Clinical Trials /

KRT-232 Versus Best Available Therapy for the Treatment of Subjects With Myelofibrosis Who Are Relapsed or Refractory to JAK Inhibitor Treatment

NCT03662126

Description:

This study evaluates KRT-232, a novel oral small molecule inhibitor of MDM2, for the treatment of patients with myelofibrosis (MF) who no longer benefit from treatment with a JAK inhibitor. Inhibition of MDM2 is a novel mechanism of action in MF. This study will be conducted in 2 phases. Phase 2 will determine the KRT-232 recommended dose and dosing schedule; Phase 3 will test KRT-232 vs Best Available Therapy (BAT). Patients in the Phase 3 part of the study will be randomized 2:1 to receive either KRT-232 (Arm 1) or BAT (Arm 2). The BAT administered will be determined by the treating physician, with the option to "cross-over" to KRT-232 treatment after 6 months of BAT or if the disease worsens at any time.

Related Conditions:
  • Primary Myelofibrosis
  • Secondary Myelofibrosis
Recruiting Status:

Recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

  • Brief Title: KRT-232 Versus Best Available Therapy for the Treatment of Subjects With Myelofibrosis Who Are Relapsed or Refractory to JAK Inhibitor Treatment
  • Official Title: A Phase 2/3 Randomized, Controlled, Open-Label Study of KRT 232 in Subjects With Primary Myelofibrosis (PMF), Post Polycythemia Vera MF (Post-PV-MF), Or Post Essential Thrombocythemia MF (Post-ET-MF) Who Are Relapsed or Refractory to Janus Kinase (JAK) Inhibitor Treatment

Clinical Trial IDs

  • ORG STUDY ID: KRT-232-101
  • NCT ID: NCT03662126

Conditions

  • Primary Myelofibrosis (PMF)
  • Post-Polycythemia Vera MF (Post-PV-MF)
  • Post-Essential Thrombocythemia MF (Post-ET-MF)

Interventions

DrugSynonymsArms
KRT-232Part A Cohort 1
Best Available Therapy (BAT)Part B Arm 2 Best Available Therapy

Purpose

This study evaluates KRT-232, a novel oral small molecule inhibitor of MDM2, for the treatment of patients with myelofibrosis (MF) who no longer benefit from treatment with a JAK inhibitor. Inhibition of MDM2 is a novel mechanism of action in MF. This study will be conducted in 2 phases. Phase 2 will determine the KRT-232 recommended dose and dosing schedule; Phase 3 will test KRT-232 vs Best Available Therapy (BAT). Patients in the Phase 3 part of the study will be randomized 2:1 to receive either KRT-232 (Arm 1) or BAT (Arm 2). The BAT administered will be determined by the treating physician, with the option to "cross-over" to KRT-232 treatment after 6 months of BAT or if the disease worsens at any time.

Trial Arms

NameTypeDescriptionInterventions
Part A Cohort 1ExperimentalKRT-232 120 mg by mouth once daily for Days 1-7, off treatment for Days 8-21 (21-day cycles)
  • KRT-232
Part A Cohort 2ExperimentalKRT-232 240 mg by mouth once daily for Days 1-7, off treatment for Days 8-21 (21-day cycles)
  • KRT-232
Part A Cohort 3ExperimentalKRT-232 240 mg by mouth once daily for Days 1-7, off treatment for Days 8-28 (28-day cycles)
  • KRT-232
Part A Cohort 4bExperimentalKRT-232 240 mg by mouth once daily for Days 1-5, off treatment for Days 6-28 (28-day cycles)
  • KRT-232
Part B Arm 1 KRT-232ExperimentalKRT-232 240 mg by mouth once daily for Days 1-7, off treatment for Days 8-28 (28-day cycles)
  • KRT-232
Part B Arm 2 Best Available TherapyActive ComparatorBest available therapy at the discretion of the investigator, on a 28-day cycle.
  • Best Available Therapy (BAT)

Eligibility Criteria

        Inclusion Criteria:

          -  Confirmed diagnosis of PMF, post-PV MF or post-ET MF (WHO)

          -  High, intermediate-2, or intermediate-1 risk Dynamic International Prognostic System
             (DIPSS)

          -  Failure of prior treatment with JAK inhibitor

          -  ECOG ≤ 2

        Exclusion Criteria:

          -  Prior splenectomy

          -  Splenic irradiation within 3 months prior to randomization

          -  History of major hemorrhage or intracranial hemorrhage within 6 months prior to
             randomization

          -  History of stroke, reversible ischemic neurological defect or transient ischemic
             attack within 6 months prior to randomizatio

          -  Prior MDM2 inhibitor therapy or p53-directed therapy

          -  Prior allogeneic stem-cell transplant or plans for allogeneic stem cell transplant

          -  History of major organ transplant

          -  Grade 2 or higher QTc prolongation (> 480 milliseconds per NCI-CTCAE criteria, version
             5.0)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:(Part A Only) Spleen Volume Reduction (SVR)
Time Frame:24 weeks
Safety Issue:
Description:The proportion of subjects achieving a ≥ 35% spleen volume reduction (SVR) from Baseline to Week 24, as assessed by magnetic resonance imaging (MRI) or computed tomography (CT) scan

Secondary Outcome Measures

Measure:(Part A only) Improvement in Total Symptom Score (TSS)
Time Frame:48 weeks
Safety Issue:
Description:The proportion of subjects who have at least a 50% reduction from Baseline to Week 24 and Week 48 in the total symptom score as measured by the modified MPN-SAF v2.0
Measure:(Part B only) Improvement of Total Symptom Score (TSS)
Time Frame:24 Weeks
Safety Issue:
Description:The proportion of subjects who have at least a 50% reduction from Baseline to Week 24 in the total symptom score as measured by the MF-SAF v4.0
Measure:(Part B only) Overall Survival (OS)
Time Frame:48 months
Safety Issue:
Description:Time from randomization to death from any cause
Measure:(Part B only) Progression free survival (PFS)
Time Frame:48 months
Safety Issue:
Description:Time from randomization to either first occurrence of disease progression or death due to any cause
Measure:(Part B Only) Overall Spleen Volume Reduction (SVR)
Time Frame:48 months
Safety Issue:
Description:The proportion of subjects in each arm achieving SVR of ≥ 35% at any time by MRI/CT scan (central review)
Measure:(Part B Only) Spleen Response Duration
Time Frame:48 months
Safety Issue:
Description:Time from initial SVR of ≥ 35% by MRI/CT (central review) until the first occurrence of disease progression
Measure:(Part B Only) Rate of conversion from RBC transfusion dependent to independent
Time Frame:24 weeks
Safety Issue:
Description:The proportion of subjects who have RBC transfusion independence at week 24

Details

Phase:Phase 2/Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Kartos Therapeutics, Inc.

Last Updated

February 2, 2021