Study to Evaluate Safety and Tolerability of CC-91633 (BMS-986397) in Participants With Relapsed or Refractory Acute Myeloid Leukemia or Relapsed or Refractory Higher-Risk Myelodysplastic Syndromes

Study Overview
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Brief Summary
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Study CC-91633-AML-001 is a Phase 1, open-label, dose escalation and expansion, first-in-human (FIH) clinical study of CC-91633 (BMS-986397) in participants with relapsed or refractory acute myeloid leukemia (R/R AML) or in participants with relapsed or refractory higher-risk myelodysplastic syndromes (R/R HR-MDS). The Dose Escalation part (Part A) of the study will enroll participants with R/R AML and R/R HR-MDS and will evaluate the safety and tolerability of escalating doses of CC-91633 (BMS-986397), administered orally, and determine the maximum tolerated dose (MTD) or preliminary recommended Phase 2 dose (RP2D) and schedule. Throughout the study, final decisions on dose escalation/de-escalation will be made by the safety review committee (SRC). Approximately 40 participants may be enrolled in Part A of the study. The expansion part (Part B) will confirm tolerability of the selected doses and schedules and evaluate whether efficacy is in a range that warrants further clinical development. Separate expansion cohorts for participants with R/R AML and R/R HR-MDS may enroll approximately 20 to 40 response evaluable participants per cohort. Parts A and B will consist of 3 periods: Screening, Treatment, and Follow-up.

Official Title
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A Phase 1, Open-label, Dose-finding Study of CC-91633 (BMS-986397) in Subjects With Relapsed or Refractory Acute Myeloid Leukemia or Relapsed or Refractory Higher-Risk Myelodysplastic Syndromes

Conditions
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Leukemia, Myeloid, Acute, Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: CC-91633


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must satisfy the criteria below to be enrolled in the Dose Escalation (Part A) or the Dose Expansion (Part B) of this study. Participant is ≥ 18 years of age, at the time of signing the ICF. Participant must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted. Participant is willing and able to adhere to the study visit schedule and other protocol requirements. Relapsed or refractory acute myeloid leukemia (R/R AML) and relapsed or refractory higher-risk myelodysplastic syndromes (R/R HR-MDS) as defined by the World Health Organization (WHO) criteria who have failed or are ineligible for all available therapies which may provide clinical benefit Participant has Eastern Cooperative Oncology Group Performance Status of 0 to 2. Participants must have the following screening laboratory values: Total White Blood Cell count (WBC) < 25 x 109/L prior to first infusion. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) ≤ 3.0 x upper limit of normal (ULN), unless considered due to leukemic organ involvement, in which case AST and ALT can be ≤ 5.0 x ULN. Uric acid ≤ 7.5 mg/dL (446 μmol/L). Serum total bilirubin ≤ 1.5 x ULN, unless considered due to Gilbert's syndrome Estimated serum creatinine clearance of ≥ 60 mL/min using the Cockcroft-Gault equation. Measured creatinine clearance from a 24-hour urine collection is acceptable if clinically indicated. INR < 1.5 x ULN and partial thromboplastin time (PTT) < 1.5 x ULN. Exclusion Criteria: The presence of any of the following will exclude a participant from enrollment: Participant has any condition, including active or uncontrolled infection, or the presence of laboratory abnormalities, which places the participant at unacceptable risk if the participant were to participate in the study. Any other significant medical condition, laboratory abnormality, or psychiatric illness which places the participant at unacceptable risk if he/she were to participate in the study or that would prevent the participant from complying with the study. Participant has any condition that confounds the ability to interpret data from the study. Participants with acute promyelocytic leukemia. Participants with clinical symptoms suggesting active central nervous system (CNS) leukemia or known CNS leukemia. Participants with immediately life-threatening, severe complications of leukemia such as disseminated/uncontrolled infection, uncontrolled bleeding, and/or uncontrolled disseminated intravascular coagulation. Participants with impaired cardiac function or clinically significant cardiac diseases, Participants who have undergone major surgery ≤ 2 weeks prior to starting CC-91633. Participants must have recovered from any clinically significant effects of recent surgery. Pregnant or nursing individuals. Participants with known human immunodeficiency virus infection. Participants with known chronic, active hepatitis B virus or hepatitis C virus C (HCV) infection. Participants with ongoing treatment with chronic, therapeutic dosing of anticoagulants (eg, warfarin, low molecular weight heparin, Factor Xa inhibitors). Participants with history of concurrent second cancers requiring active, ongoing systemic treatment Participants with clinically significant diarrhea, vomiting or malabsorption felt to limit absorption of orally administered medications.

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Participants with R/R AML and R/R HR-MDS - Part A<br>Part A (Dose Escalation) of the study will enroll R/R AML (Relapsed or Refractory Acute Myeloid Leukemia) and R/R HR-MDS (Relapsed or Refractory Higher-Risk Myelodysplastic Syndromes) participants and will evaluate the safety and tolerability of escalating doses of CC-91633, administered orally, and determine the maximum tolerated dose (MTD) or preliminary recommended Phase 2 dose (RP2D) and schedule. | Drug: CC-91633<br>* Administered orally according to the assigned treatment schedule<br>* Other names: BMS-986397;|
| Experimental: Participants with Relapsed or Refractory Acute Myeloid Leukemia (R/R AML)<br>Part B (expansion part) will confirm tolerability of the selected doses and schedules and evaluate whether efficacy is in a range that warrants further clinical development for R/R AML participants. | Drug: CC-91633<br>* Administered orally according to the assigned treatment schedule<br>* Other names: BMS-986397;|
| Experimental: Participants with Relapsed or Refractory Higher-Risk Myelodysplastic Syndromes (HR-MDS)<br>Part B (expansion part) will confirm tolerability of the selected doses and schedules and evaluate whether efficacy is in a range that warrants further clinical development for R/R HR-MDS participants. | Drug: CC-91633<br>* Administered orally according to the assigned treatment schedule<br>* Other names: BMS-986397;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | Defined as the dose with highest posterior probability of the Dose-limiting toxicity (DLT) rate falling in the target interval and fulfilling escalation with overdose control (EWOC). | Up to 2 years | 
| Dose-limiting Toxicity (DLT) | Defined as toxicities such as non-hematologic, confirmed Hy's law case, hematologic, or any AE toxicities meeting protocol specified DLT criteria and occurring within the DLT assessment period, unless the toxicity can clearly be determined to be due to other specified causes. | Up to 42 days after first dose of study treatment in Part A | 
| Incidence of Adverse Events (AEs) | An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a preexisting condition) should be considered an AE. | Up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Remission Rate (CRR) | Complete remission rate (CRR) is defined as the percent of participants whose best response is CRs including complete remission (CR), complete remission with partial hematologic recovery (CRh) and complete remission with incomplete hematologic recovery (CRi). | Up to 4 years | 
| Efficacy determined by response rates of Acute Myeloid Leukemia (AML) - Minimal residual disease negative complete remission rate (CRRMRD-) | Minimal residual disease negative complete remission rate is defined as the percent of participants with Minimal residual disease negative complete remission. | Up to 4 years | 
| Efficacy determined by response rates of Acute Myeloid Leukemia (AML) - Combined Complete Remission Rate (cCRR) | Combined complete remission rate (cCRR), is defined as the percent of participants whose best response is complete remission, includes minimal residual disease negative complete remission rate (CRRMRD-), morphologic complete remission, complete remission with incomplete hematologic recovery (CRi), complete remission with partial hematologic recovery (CRh). | Up to 4 years | 
| Efficacy determined by response rates of Acute Myeloid Leukemia (AML) - Morphologic Leukemia-free State Rate (MLFSR) | The Morphologic Leukemia-free State Rate is defined as the percent of participants with the best response of Morphologic Leukemia-free State. | Up to 4 years | 
| Partial Remission Rate (PRR) | Partial Remission Rate is defined as the percent of participant with the best response of Partial Remission. | Up to 4 years | 
| Stable Disease Rate (SDR) | Stable Disease Rate is defined as the percent of participants with the best response of Stable Disease. | Up to 4 years | 
| Progression-free Survival (PFS) rate at 3 and 9 months | Progression free survival rate is defined as the percent of participants with progression free for at least 3/9 months. | At 3 months and 9 months of PFS | 
| Overall Survival (OS) rate | Overall survival rate is defined as the percent of participant who have survived for at least 6/12 months. | At 6 and 12 months of survival | 
| Overall Response Rate (ORR) | Overall response rate is defined as the percent of participants whose best response is any of those composite complete response rate (cCRR) or morphologic Leukemia-free state (MLFS) or partial remission (PR) for AML and any of CR, marrow CR with HI (mCRHIR), PR, hematologic improvement (HI) for MDS. | Up to 4 years | 
| Overall Survival (OS) | Overall Survival is measured as the time from the first dose of CC-91633 to death due to any cause. | Up to 4 years | 
| Relapse-free Survival (RFS) | Relapse-free survival is defined only for participants who have achieved the best response of any of CR/CRh/CRi/CRRMRD- or any of PR/MLFS/mCRHIR/HI, and is measured as the interval from the date of first achieved of any CR/CRh/Cri/CRRMRD- or any of PR/ MLFS/mCRHIR/HI to the date of disease relapse or death from any cause, whichever occurs first. | Up to 4 years | 
| Progression-free Survival (PFS) | Progression-Free Survival is defined as the time from the first dose of CC-91633 to the first occurrence of relapse or progression or death from any cause. | Up to 4 years | 
| Event-free Survival (EFS) | Event-free Survival is defined as the interval from the date of the first dose to an event including disease progression, treatment failure, relapse, or death from any cause, whichever occurs first. | Up to 4 years | 
| Duration of remission/response | For participants with best response of any of CR/CRh/ CRi/CRRMRD- or any of PR/MLFS/mCRHIR/HI, duration of remission/response is measured from the time when criteria for the best response of any of CR/CRh/ Cri/CRRMRD- or any of PR/ MLFS/mCRHIR/HI are first met (whichever is first recorded) until the first date at which relapse, or progressive disease is objectively documented assessment. | Up to 4 years | 
| Time to remission/response | Time to onset of first remission/response is defined as the time interval from the date of first dose and the earliest date any remission/response (any CRs or PR) is observed. | Up to 4 years | 
| Efficacy: Time to transformation to Acute Myeloid Leukemia (AML) for High-Risk Myelodysplastic Syndrome (HR-MDS) | Time interval from first dose to onset date of having 20% more bone marrow (BM) or peripheral blood (PB) blasts. | Up to 4 years | 
| CC-91633 Pharmacokinetics - Cmax | Maximum plasma drug concentration. | Up to 4 years | 
| CC-91633 Pharmacokinetics - AUC(0-T) | Area under the plasma concentration-time curve from time zero to time t, where t is the time point of the last measurable concentration. | Up to 4 years | 
| CC-91633 Pharmacokinetics - AUC(TAU) | Area under the plasma concentration time-curve from time 0 to 24 hours postdose. | Up to 4 years | 
| CC-91633 Pharmacokinetics - Tmax | Time to peak (maximum) plasma concentration. | Up to 4 years | 
| CC-91633 Pharmacokinetics - T-HALF | Half-life. | Up to 4 years | 
| CC-91633 Pharmacokinetics - CLT/F | Apparent total clearance of the drug from plasma after oral administration, as appropriate. | Up to 4 years | 
| CC-91633 Pharmacokinetics - Vz/F | Apparent volume of distribution, as appropriate. | Up to 4 years | 
| CC-2004772 Pharmacokinetics - Cmax | Maximum plasma drug concentration, if possible. | Up to 4 years | 
| CC-2004772 Pharmacokinetics - AUC(0-T) | Area under the plasma concentration-time curve from time zero to time t, where t is the time point of the last measurable concentration, if possible. | Up to 4 years | 
| CC-2004772 Pharmacokinetics - AUC(TAU) | Area under the plasma concentration time-curve from time 0 to 24 hours postdose, if possible. | Up to 4 years | 
| CC-2004772 Pharmacokinetics - Tmax | Time to peak (maximum) plasma concentration, if possible. | Up to 4 years | 
| CC-2004772 Pharmacokinetics - T-HALF | Half-life, if possible. | Up to 4 years | 
| CC-2004772 Pharmacokinetics - CLT/F | Apparent total clearance of the drug from plasma after oral administration, if possible. | Up to 4 years | 
| CC-2004772 Pharmacokinetics - Vz/F | Apparent volume of distribution, if possible. | Up to 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed or Refractory Acute Myeloid Leukemia, Relapsed or Refractory Higher-Risk Myelodysplastic Syndromes