A Study of BGB-11417 in Participants With Myeloid Malignancies

Study Overview
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Brief Summary
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The study will determine the safety, tolerability, recommended Phase 2 dose (RP2D) and preliminary efficacy of BGB-11417 as monotherapy and in combination with azacitidine in participants with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)or MDS/myeloproliferative neoplasm (MPN) .

Official Title
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A Phase 1b/2, Open-Label, Dose Finding, and Expansion Study of the Bcl-2 Inhibitor BGB-11417 in Patients With Myeloid Malignancies

Conditions
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Acute Myeloid Leukemia, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasm

Intervention / Treatment
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* Drug: BGB-11417
* Drug: Azacitidine
* Drug: Posaconazole
* Drug: BGB-11417
* Drug: BGB-11417


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Confirmed diagnosis of one of the following by 2016 World Health Organization criteria: AML, nonacute promyelocytic leukemia MDS MDS/MPN Eastern Cooperative Oncology Group performance status of 0 to 2. Adequate organ function defined as: Creatinine clearance ≥ 50 milliliters/minute (mL/min) (or between 30 and 49 mL/min in unfit AML cohort) Adequate liver function Life expectancy of > 12 weeks. Ability to comply with the requirements of the study. Key Exclusion Criteria: A diagnosis of acute promyelocytic leukemia. Prior malignancy within the past 2 years, except for curatively treated localized skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast, or localized Gleason score ≤ 6 prostate cancer. Antecedent MPN including myelofibrosis, essential thrombocytosis, polycythemia vera, or chronic myelogenous leukemia with or without BCR-ABL1 translocation and AML with BCR-ABL1 translocation. Prior therapy with a B-cell lymphoma-2 inhibitor or azacitidine except for participants who meet HMA-failure criteria Known central nervous system involvement by leukemia. Note: Other protocol defined Inclusion/Exclusion criteria may apply.

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: Parts 1 and 2: AML Cohorts<br>Participants with AML will receive BGB-11417 and azacitidine on a 28-day cycle. | Drug: BGB-11417<br>* Oral administration for 10, 21, 14 or 28 days on a 28-day cycle.<br>* Other names: Sonrotoclax;Drug: Azacitidine<br>* Intravenous or subcutaneous administration for 7 days.<br>|
| Experimental: Parts 1 and 2: MDS Cohorts<br>Participants with MDS will receive BGB-11417 and azacitidine on a 28-day cycle. | Drug: Azacitidine<br>* Intravenous or subcutaneous administration for 7 days.<br>Drug: BGB-11417<br>* Oral administration for 10 or 21 days on a 28-day<br>|
| Experimental: Part 3: AML and MDS Cohorts<br>Participants with AML and MDS will receive BGB-11417 and azacitidine on a 28-day cycle. A subset of the participants will receive a modified second cycle of treatment to explore drug-drug interactions (DDI) with posaconazole. | Drug: BGB-11417<br>* Oral administration for 10, 21, 14 or 28 days on a 28-day cycle.<br>* Other names: Sonrotoclax;Drug: Azacitidine<br>* Intravenous or subcutaneous administration for 7 days.<br>Drug: Posaconazole<br>* Oral administration for 8 days on second cycle only.<br>|
| Experimental: Part 3: AML and MDS Cohort<br>Participants with MDS and R/R AML (China only) will receive BGB-11417 on a 28-day cycle. | Drug: BGB-11417<br>* Oral administration for 28 days on a 28-day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 And 2: Number Of Participants Experiencing Dose-limiting Toxicities (DLTs) |  | Cycle 1 (Up to 28 days for non-hematologic DLTs and up to 42 days for hematologic DLTs) | 
| Part 1 And 2: Number Of Participants Receiving BGB-11417 In Combination With Azacitidine Experiencing Treatment-emergent Adverse Events (TEAEs) |  | Approximately 24 months | 
| Part 3 AML Cohort: Complete Remission (CR) Plus CR With Partial Hematologic Recovery (CRh) Rate | CR plus CRh will be defined as the proportion of participants whose best overall response (BOR) is CR plus CRh. BOR will be defined as the best response recorded from the first dose of study drug until data cut or the initiation of new anticancer treatment. | Approximately 24 months | 
| Part 3 MDS Cohort: Modified Overall Response (mOR) Rate | The mOR will be defined as the proportion of participants whose BOR is achieving CR, marrow complete remission (mCR), or partial remission (PR) at any time point during the study for myelodysplastic/myeloproliferative neoplasm (MDS/MPN). | Approximately 24 months | 
| Part 3 AML Cohort (DDI Sub-cohort): Area Under Plasma Concentration-time Curve (AUC) from time 0 to the last quantifiable (AUC0-t) Of BGB-11417 When Co-administered With Posaconazole |  | Cycle 2 Day 12 and Cycle 2 Day 20 (predose and 1, 2, 4, 6, 8, and 24 hours postdose) | 
| Part 3 AML Cohort (DDI Sub-cohort): Maximum Observed Plasma Concentration (Cmax) Of BGB-11417 When Coadministered With Posaconazole |  | Cycle 2 Day 12 and Cycle 2 Day 20 (predose and 1, 2, 4, 6, 8, and 24 hours postdose) | 
| Part 3 AML Cohort (DDI Sub-cohort): Area Under Plasma Concentration-time Curve (AUC) from time 0 to infinity (AUC0-infinity) Of BGB-11417 When Co-administered With Posaconazole |  | Cycle 2 Day 12 and Cycle 2 Day 20 (predose and 1, , 4, 6, 8, and 24 hours postdose) | 
| Part 3 AML and MDS Cohorts (Treated with Monotherapy): Number Of Participants Experiencing DLTs |  | Cycle 2 | 
| Part 3 AML and MDS Cohorts (Treated with Monotherapy): Number of Participants Experiencing TEAEs |  | Approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts 1 And 2 AML Cohort: CR Plus CRh Rate |  | Approximately 24 months | 
| Parts 1 And 2 MDS Cohort: mOR Rate |  | Approximately 24 months | 
| Parts 1 And 2: Cmax Of Azacitidine When Coadministered With BGB-11417 |  | Day 0 and 4 (Cycle 1) predose and at multiple time points up to 4 hours postdose | 
| Parts 1 And 2: t1/2 Of Azacitidine When Coadministered With BGB-11417 |  | Day 0 and 4 (Cycle 1) predose and at multiple time points up to 4 hours postdose | 
| Parts 1 And 2: AUC From Time Zero To Time t (AUC0-t) Of Azacitidine When Coadministered With BGB-11417 |  | Day 0 and 4 (Cycle 1) predose and at multiple time points up to 4 hours postdose | 
| Parts 1 And 2: AUC From Time Zero To Infinity (AUC0-inf) Of Azacitidine When Coadministered With BGB-11417 |  | Day 0 and 4 (Cycle 1) predose and at multiple time points up to 4 hours postdose | 
| Parts 1 And 2: Apparent Total Clearance Of Drug From Plasma After Oral Administration (CL/F) Of Azacitidine When Coadministered With BGB-11417 |  | Day 0 and 4 (Cycle 1) predose and at multiple time points up to 4 hours postdose | 
| Parts 1 And 2: Apparent Volume Of Distribution (Vz/F) Of Azacitidine When Coadministered With BGB-11417 |  | Day 0 and 4 (Cycle 1) predose and at multiple time points up to 4 hours postdose | 
| Parts 1 And 2: Steady-state AUC From Time Zero To Time Of Last Measurable Concentration (AUClast,ss) Of BGB-11417 When Coadministered With Azacitidine |  | Day 1-4 and 28 (Cycle 1) Day 5 (Cycle 2) predose and at multiple time points up to 8 hours postdose | 
| Parts 1 And 2: Steady-state Cmax (Cmax,ss) Of BGB-11417 When Coadministered With Azacitidine |  | Day 1-4 and 28 (Cycle 1) Day 5 (Cycle 2) predose and at multiple time points up to 8 hours postdose | 
| Parts 1 And 2: Steady-state Trough Plasma Concentration (Ctrough,ss) Of BGB-11417 When Coadministered With Azacitidine |  | Day 1-4 and 28 (Cycle 1) Day 5 (Cycle 2) predose and at multiple time points up to 8 hours postdose | 
| Parts 1 And 2: Steady-state Time To Maximum Observed Plasma Concentration (tmax,ss) Of BGB-11417 When Coadministered With Azacitidine |  | Day 1-4 and 28 (Cycle 1) Day 5 (Cycle 2) predose and at multiple time points up to 8 hours postdose | 
| Part 3: Number Of Participants Receiving BGB-11417 In Combination With Azacitidine Experiencing TEAEs |  | Approximately 24 months | 
| Part 3: Complete Response | CR will be defined as the proportion of participants whose BOR is CR. BOR will be defined as the best response recorded from the first dose of study drug until data cut or the initiation of new anticancer treatment. | Approximately 24 months | 
| Part 3 AML Cohort: CR With Incomplete Hematologic Recovery (CRi) Rate | CRi will be defined as the proportion of participants whose BOR is CRi. | Approximately 24 months | 
| Part 3 AML Cohort: Overall Response Rate (ORR) | The ORR will include participants whose BOR include CR, CRi, PR, and morphologic leukemia-free state. | Approximately 24 months | 
| Part 3 AML Cohort: Duration Of Response (DOR) | DOR will be defined as the time from the first response to disease progression documented after treatment initiation or death, whichever occurs first. DOR will include CR, CR plus CRi, overall response (OR), and CR plus CRh. | Approximately 24 months | 
| Part 3 AML Cohort: Time To Response (TTR) | TTR will be defined as the time from treatment initiation to the first documented response and will include CR, CR plus CRi, OR, and CR plus CRh. | Approximately 24 months | 
| Part 3 AML Cohort: Event-free Survival (EFS) | EFS will be defined as the time from treatment initiation to disease progression, treatment failure, relapse (hematologic relapse for AML) for those who have treatment success, or death due to any cause, whichever happens first. | Approximately 24 months | 
| Part 3 AML Cohort: Overall Survival (OS) | OS will be defined as the time from treatment initiation to death. OS will be analyzed using the same methods as the EFS analysis except for the censoring rules. | Approximately 24 months | 
| Part 3 AML Cohort: Number Of Participants Receiving BGB-11417 In Combination With Posaconazole Experiencing TEAEs |  | Approximately 24 months | 
| Part 3 AML Cohort: Number of Participants with Transfusion Independence | Transfusion independence will be defined as the proportion of participants whose BOR is transfusion independence. Transfusion independence will need to last for at least 56 consecutive days postbaseline. | Approximately 24 months | 
| Part 3 MDS Cohort: Number Of Participants With Hematological Improvement-erythroid (HI-E) | The proportion of participants whose BOR is HI-E | Approximately 24 months | 
| Part 3 MDS Cohort: Proportion Of Participants With Hematological Improvement-platelet (HI-P) | The proportion of participants whose BOR is HI-P | Approximately 24 months | 
| Part 3 MDS Cohort: Proportion Of Participants With Hematological Improvement-neutrophil (HI-N) | The proportion of participants whose BOR is HI-N will be reported. | Approximately 24 months | 
| Part 3 MDS Cohort: Number of participants with Transfusion Independence | Transfusion independence will be defined as the proportion of participants whose BOR is transfusion independence. Transfusion independence will need to last for at least 56 consecutive days postbaseline. | Approximately 24 months | 
| Part 3: Ctrough,ss Of BGB-11417 When Coadministered With Azacitidine |  | Cycle 1 Day 1 and Cycle 2 Day 5 (predose and 4 and 6 hours postdose) | 
| Part 3 MDS cohort: Partial Hematologic Recovery CRh | Proportion of participants with partial hematologic recovery will be reported | Approximately 24 months | 
| Part 3 AML (Treated with Monotherapy): Complete Response + Morphologic complete Remission with Partial Hematologic Recovery | Proportion of participants with Complete Response + Morphologic complete Remission with Partial Hematologic Recovery will be reported. | Approximately 24 months | 
| Part 3 AML (Treated with Monotherapy): Steady State trough plasma concentration of BGB-11417 |  | Cycle 2 Day 12 and Cycle 2 Day 20 (predose and 1, 4, 6, 8, and 24 hours postdose) | 
| Part 3 MDS (Treated with Monotherapy): Modified Overall Response | Proportion of participants with modified overall response including CR, marrow CR (mCR) or partial remission (PR) | Approximately 24 months | 
| Part 3 MDS (Treated with Monotherapy): Steady State trough plasma concentration of BGB-11417 |  | Cycle 2 Day 12 and Cycle 2 Day 20 (predose and 1, 4, 6, 8, and 24 hours postdose) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BGB-11417, Azacitidine, Posaconazole, AML, MDS, MDS/MPN