KRT-232 and TKI Study in Chronic Myeloid Leukemia

Study Overview
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Brief Summary
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This study evaluates KRT-232, a novel oral small molecule inhibitor of MDM2, for the treatment of patients with Ph+ Chronic Myeloid Leukemia (CML) who have relapsed or are refractory or intolerant to a Tyrosine Kinase Inhibitor (TKI). This study is a global, open label Phase 1b/2 to determine the efficacy and safety of KRT-232 in patients with chronic phase CML (CML-CP) and accelerated phase (CML-AP) who have failed TKI treatments.

Official Title
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An Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of KRT-232 Combined With a Tyrosine Kinase Inhibitor (TKI) in Patients With Relapsed or Refractory Ph+ Chronic Myeloid Leukemia (CML)

Conditions
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Chronic Myeloid Leukemia

Intervention / Treatment
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* Drug: KRT-232
* Drug: Dasatinib
* Drug: Nilotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Phase 1b and Phase 2 Arms A and B: Documented TP53wt, Ph+, BCR-ABL+ CML-CP Phase 2 Arm C ONLY: Documented TP53wt, Ph+, BCR-ABL+ CML-AP Subject is resistant (relapsed or refractory) and/or intolerant to at least 1 prior TKI. Adults ≥ 18 years of age. ECOG performance status of 0 to 2 Adequate hematologic, hepatic, and renal functions Exclusion Criteria: Phase 1b and Phase 2 Arms A and B: Documented Ph+, BCR-ABL+ CML-AP Documented Ph+, BCR-ABL+ CML-BC Known T315I mutation. Prior treatment with MDM2 antagonist therapies. Intolerance to current TKI therapy.

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1, KRT-232 combined with TKI (Dasatinib or Nilotinib) in patients with CML-CP<br>KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 28-day cycle. TKI (dasatinib or nilotinib) will be administered orally, per locally prescribed dose and schedule. | Drug: KRT-232<br>* KRT-232 is an experimental MDM2 inhibitor anticancer drug taken by mouth.<br>Drug: Dasatinib<br>* Dasatinib is a Tyrosine Kinase Inhibitor anticancer drug taken by mouth.<br>* Other names: Dasatinib Zentiva;Drug: Nilotinib<br>* Nilotinib is an Tyrosine Kinase Inhibitor anticancer drug taken by mouth.<br>* Other names: Tasigna;|
| Experimental: Part 2, Arm A (KRT-232 combined with Dasatinib in patients with CML-CP)<br>KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 28-day cycle. Dasastinib will be administered orally, per locally prescribed dose and schedule. | Drug: KRT-232<br>* KRT-232 is an experimental MDM2 inhibitor anticancer drug taken by mouth.<br>Drug: Dasatinib<br>* Dasatinib is a Tyrosine Kinase Inhibitor anticancer drug taken by mouth.<br>* Other names: Dasatinib Zentiva;|
| Experimental: Part 2, Arm B (KRT-232 combined with Nilotinib in patients with CML-CP)<br>KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 28-day cycle. Nilotinib will be administered orally, per locally prescribed dose and schedule. | Drug: KRT-232<br>* KRT-232 is an experimental MDM2 inhibitor anticancer drug taken by mouth.<br>Drug: Nilotinib<br>* Nilotinib is an Tyrosine Kinase Inhibitor anticancer drug taken by mouth.<br>* Other names: Tasigna;|
| Experimental: Part 2, Arm C (KRT-232 combined with Dasatinib or Nilotinib in patients with CML-AP)<br>KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 28-day cycle. Dasatinib or Nilotinib will be administered orally, per locally prescribed dose and schedule. | Drug: KRT-232<br>* KRT-232 is an experimental MDM2 inhibitor anticancer drug taken by mouth.<br>Drug: Dasatinib<br>* Dasatinib is a Tyrosine Kinase Inhibitor anticancer drug taken by mouth.<br>* Other names: Dasatinib Zentiva;Drug: Nilotinib<br>* Nilotinib is an Tyrosine Kinase Inhibitor anticancer drug taken by mouth.<br>* Other names: Tasigna;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Maximum tolerated dose (MTD)/maximum administered dose (MAD) of KRT-232 | DLTs will be used to establish the MTD/MAD of KRT-232 in combination with dasatinib or nilotinib | 28 Days | 
| Part 2, Arm A and B: Major molecular response (MMR) rate | The proportion of subjects who achieved complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR) according to modified ELN criteria | 6 months | 
| Part 2, Arm C: Major hematological response (MaHR) rate | The proportion of subjects who achieved MaHR according to modified ELN criteria | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CCyR rate | The proportion of subjects who achieved CCyR or PCyR according to modified ELN criteria in Arms A and B | 12 months | 
| MCyR rate | The proportion of subjects who achieved CCyR or PCyR according to modified ELN criteria in Arm C | 47 months | 
| Duration of response | DOR (Kaplan-Meier estimate) defined as the time from first observation of response to progression/relapse or death, whichever comes first | 47 months | 
| Rate of complete hematologic response (CHR) | The proportion of subjects who achieve a CHR according to modified ELN criteria in Arms A and B | 47 months | 
| Progression-free survival (PFS) in each Arm | PFS is defined as the time from the first treatment dose date to progression/relapse or death, whichever comes first | 47 months | 
| Overall survival (OS) in each Arm | OS is defined as the time from the first treatment dose date to death from any cause | 47 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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navtemadlin