KRT-232 in Combination With TL-895 for the Treatment of R/R MF and KRT-232 for the Treatment of JAKi Intolerant MF

Kartos Therapeutics

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Myelofibrosis; Primary Myelofibrosis; Post-ET Myelofibrosis; Post-PV MF

Treatments: Drug: TL-895; Drug: KRT-232

Study type: Interventional

Funder types: Industry

Identifiers

NCT04640532

KRT-232-113

Details and patient eligibility

About

This study evaluates KRT-232 in Combination With TL-895 for the Treatment of Relapsed or Refractory Myelofibrosis and KRT-232 for the Treatment of JAK Inhibitor Intolerant Myelofibrosis.

Full description

Cohorts 1 and 2 will undergo dose finding and dose expansion. Eligible patients will be randomly assigned to an open cohort, either Cohort 1 or Cohort 2. Cohort 3 will be conducted as a dose expansion, independent of Cohorts 1 and 2.

Cohort 1 will follow a 3+3 dose escalation design to determine the maximum tolerated dose (MTD)/maximum administered dose (MAD) and recommended Phase 2 dose (RP2D) of TL-895 administered QD in combination with KRT-232. A Safety Review Committee (SRC) will review the safety data during the dose escalation to decide on dose escalation and/or exploration of intermediate doses.

Cohort 2 will follow a 3+3 dose escalation design to determine the MTD/MAD and recommended RP2D of TL-895 administered BID in combination with KRT-232. An SRC will review the safety data during the dose escalation to decide on dose escalation and/or exploration of intermediate doses.

Cohort 3 will be conducted a 2-stage design. In stage 1, enrollment will continue until 15 evaluable patients have been enrolled. An SRC will review the data during the study and if there are ≥4 responders based on the futility criteria and safety data from Stage 1, Cohort 3 expansion will commence. If there are ≤3 patients responding to therapy, Cohort 3 will be terminated. Once expansion criteria have been met, Cohort 3 will be expanded to a total of 46 evaluable patients for Stage 2 analyses.

Enrollment: 116 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Confirmed diagnosis of primary MF, post-PV MF, or post-ET MF, (WHO 2016)
• ECOG ≤ 2
• Cohort 1 and Cohort 2: R/R following JAK inhibitor treatment
• Cohort 3: patients who are intolerant to JAK inhibitor treatment

Exclusion criteria

• Prior treatment with MDM2 inhibitors or p53-directed therapies
• Prior treatment with a BCR-ABL, phosphoinositide 3-kinase (PI3k), mammalian target of rapamycin (mTOR), bromodomain and extraterminal domain (BET), histone deacetylase (HDAC), or spleen tyrosine kinase (Syk) inhibitor
• Prior splenectomy
• Splenic irradiation within 3 months prior to the first dose of study treatment
• Clinically significant thrombosis within 3 months of screening
• Grade 2 or higher QTc prolongation

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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116 participants in 5 patient groups

Cohort 1 (R/R MF), Dose Level 1

Experimental group

Description:

TL-895 at 200 mg once a day (QD) continuously starting on Cycle 1 Day 1 in a 28-day cycle. KRT-232 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle starting on Cycle 2 Day 1.

Treatment:

Drug: KRT-232

Drug: TL-895

Cohort 1 (R/R MF), Dose Level 2

Experimental group

Description:

TL-895 at 300 mg once a day (QD) continuously starting on Cycle 1 Day 1 in a 28-day cycle. KRT-232 at 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle starting on Cycle 2 Day 1.

Treatment:

Drug: KRT-232

Drug: TL-895

Cohort 2 (R/R MF), Dose Level 1

Experimental group

Description:

TL-895 at 100 mg twice a day (BID) continuously starting on Cycle 1 Day 1 in a 28-day cycle. KRT-232 at 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle starting on Cycle 2 Day 1.

Treatment:

Drug: KRT-232

Drug: TL-895

Cohort 2 (R/R MF), Dose Level 2

Experimental group

Description:

TL-895 at 150 mg twice a day (BID) continuously starting on Cycle 1 Day 1 in a 28-day cycle. KRT-232 at 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle starting on Cycle 2 Day 1.

Treatment:

Drug: KRT-232

Drug: TL-895

Cohort 3 (JAKi Intolerant MF)

Experimental group

Description:

KRT-232 at 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle.

Treatment:

Drug: KRT-232