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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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.

Conditions
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Post-PV MF, Myelofibrosis, Post-ET Myelofibrosis, Primary Myelofibrosis

Intervention / Treatment
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* Drug: KRT-232
* Drug: TL-895


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 (R/R MF), Dose Level 1<br>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. | Drug: KRT-232<br>* KRT-232, administered by mouth<br>Drug: TL-895<br>* TL-895, administered by mouth<br>|
| Experimental: Cohort 1 (R/R MF), Dose Level 2<br>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. | Drug: KRT-232<br>* KRT-232, administered by mouth<br>Drug: TL-895<br>* TL-895, administered by mouth<br>|
| Experimental: Cohort 2 (R/R MF), Dose Level 1<br>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. | Drug: KRT-232<br>* KRT-232, administered by mouth<br>Drug: TL-895<br>* TL-895, administered by mouth<br>|
| Experimental: Cohort 2 (R/R MF), Dose Level 2<br>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. | Drug: KRT-232<br>* KRT-232, administered by mouth<br>Drug: TL-895<br>* TL-895, administered by mouth<br>|
| Experimental: Cohort 3 (JAKi Intolerant MF)<br>KRT-232 at 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle. | Drug: KRT-232<br>* KRT-232, administered by mouth<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b - The MTD/MAD and RP2D of TL-895 in combination with KRT-232 in patients with R/R MF (Cohort 1 and Cohort 2) | 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. | 56 Days | 
| Phase 2 - Spleen response rate for each cohort | A reduction in spleen volume as assessed by MRI (or CT) ≥ 35% from baseline at Week 24 | 24 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Symptom Score (TSS) | The change in TSS based Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) | 24 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed/Refractory Myelofibrosis, Janus associated Kinase Inhibitor-Intolerant Myelofibrosis, MDM2, navtemadlin