Clinical Trials /

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

NCT04640532

Description:

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.

Related Conditions:
  • Myelofibrosis
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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
  • Official Title: An Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of 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.

Clinical Trial IDs

  • ORG STUDY ID: KRT-232-113
  • NCT ID: NCT04640532

Conditions

  • Myelofibrosis
  • Post-PV MF
  • Post-ET Myelofibrosis
  • Primary Myelofibrosis

Interventions

DrugSynonymsArms
KRT-232Cohort 1 (R/R MF), Dose Level 1
TL-895Cohort 1 (R/R MF), Dose Level 1

Purpose

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.

Detailed 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.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 1 (R/R MF), Dose Level 1ExperimentalTL-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.
  • KRT-232
  • TL-895
Cohort 1 (R/R MF), Dose Level 2ExperimentalTL-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.
  • KRT-232
  • TL-895
Cohort 2 (R/R MF), Dose Level 1ExperimentalTL-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.
  • KRT-232
  • TL-895
Cohort 2 (R/R MF), Dose Level 2ExperimentalTL-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.
  • KRT-232
  • TL-895
Cohort 3 (JAKi Intolerant MF)ExperimentalKRT-232 at 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle.
  • KRT-232

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1b - To determine the MTD/MAD and RP2D of TL-895 in combination with KRT-232 in patients with R/R MF (Cohort 1 and Cohort 2)
Time Frame:56 Days
Safety Issue:
Description:DLTs will be used to establish the MTD. RP2D will be determined by the SRC based on safety data from the combination of TL-895 and KRT-232.

Secondary Outcome Measures

Measure:Total Symptom Score (TSS)
Time Frame:24 Weeks
Safety Issue:
Description:To determine the change in TSS based Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0)

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Kartos Therapeutics, Inc.

Trial Keywords

  • Relapsed/Refractory Myelofibrosis
  • Janus associated Kinase Inhibitor-Intolerant Myelofibrosis
  • MDM2

Last Updated

November 23, 2020