 5 years
measure: Part 1: Pharmacokinetic Profile of Ruxolitinib Time to Reach Maximum Plasma Concentration [Tmax])
timeFrame: From first dose of imetelstat treatment up to approximately 5 years
measure: Part 1 and Part 2: Pharmacokinetic Profile of Imetelstat Sodium Maximum Observed Plasma Concentration [Cmax]
timeFrame: From first dose of imetelstat treatment up to approximately 5 years
measure: Part 1 and Part 2: Pharmacokinetic Profile of Imetelstat Time to Reach Maximum Plasma Concentration [Tmax])
timeFrame: From first dose of imetelstat treatment up to approximately 5 years
measure: Part 1 and Part 2: Percentage of Participants with Anti-imetelstat Antibodies
timeFrame: From first dose of imetelstat treatment up to approximately 5 years
measure: Part 1: Symptom Response at Week 24
timeFrame: Baseline, Week 24
measure: Part 1 and Part 2: Absolute Change From Baseline in TSS at Week 24
timeFrame: Baseline, Week 24
measure: Part 1 and Part 2: Average Absolute Change in TSS Over 24 weeks
timeFrame: Baseline, Week 24
measure: Part 1 and Part 2: Spleen Response at Week 24
timeFrame: Week 24
measure: Part 1 and Part 2: Progression Free Survival (PFS)
timeFrame: From start of study treatment date to the disease progression or death (up to approximately 5 years)
measure: 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.
timeFrame: From first dose to end of the treatment (up to approximately 5 years)
measure: Part 1 and Part 2: Time to Response
timeFrame: From first dose of study treatment to the earliest date that a response was first documented (Up to approximately 5 years)
measure: Part 1 and Part 2: Duration of Response (DOR) Per IWG-MRT Criteria
timeFrame: From time of initial response to PD or death whichever occurs first (up to approximately 5 years)
measure: Part 1 and Part 2: Reduction of Bone Marrow Fibrosis
timeFrame: From first dose to end of the treatment (up to approximately 5 years)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Irvine
country: United States
facility: City of Hope
state: California
city: Coral Gables
country: United States
facility: University of Miami
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research Institute, Inc.
state: Florida
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Denison
country: United States
facility: Texas Oncology
state: Texas
city: Tyler
country: United States
facility: Texas Oncology
state: Texas
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Center
state: Washington
Study officials:
affiliation: Geron Corporation
name: Shyamala Navada, MD
role: STUDY_DIRECTOR
References: