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

Kartos Therapeutics

Status and phase: Enrolling; Phase 3; Phase 2

Conditions: Post-Polycythemia Vera MF (Post-PV-MF); Primary Myelofibrosis (PMF); Post-Essential Thrombocythemia MF (Post-ET-MF)

Treatments: Drug: Best Available Therapy (BAT); Drug: KRT-232

Study type: Interventional

Funder types: Industry

Identifiers

NCT03662126

KRT-232-101

Details and patient eligibility

About

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.

Enrollment: 385 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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)

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Single Blind

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385 participants in 6 patient groups

Part A Cohort 1

Experimental group

Description:

KRT-232 120 mg by mouth once daily for Days 1-7, off treatment for Days 8-21 (21-day cycles)

Treatment:

Drug: KRT-232

Part A Cohort 2

Experimental group

Description:

KRT-232 240 mg by mouth once daily for Days 1-7, off treatment for Days 8-21 (21-day cycles)

Treatment:

Drug: KRT-232

Part A Cohort 3

Experimental group

Description:

KRT-232 240 mg by mouth once daily for Days 1-7, off treatment for Days 8-28 (28-day cycles)

Treatment:

Drug: KRT-232

Part A Cohort 4b

Experimental group

Description:

KRT-232 240 mg by mouth once daily for Days 1-5, off treatment for Days 6-28 (28-day cycles)

Treatment:

Drug: KRT-232

Part B Arm 1 KRT-232

Experimental group

Description:

KRT-232 240 mg by mouth once daily for Days 1-7, off treatment for Days 8-28 (28-day cycles)

Treatment:

Drug: KRT-232

Part B Arm 2 Best Available Therapy

Active Comparator group

Description:

Best available therapy at the discretion of the investigator, on a 28-day cycle.

Treatment:

Drug: Best Available Therapy (BAT)