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

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ClinicalTrials.gov Identifier: NCT03662126
Recruitment Status : Recruiting
First Posted : September 7, 2018
Last Update Posted : February 2, 2021
Sponsor:
Information provided by (Responsible Party):
Kartos Therapeutics, Inc.

Tracking Information
First Submitted Date  ICMJE September 5, 2018
First Posted Date  ICMJE September 7, 2018
Last Update Posted Date February 2, 2021
Actual Study Start Date  ICMJE January 15, 2019
Estimated Primary Completion Date December 31, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 28, 2021)
  • (Part A Only) Spleen Volume Reduction (SVR) [ Time Frame: 24 weeks ]
    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
  • (Part B Only) Spleen Volume Reduction (SVR) [ Time Frame: 24 Weeks ]
    The proportion of subjects achieving SVR of ≥ 35% at Week 24 by MRI/CT scan (central review)
Original Primary Outcome Measures  ICMJE
 (submitted: September 5, 2018)
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
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 28, 2021)
  • (Part A only) Improvement in Total Symptom Score (TSS) [ Time Frame: 48 weeks ]
    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
  • (Part B only) Improvement of Total Symptom Score (TSS) [ Time Frame: 24 Weeks ]
    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
  • (Part B only) Overall Survival (OS) [ Time Frame: 48 months ]
    Time from randomization to death from any cause
  • (Part B only) Progression free survival (PFS) [ Time Frame: 48 months ]
    Time from randomization to either first occurrence of disease progression or death due to any cause
  • (Part B Only) Overall Spleen Volume Reduction (SVR) [ Time Frame: 48 months ]
    The proportion of subjects in each arm achieving SVR of ≥ 35% at any time by MRI/CT scan (central review)
  • (Part B Only) Spleen Response Duration [ Time Frame: 48 months ]
    Time from initial SVR of ≥ 35% by MRI/CT (central review) until the first occurrence of disease progression
  • (Part B Only) Rate of conversion from RBC transfusion dependent to independent [ Time Frame: 24 weeks ]
    The proportion of subjects who have RBC transfusion independence at week 24
Original Secondary Outcome Measures  ICMJE
 (submitted: September 5, 2018)
  • 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
  • RBC transfusion independence at Week 24 [ Time Frame: 24 weeks ]
    Proportion of patients who have RBC transfusion independence at week 24
  • 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
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE KRT-232 Versus Best Available Therapy for the Treatment of Subjects With Myelofibrosis Who Are Relapsed or Refractory to JAK Inhibitor Treatment
Official Title  ICMJE 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
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 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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Primary Myelofibrosis (PMF)
  • Post-Polycythemia Vera MF (Post-PV-MF)
  • Post-Essential Thrombocythemia MF (Post-ET-MF)
Intervention  ICMJE
  • Drug: KRT-232
    KRT-232, administered by mouth
  • Drug: Best Available Therapy (BAT)

    Best available therapy options include:

    1. hydroxyurea
    2. chemotherapy or
    3. supportive care (including but not limited to corticosteroids and androgens; JAK inhibitors not allowed).
Study Arms  ICMJE
  • Experimental: Part A Cohort 1
    KRT-232 120 mg by mouth once daily for Days 1-7, off treatment for Days 8-21 (21-day cycles)
    Intervention: Drug: KRT-232
  • Experimental: Part A Cohort 2
    KRT-232 240 mg by mouth once daily for Days 1-7, off treatment for Days 8-21 (21-day cycles)
    Intervention: Drug: KRT-232
  • Experimental: Part A Cohort 3
    KRT-232 240 mg by mouth once daily for Days 1-7, off treatment for Days 8-28 (28-day cycles)
    Intervention: Drug: KRT-232
  • Experimental: Part A Cohort 4b
    KRT-232 240 mg by mouth once daily for Days 1-5, off treatment for Days 6-28 (28-day cycles)
    Intervention: Drug: KRT-232
  • Experimental: Part B Arm 1 KRT-232
    KRT-232 240 mg by mouth once daily for Days 1-7, off treatment for Days 8-28 (28-day cycles)
    Intervention: Drug: KRT-232
  • Active Comparator: Part B Arm 2 Best Available Therapy
    Best available therapy at the discretion of the investigator, on a 28-day cycle.
    Intervention: Drug: Best Available Therapy (BAT)
Publications * Al-Ali, H.K.; Delgado, R.G.; Lange, A.; Pluta, A.; McLornan, D.; Vachhani, P.; Damaj, G.L.; Jost, P.J.; Rejto, L.; Hus, M.; et al. KRT-232, A First-In-Class, Murine Double Minute 2 Inhibitor, for Myelofibrosis Relapsed or Refractory to Janus-Associated Kinase Inhibitor Treatment. Eha. Libr. 2020, 295035, S215

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 28, 2021)
385
Original Estimated Enrollment  ICMJE
 (submitted: September 5, 2018)
190
Estimated Study Completion Date  ICMJE December 31, 2025
Estimated Primary Completion Date December 31, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: John Mei 650-542-0136 jmei@kartosthera.com
Contact: Yulia Khalina 908-656-2799 ykhalina@kartosthera.com
Listed Location Countries  ICMJE Australia,   Bulgaria,   Canada,   Czechia,   France,   Germany,   Hungary,   Poland,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03662126
Other Study ID Numbers  ICMJE KRT-232-101
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Kartos Therapeutics, Inc.
Study Sponsor  ICMJE Kartos Therapeutics, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Kartos Therapeutics, Inc.
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP