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Bomedemstat (IMG-7289) Plus Ruxolitinib for Myelofibrosis

Primary Purpose

Myelofibrosis

Status
Recruiting
Phase
Phase 2
Locations
Hong Kong
Study Type
Interventional
Intervention
Bomedemstat
Sponsored by
The University of Hong Kong
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Myelofibrosis focused on measuring Myelofibrosis, Bomedemstat, Ruxolitinib

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Cohort A:

1. Patients refractory to, relapsed or intolerant of ruxolitinib as per one of the below:

  • Refractory is defined as <30% reduction in spleen length or <10% SVR compared to baseline having received ruxolitinib for ≥12 weeks prior to enrollment, AND on a stable dose for ≥8 weeks prior to starting investigational therapy
  • Relapsed is defined as an increase in spleen volume of ≥25% by MRI/CT from nadir, or, ≥100% in palpable spleen length from a baseline of 5 to 10 cm BLCM or, ≥50% increase in spleen length from a baseline spleen length ≥10 cm BLCM
  • Intolerance is defined as the development in patients treated with ruxolitinib for ≥28 days of:

    • Red blood cell transfusion requirement of 2 units/month for 2 months
    • Grade 3 thrombocytopenia, anemia, hematoma, and/or hemorrhage while on ruxolitinib treatment

Cohort B:

  1. Patients who are JAK inhibitor naïve, AND:

    • Require MF-directed treatment, AND
    • Have measurable disease burden including one of the following:

      • Disease-related symptoms, determined by a MFSAF or MPN-SAF TSS of ≥10, or at least 2 symptoms with scores ≥3
      • Documented splenomegaly by physical exam, with spleen palpated ≥5 cm below the left costal margin

    Both Cohorts A and B:

  2. Willing and able to provide informed consent
  3. Age ≥18 years
  4. Diagnosis of Overt Myelofibrosis (primary, post-ET, or post-PV) per World Health Organization (WHO) diagnostic criteria
  5. Intermediate-1, Intermediate-2, or high-risk disease by Dynamic International Prognostic Scoring System (DIPSS)
  6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
  7. Platelet count ≥100 x 10^9/L prior to dosing on Cycle 1 Day 1
  8. Absolute neutrophil count ≥0.5 x 10^9/L prior to dosing on Cycle 1 Day 1
  9. Peripheral blast count ≤10% prior to dosing on Cycle 1 Day 1
  10. Able to swallow capsules
  11. Women of childbearing potential and fertile men must agree to use an approved method of contraception from Screening until 30 days after the last dose of bomedemstat and ruxolitinib.

Exclusion Criteria:

  1. Those with increased risk of bleeding, including any of the following:

    1. Activated partial thromboplastin time (aPTT) ≥1.3 x the local upper limit of normal
    2. International normalized ratio (INR) ≥1.3 x the local upper limit of normal
    3. Known history of a platelet function disorder
    4. Other known bleeding disorder that is active at the time of screening (Von Willebrand's disease, dysfibrinogenemia, hemophilia, etc.)
  2. History of splenectomy or prior splenic irradiation
  3. Use of an investigational agent within 14 days of study treatment (or at least 7 half-lives of that agent, whichever is longer), prior to the first dose of bomedemstat
  4. Current use of monoamine oxidase A and B inhibitors (MAOIs)
  5. Uncontrolled, active infection
  6. Major surgery within 4 weeks of starting the study drug, or not recovered from side effects of surgery
  7. Any other serious medical conditions that could compromise study participation, in the opinion of the investigator
  8. Known HIV infection or known, active hepatitis B or hepatitis C infection
  9. Concurrent second active and non-stable malignancy (patients with a concurrent second active but stable malignancy, i.e., non-melanoma skin cancers, are eligible)
  10. Current use of a prohibited medication (e.g., romiplostim) or expected to require any of these medications during treatment
  11. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to bomedemstat or LSD1 inhibitors (i.e., monoamine oxidase inhibitors; MAOIs) that contraindicates participation
  12. Evidence at the time of Screening of significant renal or hepatic insufficiency (unless due to hemolysis) as defined by any of the following local lab parameters:

    1. Calculated glomerular filtration rate (GFR; using the Cockcroft-Gault equation) <40 mL/min or serum creatinine >1.5 x the local upper limit of normal
    2. Aspartate transaminase (AST) or alanine aminotransferase (ALT) ≥2.5 x the local upper limit of normal
  13. Pregnant or lactating females, or females planning to become pregnant at any time during the study
  14. Unwilling or unable to comply with the study protocol

Sites / Locations

  • Department of Medicine, the University of Hong Kong, Queen Mary HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Cohort A (Patients refractory to, relapsed or intolerant of ruxolitinib):

Cohort B (Cohort B will consist of 10 patients who are JAK inhibitor naïve):

Arm Description

Bomedemstat : The starting dose of bomedemstat at Initial Treatment Period Cycle 1 Day 1 will be 0.4 mg/kg daily for all patients in Cohort A. The first up-titration is not permitted until Initial Treatment Period Cycle 2 Day 1; thereafter, the dose may be up-titrated no more frequently than every 4 weeks from the prior up- or down-titration (note: down-titrations may occur at any time (or the current dose maintained) in the best interest and safety of the patient), to a target platelet count range of 50-100 x 10^9/L. Ruxolitinib: Patients will continue their prior, stable dose of ruxolitinib. This same dose will be continued throughout the study unless dose modification is required because of toxicity.

Bomedemstat: The starting dose of bomedemstat at Initial Treatment Period Cycle 1 Day 1 will be 0.4 mg/kg daily for all patients in Cohort B. The first up-titration is not permitted until Initial Treatment Period Cycle 2 Day 1; thereafter, the dose may be up-titrated no more frequently than every 4 weeks from the prior up- or down-titration (note: down-titrations may occur at any time (or the current dose maintained) in the best interest and safety of the patient), to a target platelet count range of 50-100 x 10^9/L. Ruxolitinib: Patients will start treatment with ruxolitinib at Initial Treatment Period Cycle 1 Day 1. The starting dose of ruxolitinib will be 10 mg BID. This same dose will be continued throughout the study unless dose modification is required because of toxicity.

Outcomes

Primary Outcome Measures

Adverse events
Enumeration and description of adverse events (AEs), including determination of dose limiting toxicities (DLTs), serious adverse events (SAEs), and other AEs

Secondary Outcome Measures

Spleen response at 24 weeks
Proportion of patients who experience a spleen length reduction by palpation of ≥30% OR spleen volume reduction (SVR) of ≥35% by MRI or CT by 24 weeks of treatment
Symptom response at 24 weeks
Proportion of patients who describe a ≥50% reduction in symptom burden by the Myelofibrosis Symptom Assessment Form (MFSAF) by 24 weeks of treatment

Full Information

First Posted
October 3, 2022
Last Updated
May 21, 2023
Sponsor
The University of Hong Kong
Collaborators
Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc., (Rahway, New Jersey USA)
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1. Study Identification

Unique Protocol Identification Number
NCT05569538
Brief Title
Bomedemstat (IMG-7289) Plus Ruxolitinib for Myelofibrosis
Official Title
Phase 2 Study to Assess the Safety and Efficacy of Bomedemstat (IMG-7289) in Combination With Ruxolitinib in Patients With Myelofibrosis
Study Type
Interventional

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Recruiting
Study Start Date
December 1, 2022 (Actual)
Primary Completion Date
December 31, 2024 (Anticipated)
Study Completion Date
December 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
The University of Hong Kong
Collaborators
Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc., (Rahway, New Jersey USA)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is an open-label, Phase 2 study of bomedemstat (IMG-7289), an inhibitor of lysine-specific demethylase 1 (LSD1), in combination with JAK inhibition (JAKi) in patients with myelofibrosis.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myelofibrosis
Keywords
Myelofibrosis, Bomedemstat, Ruxolitinib

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Cohort A (Patients refractory to, relapsed or intolerant of ruxolitinib):
Arm Type
Experimental
Arm Description
Bomedemstat : The starting dose of bomedemstat at Initial Treatment Period Cycle 1 Day 1 will be 0.4 mg/kg daily for all patients in Cohort A. The first up-titration is not permitted until Initial Treatment Period Cycle 2 Day 1; thereafter, the dose may be up-titrated no more frequently than every 4 weeks from the prior up- or down-titration (note: down-titrations may occur at any time (or the current dose maintained) in the best interest and safety of the patient), to a target platelet count range of 50-100 x 10^9/L. Ruxolitinib: Patients will continue their prior, stable dose of ruxolitinib. This same dose will be continued throughout the study unless dose modification is required because of toxicity.
Arm Title
Cohort B (Cohort B will consist of 10 patients who are JAK inhibitor naïve):
Arm Type
Experimental
Arm Description
Bomedemstat: The starting dose of bomedemstat at Initial Treatment Period Cycle 1 Day 1 will be 0.4 mg/kg daily for all patients in Cohort B. The first up-titration is not permitted until Initial Treatment Period Cycle 2 Day 1; thereafter, the dose may be up-titrated no more frequently than every 4 weeks from the prior up- or down-titration (note: down-titrations may occur at any time (or the current dose maintained) in the best interest and safety of the patient), to a target platelet count range of 50-100 x 10^9/L. Ruxolitinib: Patients will start treatment with ruxolitinib at Initial Treatment Period Cycle 1 Day 1. The starting dose of ruxolitinib will be 10 mg BID. This same dose will be continued throughout the study unless dose modification is required because of toxicity.
Intervention Type
Drug
Intervention Name(s)
Bomedemstat
Other Intervention Name(s)
IMG-7289
Intervention Description
Bomedemstat will be self-administered orally once daily. In both cohorts, the dose of bomedemstat will be adjusted in each patient based on titration of the patient's platelet count to the target range. Ruxolitinib will be self-administered orally. Both medications will continue uninterrupted in 28-day cycles. Subjects will continue combination treatment through the Initial Treatment Period (first 6 cycles), which includes a Qualification Assessment. Those deriving clinical benefit in the opinion of the treating physician may continue receiving combination treatment in the Additional Treatment Period (6 cycles). Qualification Assessments will be performed at the end of each Additional Treatment Period, which is iterative, and may repeat for as long as clinical benefit is sustained, at the discretion of the treating physician.
Primary Outcome Measure Information:
Title
Adverse events
Description
Enumeration and description of adverse events (AEs), including determination of dose limiting toxicities (DLTs), serious adverse events (SAEs), and other AEs
Time Frame
24 months
Secondary Outcome Measure Information:
Title
Spleen response at 24 weeks
Description
Proportion of patients who experience a spleen length reduction by palpation of ≥30% OR spleen volume reduction (SVR) of ≥35% by MRI or CT by 24 weeks of treatment
Time Frame
24 weeks
Title
Symptom response at 24 weeks
Description
Proportion of patients who describe a ≥50% reduction in symptom burden by the Myelofibrosis Symptom Assessment Form (MFSAF) by 24 weeks of treatment
Time Frame
24 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Cohort A: 1. Patients refractory to, relapsed or intolerant of ruxolitinib as per one of the below: Refractory is defined as <30% reduction in spleen length or <10% SVR compared to baseline having received ruxolitinib for ≥12 weeks prior to enrollment, AND on a stable dose for ≥8 weeks prior to starting investigational therapy Relapsed is defined as an increase in spleen volume of ≥25% by MRI/CT from nadir, or, ≥100% in palpable spleen length from a baseline of 5 to 10 cm BLCM or, ≥50% increase in spleen length from a baseline spleen length ≥10 cm BLCM Intolerance is defined as the development in patients treated with ruxolitinib for ≥28 days of: Red blood cell transfusion requirement of 2 units/month for 2 months Grade 3 thrombocytopenia, anemia, hematoma, and/or hemorrhage while on ruxolitinib treatment Cohort B: Patients who are JAK inhibitor naïve, AND: Require MF-directed treatment, AND Have measurable disease burden including one of the following: Disease-related symptoms, determined by a MFSAF or MPN-SAF TSS of ≥10, or at least 2 symptoms with scores ≥3 Documented splenomegaly by physical exam, with spleen palpated ≥5 cm below the left costal margin Both Cohorts A and B: Willing and able to provide informed consent Age ≥18 years Diagnosis of Overt Myelofibrosis (primary, post-ET, or post-PV) per World Health Organization (WHO) diagnostic criteria Intermediate-1, Intermediate-2, or high-risk disease by Dynamic International Prognostic Scoring System (DIPSS) Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 Platelet count ≥100 x 10^9/L prior to dosing on Cycle 1 Day 1 Absolute neutrophil count ≥0.5 x 10^9/L prior to dosing on Cycle 1 Day 1 Peripheral blast count ≤10% prior to dosing on Cycle 1 Day 1 Able to swallow capsules Women of childbearing potential and fertile men must agree to use an approved method of contraception from Screening until 30 days after the last dose of bomedemstat and ruxolitinib. Exclusion Criteria: Those with increased risk of bleeding, including any of the following: Activated partial thromboplastin time (aPTT) ≥1.3 x the local upper limit of normal International normalized ratio (INR) ≥1.3 x the local upper limit of normal Known history of a platelet function disorder Other known bleeding disorder that is active at the time of screening (Von Willebrand's disease, dysfibrinogenemia, hemophilia, etc.) History of splenectomy or prior splenic irradiation Use of an investigational agent within 14 days of study treatment (or at least 7 half-lives of that agent, whichever is longer), prior to the first dose of bomedemstat Current use of monoamine oxidase A and B inhibitors (MAOIs) Uncontrolled, active infection Major surgery within 4 weeks of starting the study drug, or not recovered from side effects of surgery Any other serious medical conditions that could compromise study participation, in the opinion of the investigator Known HIV infection or known, active hepatitis B or hepatitis C infection Concurrent second active and non-stable malignancy (patients with a concurrent second active but stable malignancy, i.e., non-melanoma skin cancers, are eligible) Current use of a prohibited medication (e.g., romiplostim) or expected to require any of these medications during treatment Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to bomedemstat or LSD1 inhibitors (i.e., monoamine oxidase inhibitors; MAOIs) that contraindicates participation Evidence at the time of Screening of significant renal or hepatic insufficiency (unless due to hemolysis) as defined by any of the following local lab parameters: Calculated glomerular filtration rate (GFR; using the Cockcroft-Gault equation) <40 mL/min or serum creatinine >1.5 x the local upper limit of normal Aspartate transaminase (AST) or alanine aminotransferase (ALT) ≥2.5 x the local upper limit of normal Pregnant or lactating females, or females planning to become pregnant at any time during the study Unwilling or unable to comply with the study protocol
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Harinder Gill, MD
Phone
+852 22554542
Email
gillhsh@hku.hk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Harinder Gill, MD
Organizational Affiliation
Department of Medicine, the University of Hong Kong
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Medicine, the University of Hong Kong, Queen Mary Hospital
City
Hong Kong
Country
Hong Kong
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Harinder Singh Harry Gill, MD
Phone
+852 22554254
Email
gillhsh@hku.hk

12. IPD Sharing Statement

Plan to Share IPD
No

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Bomedemstat (IMG-7289) Plus Ruxolitinib for Myelofibrosis

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