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KRT-232 in Subjects With PMF, Post-PV MF, or Post-ET MF Who Have Failed a JAK Inhibitor

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ClinicalTrials.gov Identifier: NCT03662126
Recruitment Status : Recruiting
First Posted : September 7, 2018
Last Update Posted : July 30, 2019
Sponsor:
Information provided by (Responsible Party):
Kartos Therapeutics, Inc.

Brief Summary:

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 JAK inhibitor. Inhibition of MDM2 is a novel mechanism of action in MF.

This study is a global, open-label Phase 2 study to determine the efficacy and safety of KRT-232 in patients with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF who have failed previous treatment with JAK inhibitor (Part A), or Ruxolitinib (Part B). In Part A of the study, patients will be randomly assigned to 2 different doses and 2 different dosing schedules of KRT-232. In Part B of the study, patients will be treated at the recommended dose and schedule from Part A.


Condition or disease Intervention/treatment Phase
Primary Myelofibrosis (PMF) Post-Polycythemia Vera MF (Post-PV-MF) Post-Essential Thrombocythemia MF (Post-ET-MF) Drug: KRT-232 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 247 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label, Phase 2a/2b 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 Have Failed a JAK Inhibitor
Actual Study Start Date : January 15, 2019
Estimated Primary Completion Date : August 1, 2021
Estimated Study Completion Date : February 28, 2023


Arm Intervention/treatment
Experimental: Part A Cohort 1
KRT-232 120mg by mouth once daily for Days 1-7, off treatment for Days 8-21 (21-day cycles)
Drug: KRT-232
KRT-232, administered by mouth

Experimental: Part A Cohort 2
KRT-232 240mg by mouth once daily for Days 1-7, off treatment for Days 8-21 (21-day cycles)
Drug: KRT-232
KRT-232, administered by mouth

Experimental: Part A Cohort 3
KRT-232 240mg by mouth once daily for Days 1-7, off treatment for Days 8-28 (28-day cycles)
Drug: KRT-232
KRT-232, administered by mouth

Experimental: Part B
Recommended KRT-232 dose and schedule from Part A
Drug: KRT-232
KRT-232, administered by mouth

Experimental: Part A Cohort 4
KRT-232 360mg by mouth once daily for Days 1-7, off treatment for Days 8-21 (21-day cycles)
Drug: KRT-232
KRT-232, administered by mouth

Experimental: Part A Cohort 5
KRT-232 180mg by mouth once daily for Days 1-7, off treatment for Days 8-14, on treatment for Days 15-21, off treatment for Days 22-28 (28-day cycles)
Drug: KRT-232
KRT-232, administered by mouth

Experimental: Part A Cohort 6
KRT-232 120mg by mouth once daily for Days 1-14, off treatment for Days 15-21 (21-day cycles)
Drug: KRT-232
KRT-232, administered by mouth

Experimental: Part A Cohort 7
KRT-232 60mg by mouth once daily for Days 1-21, off treatment for Days 22-28 (28-day cycles)
Drug: KRT-232
KRT-232, administered by mouth




Primary Outcome Measures :
  1. To determine spleen response [ Time Frame: 24 weeks ]
    The proportion of patients achieving a ≥ 35% spleen volume reduction from Baseline to Week 24, as assessed by magnetic resonance imaging (MRI) or computed tomography (CT) scan


Secondary Outcome Measures :
  1. To determine the change in modified MPN-SAF Total Symptom Score (TSS) at Week 24 and Week 48 [ Time Frame: 48 weeks ]
    Proportion of patients 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

  2. RBC transfusion independence at Week 24 [ Time Frame: 24 weeks ]
    Proportion of patients who have RBC transfusion independence at week 24

  3. Complete remission and partial remission defined according to International Working Group-Myeloproliferative Neoplasms Research and Treatment and modified European LeukemiaNet criteria [ Time Frame: 24 weeks ]
    Proportion of patients who have complete remission and partial remission at week 24



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 (Part A) or ruxolitinib (Part B)
  • ECOG ≤ 2

Exclusion Criteria:

  • Prior splenectomy
  • Splenic irradiation within 3 months prior to the first dose of KRT-232
  • Active or chronic bleeding within 4 weeks prior to the first dose of KRT-232
  • Prior MDM2 inhibitor therapy or p53-directed therapy
  • Prior treatment with HDAC or BCL-2 inhibitors
  • Grade 2 or higher QTc prolongation (> 480 milliseconds per NCI-CTCAE criteria, version 5.0)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03662126


Contacts
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Contact: John Mei 650-542-0136 jmei@kartosthera.com

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Sponsors and Collaborators
Kartos Therapeutics, Inc.

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Responsible Party: Kartos Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT03662126     History of Changes
Other Study ID Numbers: KRT-232-101
First Posted: September 7, 2018    Key Record Dates
Last Update Posted: July 30, 2019
Last Verified: July 2019

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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
Additional relevant MeSH terms:
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Polycythemia Vera
Primary Myelofibrosis
Polycythemia
Thrombocytosis
Thrombocythemia, Essential
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Bone Marrow Neoplasms
Hematologic Neoplasms
Neoplasms by Site
Neoplasms
Blood Platelet Disorders
Blood Coagulation Disorders
Hemorrhagic Disorders
Janus Kinase Inhibitors
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action