An Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of KRT-232 When Administered Alone and in Combination With Low-Dose Cytarabine (LDAC) or Decitabine in Patients With Acute Myeloid Leukemia (AML)

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, when administered alone and in combination with low-dose cytarabine (LDAC) or Decitabine for the treatment of adults with Acute Myeloid Leukemia (AML) and AML secondary to myeloproliferative neoplasms (MPN). Participants must be relapsed/refractory (having failed prior therapy) and will be assigned to receive monotherapy (KRT-232 alone) or combination therapy (KRT-232 with LDAC or KRT-232 with Decitabine).

Official Title
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An Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of KRT-232 When Administered Alone and in Combination With Low-Dose Cytarabine (LDAC) or Decitabine in Patients With Acute Myeloid Leukemia (AML)

Conditions
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Relapsed or Refractory Acute Myeloid Leukemia (AML), Acute Myeloid Leukemia (AML), Secondary to Myeloproliferative Neoplasms (MPN)

Intervention / Treatment
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* Drug: KRT-232
* Drug: Cytarabine
* Drug: Decitabine


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Part A: Patients with relapsed or refractory AML, or newly-diagnosed AML secondary to MPN Part B:Patients with relapsed or refractory AML secondary to MPN (myelofibrosis [MF], polycythemia vera [PV], or essential thrombocythemia [ET]); patients may have been treated with ≥1 prior lines of therapy for their AML secondary to MPN. Adequate hepatic and renal function Appropriate prior treatment with an FLT3 or IDH1/2 inhibitor where applicable Key Exclusion Criteria: Patients who are TP53 mutation positive Prior treatment with an MDM2 antagonist therapy Patients treated with ≥ 18 g/m2 of cytarabine within the prior 90 days are not eligible to be treated with cytarabine on this study but may be treated with decitabine (for Part A) . Patients previously treated with decitabine are not eligible to receive decitabine on this study but may be treated with cytarabine (for Part A) . Patients who have received an allogeneic HSCT within 90 days of enrollment or who have active graft-versus-host disease requiring active therapy (for Part A) Allogeneic stem cell transplant within 3 months; autologous stem cell transplant within 3 months or active graft-versus-host disease prior to first dose of study treatment (for Part B) Patients who have received immunosuppressive therapy for graft-versus-host disease within 1 month prior to enrollment into this study Patients who are eligible for an allogeneic HSCT per the opinion of the investigator and have a donor. Patients who are HSCT-eligible in the opinion of the investigator, but who refuse a transplant, are eligible for the study. Patients with known CNS involvement with AML, acute promyelocytic leukemia (APL), or a history of bleeding diathesis Patients who have had major surgery within 28 days prior to the first treatment with KRT-232 Women who are pregnant or breastfeeding

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A - Arm 1<br>KRT-232+LDAC: KRT-232 will be administered orally, once daily (QD), on Days 1-7 in combination with LDAC administered at 20 mg/m2/day subcutaneously on Days 1-10 in a 28-day cycle. | Drug: KRT-232<br>* KRT-232 is an experimental MDM2 inhibitor anti-cancer drug taken by mouth.<br>Drug: Cytarabine<br>* Cytarabine is an anti-cancer chemotherapy drug taken via injection.<br>* Other names: Ara-C;|
| Experimental: Part A - Arm 2<br>KRT-232(7-Day)+Decitabine: KRT-232 will be administered orally, once daily (QD), on Days 1-7 in combination with Decitabine administered at 20 mg/m2/day intravenously on Days 1-5 in a 28-day cycle. | Drug: KRT-232<br>* KRT-232 is an experimental MDM2 inhibitor anti-cancer drug taken by mouth.<br>Drug: Decitabine<br>* Decitabine is an anti-cancer chemotherapy drug taken via injection.<br>* Other names: Dacogen;|
| Experimental: Part A - Arm 3<br>KRT-232(14-Day)+Decitabine: KRT-232 will be administered orally, once daily (QD), on Days 1-7 and Days 15-21 (7 days on/7 days off/7 days on/7 days off) in combination with Decitabine administered at 20 mg/m2/day intravenously on Days 1-5 in a 28-day cycle. | Drug: KRT-232<br>* KRT-232 is an experimental MDM2 inhibitor anti-cancer drug taken by mouth.<br>Drug: Decitabine<br>* Decitabine is an anti-cancer chemotherapy drug taken via injection.<br>* Other names: Dacogen;|
| Experimental: Part B - Arm 1<br>KRT-232 administered at 360 mg orally, once daily (QD) on Days 1-7 with 21 days off on a 28-day treatment cycle | Drug: KRT-232<br>* KRT-232 is an experimental MDM2 inhibitor anti-cancer drug taken by mouth.<br>|
| Experimental: Part B - Arm 2<br>KRT-232 administered at 360 mg orally, once daily (QD) on Days 1-7 with 21 days off on a 28-day treatment cycle in Cycle 1, followed by 240 mg orally, once daily (QD) on Days 1-7 with 21 days off on a 28-day cycle, in the subsequent cycles. | Drug: KRT-232<br>* KRT-232 is an experimental MDM2 inhibitor anti-cancer drug taken by mouth.<br>|
| Experimental: Part B - Arm 3<br>KRT-232 administered at 180 mg orally, once daily (QD) on Days 1-7 with 14 days off on a 21-day treatment cycle. | Drug: KRT-232<br>* KRT-232 is an experimental MDM2 inhibitor anti-cancer drug taken by mouth.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: To determine KRT-232 recommended phase 2 dose (RP2D) | Number of dose-limiting toxicities (DLTs) of KRT-232 in combination with cytarabine or decitabine | 28 Days | 
| Part B: To determine the RP2D of KRT-232 | The safety review committee (SRC) will determine the RP2D based on safety and tolerability data obtained from each arm | 2 years after last patient enrolled | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: To determine the rates of complete remission (CR) and complete remission with partial hematological improvement (CRh) | Proportion of patients achieving complete remission (CR) or complete remission with partial hematological improvement (CRh) as determined by Modified 2017 European LeukemiaNet (ELN) response criteria | 12 weeks | 
| Part B: To determine the rates of complete remission (CR), CR with partial hematological improvement (CRh) and CR with incomplete hematologic recovery (CRi) | Proportion of patients achieving complete remission (CR), complete remission with partial hematological improvement (CRh), and CR with incomplete hematologic recovery (CRi) as determined by Modified 2017 European LeukemiaNet (ELN) response criteria | 12 weeks | 

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