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

• ClinicalTrials.gov Identifier: NCT03662126
• Recruitment Status: Recruiting
• First Posted: September 7, 2018
• Last Update Posted: April 28, 2023
• Sponsor: Kartos Therapeutics, Inc.
• Information provided by (Responsible Party): Kartos Therapeutics, Inc.

Tracking Information

• First Submitted Date: September 5, 2018
• First Posted Date: September 7, 2018
• Last Update Posted Date: April 28, 2023
• Actual Study Start Date: January 15, 2019
• Estimated Primary Completion Date: December 31, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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 (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

Current Secondary Outcome Measures (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 (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: 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

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: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Single (Outcomes Assessor); Primary Purpose: Treatment

Condition

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

Intervention

• 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

• 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

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: January 28, 2021): 385
• Original Estimated Enrollment (submitted: September 5, 2018): 190
• Estimated Study Completion Date: December 31, 2025
• Estimated Primary Completion Date: December 31, 2023 (Final data collection date for primary outcome measure)

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 randomization
• 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

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

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

• Listed Location Countries: Argentina, Australia, Brazil, Bulgaria, Canada, Croatia, Czechia, France, Germany, Greece, Hong Kong, Hungary, Israel, Italy, Korea, Republic of, Lithuania, Mexico, Philippines, Poland, Portugal, Romania, Russian Federation, Spain, Taiwan, Thailand, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT03662126
• Other Study ID Numbers: 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: Not Provided
• Current Responsible Party: Kartos Therapeutics, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Kartos Therapeutics, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Kartos Therapeutics, Inc.
• Verification Date: April 2023