TL-895 and KRT-232 Study in Acute Myeloid Leukemia

Study Overview
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Brief Summary
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This study evaluates TL-895, a potent, orally available and highly selective irreversible tyrosine kinase inhibitor combined with navtemadlin (KRT-232), a novel oral small molecule inhibitor of MDM2 for the treatment of adults with FLT3 mutated Acute Myeloid Leukemia. Participants must be relapsed/refractory (e.g., having failed prior therapy) to be eligible for this study.

Official Title
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An Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of TL-895 Combined With KRT-232 in Patients With Relapsed/Refractory (R/R) FLT3+ Acute Myeloid Leukemia (AML)

Conditions
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Acute Myeloid Leukemia

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: TP53 wildtype AML Relapsed/Refractory to at least one prior therapy, one of which must have included a FLT-3 inhibitor FLT3 mutation (FLT3-TKD or FLT3-ITD) ECOG 0-2 Adequate hematologic, hepatic, and renal functions Exclusion Criteria: AML subtype 3 Prior treatment with MDM2 antagonist therapies Eligible for HSCT

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b - Dose Level 1<br>KRT-232 240mg QD, orally administered on days 1 through 7 of each 28-day cycle in combination with TL-895 150mg BID continuously for each 28-day cycle. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>Drug: KRT-232<br>* KRT-232 is an experimental MDM2 inhibitor anticancer drug taken by mouth.<br>|
| Experimental: Phase 1b - Dose Level 2<br>KRT-232 300mg QD, orally administered on days 1 through 7 of each 28-day cycle in combination with TL-895 150mg BID continuously for each 28-day cycle. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>Drug: KRT-232<br>* KRT-232 is an experimental MDM2 inhibitor anticancer drug taken by mouth.<br>|
| Experimental: Phase 1b - Dose Level 3<br>Cycle 1 only: KRT-232 360 mg QD orally administered on Days 1 through 7 of the first 28-day cycle in combination with TL-895 150 mg BID continuously for the first 28-day cycle Cycle 2 and beyond: KRT-232 300 mg QD orally administered on Days 1 through 7 of each 28-day cycle in combination with TL-895 150 mg BID continuously for each 28-day cycle. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>Drug: KRT-232<br>* KRT-232 is an experimental MDM2 inhibitor anticancer drug taken by mouth.<br>|
| Experimental: Phase 1b - Dose Level 4<br>Cycle 1 only: KRT-232 360 mg QD orally administered on Days 1 through 7 of the first 28-day cycle in combination with TL-895 300 mg BID continuously for the first 28-day cycle. Cycle 2 and beyond: KRT-232 300 mg QD orally administered on Days 1 through 7 of each 28-day cycle in combination with TL-895 300 mg BID continuously for each 28-day cycle. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>Drug: KRT-232<br>* KRT-232 is an experimental MDM2 inhibitor anticancer drug taken by mouth.<br>|
| Experimental: Phase 1b - Dose Level 5<br>Cycle 1 only: KRT-232 360 mg QD orally administered on Days 1 through 7 of the first 28-day cycle in combination with TL-895 450 mg BID continuously for the first 28-day cycle. Cycle 2 and beyond: KRT-232 300 mg QD orally administered on Days 1 through 7 of each 28-day cycle in combination with TL-895 450 mg BID continuously for each 28-day cycle. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>Drug: KRT-232<br>* KRT-232 is an experimental MDM2 inhibitor anticancer drug taken by mouth.<br>|
| Experimental: Phase 2 - Dose Expansion<br>Dose expansion of the recommended phase 2 dose of TL-895 in combination with KRT-232 as determined in Phase 1b. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>Drug: KRT-232<br>* KRT-232 is an experimental MDM2 inhibitor anticancer drug taken by mouth.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Objective, Phase 1b: To determine the MTD/MAD and recommended Phase 2 dose (RP2D) of TL-895 in combination with KRT-232 | Dose limiting toxicities will be used to established the MTD/MAD of TL-895 combined with KRT-232. The Safety Review Committee (SRC) will determine the RP2D based on safety data of the combination of TL-895 and KRT-232. | 13 months | 
| Primary Objective, Phase 2: To determine the rates of complete remission (CR) and complete remission with partial hematologic recovery (CRh) | The proportion of subjects who achieved CR or CRh as their best response based on the Modified 2017 European LeukemiaNet (ELN) Response Criteria (Appendix 4). | 41 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Key Secondary Objective: To determine the overall response rate (ORR) | The proportion of subjects who achieve PR or better. | 41 months | 
| Key Secondary Objective: To determine the duration of CR/CRh response (DOR) | Median DOR (Kaplan-Meier estimate) defined as the time from first observation of CR/CRh to relapse or death from any cause, whichever occurs first. Subjects with MLFS by bone marrow biopsy performed earlier in the course of therapy who convert to CR or CRh do not require a separate bone marrow aspirate at the time of CR or CRh to document this. | 41 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, TP53, FLT3+, Navtemadlin