A Phase 1, Study of BMF-500 in Adults With Acute Leukemia

Study Overview
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Brief Summary
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A Phase 1 first-in-human dose-escalation and dose-expansion study of BMF-500, an oral FLT3 inhibitor, in adult patients with acute leukemia.

Detailed Description
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A Phase 1 first-in-human dose-escalation and dose-expansion study of BMF-500, an oral covalent FLT3 inhibitor, in adult patients with acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL) and Acute Mixed-Phenotype Leukemia (MPAL) who may or may not be on Antifungals.

Official Title
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A Phase 1, Open-label, Dose-escalation, and Dose-expansion Study of BMF-500, an Oral Covalent FLT3 Inhibitor, in Adults With Acute Leukemia

Conditions
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Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Acute Mixed-Phenotype Leukemia

Intervention / Treatment
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* Drug: BMF-500


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Age ≥ 18 years. Individuals with histologically or pathologically confirmed diagnosis of relapsed or refractory AML, ALL, or MPAL with documented FLT3 mutation, and/or Individuals with histologically or pathologically confirmed diagnosis of their malignancy with wild-type FLT3 (including those with MLL1-R and NPM1 mutations). ECOG performance status of 0-2. Adequate liver and renal function Adhere to the CYP3A4 inhibitor concomitant therapy use requirements, as follows: Arm A: Participants must not have received a moderate or strong CYP3A4 inhibitor for at least 7 days prior to enrollment and are not anticipated to require such agents in the near term (for at least 4 weeks). Arm B: Participants must have received a necessary azole antifungal(s) that is a moderate or strong CYP3A4 inhibitor (excluding other moderate or strong CYP3A4 inhibitor[s]) for at least 7 days prior to enrollment and be able to continue such azole antifungal(s) while on BMF-500 treatment for at least 4 weeks. Key Exclusion Criteria: Significant cardiovascular disease including unstable angina pectoris, uncontrolled hypertension or arrhythmia, history of cerebrovascular accident including transient ischemic attack within 6 months prior to the first dose of the trial intervention. WBC count >50,000/µL (uncontrollable with cytoreductive therapy). Women who are pregnant or lactating or plan to become pregnant.

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
Interventional Model Description: Accelerated Titration Design, Followed by Modified 3+3
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Escalation Phase<br>BMF-500 taken twice daily by participants who are not receiving drugs that inhibit CYP3A4 activity or who are receiving necessary azole antifungals that are moderate or strong CYP3A4 inhibitors excluding other moderate or strong CYP3A4 inhibitors. | Drug: BMF-500<br>* Investigational Product<br>|
| Experimental: Expansion Phase<br>BMF-500 taken twice daily by participants who are not receiving drugs that inhibit CYP3A4 activity or who are receiving necessary azole antifungals that are moderate or strong CYP3A4 inhibitors excluding other moderate or strong CYP3A4 inhibitors. | Drug: BMF-500<br>* Investigational Product<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the safety and tolerability of BMF-500 monotherapy by incidence of Treatment Emerging Adverse Events (TEAEs). | Assessed by the NCI CTCAE version 5.0. | At the end of each 28 Day cycle for a maximum of 32 cycles | 
| Evaluate the safety and tolerability of BMF-500 monotherapy by incidence of Serious Adverse Events (SAEs). | Assessed by the NCI CTCAE version 5.0. | At the end of each 28 Day cycle for a maximum of 32 cycles | 
| Determine the recommended Phase 2 Dose (RP2D) of BMF-500. | Safety, as determined by Dose-Limiting Toxicities (clinically significant Adverse Event) within each dose level assessed NCI CTCAE version 5.0. | At the end of 28 day Dose-Limiting Toxicities (DLT) observation Period | 
| Determine the recommended Phase 2 Dose (RP2D) of BMF-500. | Efficacy within each dose level as determined by composite complete remission (CRc). | At the end of 28 day Dose-Limiting Toxicities (DLT) observation Period | 
| Determine the recommended Phase 2 Dose (RP2D) of BMF-500. | Pharmacovigilance (PK) at each dose level as determined by the maximum plasma concentration (Cmax). | At the end of 28 day Dose-Limiting Toxicities (DLT) observation Period | 
| Determine the recommended Phase 2 Dose (RP2D) of BMF-500. | Pharmacovigilance (PK) at each dose level as determined by area under the plasma concentration from time 0 to last quantifiable concentration (AUClast). | At the end of 28 day Dose-Limiting Toxicities (DLT) observation Period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the pharmacokinetics of BMF-500. | Maximum plasma concentration (Cmax). | At the end of each cycle (each cycle is 28 days in duration) for 7 cycles | 
| Determine the pharmacokinetics of BMF-500. | Area under the plasma concentration from time 0 to last quantifiable concentration (AUClast). | At the end of each cycle (each cycle is 28 days in duration) for 7 cycles | 
| Assess the effect of food on the PK exposure of BMF-500 in participants receiving BMF-500 (for escalation only). | Maximum plasma concentration (Cmax). | At the end of cycle 1 and 2 (each cycle is 28 days in duration) | 
| Assess the effect of food on the PK exposure of BMF-500 in participants receiving BMF-500 (for escalation only). | Area under the plasma concentration from time 0 to last quantifiable concentration (AUClast). | At the end of cycle 1 and 2 (each cycle is 28 days in duration) | 
| Evaluate the efficacy of BMF-500 | Composite Complete Remission (CRc). | At the end of each cycle (each cycle is 28 days in duration) for a maximum of 32 cycles | 
| Assess additional evidence of antitumor activity per investigator assessment as per corresponding response criteria. | Duration of Response (DOR). | At the end of each cycle (each cycle is 28 days in duration) for a maximum of 32 cycles | 
| Evaluate the efficacy of BMF-500 | Overall Reasons Rate (ORR). | At the end of each cycle (each cycle is 28 days in duration) for a maximum of 32 cycles | 
| Assess additional evidence of antitumor activity per investigator assessment as per corresponding response criteria. | Relapse free survival (RFS). | At the end of each cycle (each cycle is 28 days in duration) for a maximum of 32 cycles | 
| Assess additional evidence of antitumor activity per investigator assessment as per corresponding response criteria. | Overall Survival (OS). | At the end of each cycle (each cycle is 28 days in duration) for a maximum of 32 cycles | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FLT3, FLT3-ITD, FLT-TKD, AML, ALL, AMPL, FLT3 Wild-Type, MLL-R, NPM1