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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.

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.


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 Drug: Best Available Therapy (BAT) Phase 2 Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 385 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: 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
Actual Study Start Date : January 15, 2019
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2025


Arm Intervention/treatment
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)
Drug: KRT-232
KRT-232, administered by mouth

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)
Drug: KRT-232
KRT-232, administered by mouth

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)
Drug: KRT-232
KRT-232, administered by mouth

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)
Drug: KRT-232
KRT-232, administered by mouth

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)
Drug: KRT-232
KRT-232, administered by mouth

Active Comparator: Part B Arm 2 Best Available Therapy
Best available therapy at the discretion of the investigator, on a 28-day cycle.
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).




Primary Outcome Measures :
  1. (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

  2. (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)


Secondary Outcome Measures :
  1. (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

  2. (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

  3. (Part B only) Overall Survival (OS) [ Time Frame: 48 months ]
    Time from randomization to death from any cause

  4. (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

  5. (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)

  6. (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

  7. (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



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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
  • 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)

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
Contact: Yulia Khalina 908-656-2799 ykhalina@kartosthera.com

Locations
Show Show 73 study locations
Sponsors and Collaborators
Kartos Therapeutics, Inc.
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

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Responsible Party: Kartos Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT03662126    
Other Study ID Numbers: KRT-232-101
First Posted: September 7, 2018    Key Record Dates
Last Update Posted: February 2, 2021
Last Verified: January 2021

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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