A Phase 1b/2, Open-Label, Dose Finding, and Expansion Study of the Bcl-2 Inhibitor BGB-11417 in Patients With Myeloid Malignancies
Overview
- Phase
- Phase 1
- Intervention
- BGB-11417
- Conditions
- Acute Myeloid Leukemia
- Sponsor
- BeiGene
- Enrollment
- 260
- Locations
- 78
- Primary Endpoint
- Part 1 And 2: Number Of Participants Experiencing Dose-limiting Toxicities (DLTs)
- Status
- Recruiting
- Last Updated
- 18 days ago
Overview
Brief Summary
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) .
Investigators
Eligibility Criteria
Inclusion Criteria
- •Confirmed diagnosis of one of the following by 2016 World Health Organization criteria:
- •AML, nonacute promyelocytic leukemia
- •Eastern Cooperative Oncology Group performance status of 0 to
- •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.
Exclusion Criteria
- •A diagnosis of acute promyelocytic leukemia.
- •History of prior malignancy, with the exception of either a history of MDS or MDS/MPN that has transformed to AML, or other prior malignancy that was treated with a full curative intent and no evidence of recurrence within the past 2 years (eg, 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
- •Known central nervous system involvement by leukemia.
- •Note: Other protocol defined Inclusion/Exclusion criteria may apply.
Arms & Interventions
Parts 1 and 2: AML Cohorts
Participants with AML will receive BGB-11417 and azacitidine on a 28-day cycle.
Intervention: BGB-11417
Parts 1 and 2: AML Cohorts
Participants with AML will receive BGB-11417 and azacitidine on a 28-day cycle.
Intervention: Azacitidine
Parts 1 and 2: MDS Cohorts
Participants with MDS will receive BGB-11417 and azacitidine on a 28-day cycle.
Intervention: Azacitidine
Part 3: AML and MDS Cohorts
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.
Intervention: Azacitidine
Part 3: AML and MDS Cohorts
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.
Intervention: Posaconazole
Part 3: AML and MDS Cohort
Participants with MDS and R/R AML (China only) will receive BGB-11417 on a 28-day cycle.
Intervention: BGB-11417
Parts 1 and 2: MDS Cohorts
Participants with MDS will receive BGB-11417 and azacitidine on a 28-day cycle.
Intervention: BGB-11417
Part 3: AML and MDS Cohorts
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.
Intervention: BGB-11417
Outcomes
Primary Outcomes
Part 1 And 2: Number Of Participants Experiencing Dose-limiting Toxicities (DLTs)
Time Frame: 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 Experiencing Treatment-emergent Adverse Events (TEAEs)
Time Frame: Approximately 24 months
Part 3 AML Cohort: Complete Remission (CR) Plus CR With Partial Hematologic Recovery (CRh) Rate
Time Frame: Approximately 24 months
CR plus CRh will be defined as the percentage 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.
Part 3 MDS Cohort: Modified Overall Response (mOR) Rate
Time Frame: Approximately 24 months
The mOR will be defined as the percentage 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).
Part 3 AML Cohort (DDI Sub-cohort): Area Under Plasma Concentration-time Curve (AUC) from time 0 to the last quantifiable timepoint (t) (AUC0-t) Of BGB-11417 When Administered Alone and when Co-administered With Posaconazole
Time Frame: 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 Administered Alone and When Co-administered With Posaconazole
Time Frame: 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 Administered Alone and When Co-administered With Posaconazole
Time Frame: 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
Time Frame: Cycle 2
Part 3 AML and MDS Cohorts (Treated with Monotherapy): Number of Participants Experiencing TEAEs
Time Frame: Approximately 24 months
Secondary Outcomes
- Parts 1 And 2 AML Cohort: Complete remission (CR) + Morphologic CR With Partial Hematologic Recovery (CRh)(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: Terminal Half-life (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 Azacitidine From Plasma (CL/F) 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 Experiencing TEAEs(Approximately 24 months)
- Part 3: Complete Response Rate(Approximately 24 months)
- Part 3 AML Cohort: CR With Incomplete Hematologic Recovery (CRi) Rate(Approximately 24 months)
- Part 3 AML Cohort: Overall Response Rate (ORR)(Approximately 24 months)
- Part 3 AML Cohort: Duration Of Response (DOR)(Approximately 24 months)
- Part 3 AML Cohort: Time To Response (TTR)(Approximately 24 months)
- Part 3 Event-free Survival (EFS)(Approximately 24 months)
- Part 3 Overall Survival (OS)(Approximately 24 months)
- Part 3 AML Cohort: Number of Participants with Transfusion Independence(Approximately 24 months)
- Part 3 MDS Cohort: Number Of Participants With Hematological Improvement-erythroid (HI-E)(Approximately 24 months)
- Part 3 MDS Cohort: Proportion Of Participants With Hematological Improvement-platelet (HI-P)(Approximately 24 months)
- Part 3 MDS Cohort: Proportion Of Participants With Hematological Improvement-neutrophil (HI-N)(Approximately 24 months)
- Part 3 MDS Cohort: Number of participants with Transfusion Independence(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(Approximately 24 months)
- Part 3 AML (Treated with Monotherapy): Complete Response + Morphologic complete Remission with Partial Hematologic Recovery(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(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))