A Phase 1b/2 Study of BGB-11417in Monotherapy and in Various Combinations With Dexamethasone and Carfilzomib in Multiple Myeloma

Study Overview
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Brief Summary
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Study consists of two parts, a part 1 dose escalation and a part 2 cohort expansion in combination with dexamethasone and carfilzomib intravenously across two cohorts with a monotherapy component as well.

Official Title
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A Phase 1b/2 Dose-Escalation and Cohort-Expansion Study to Determine the Safety and Efficacy of BGB-11417as Monotherapy, in Combination With Dexamethasone and Carfilzomib/Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma and t(11;14)

Conditions
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Relapsed/Refractory Multiple Myeloma

Intervention / Treatment
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* Drug: BGB-11417
* Drug: Dexamethasone
* Drug: Carfilzomib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 A confirmed diagnosis of multiple myeloma (must have an M-component in serum and/or urine) Measurable disease defined as: i. M-spike ≥ 500mg/dL, or ii. Urine protein M-spike of ≥ 200 mg/day, or iii. Serum free light chains ≥ 10 mg/dL, and an abnormal κ:λ ratio Participant has documented relapsed or progressive MM on or after any regimen or who are refractory to the most recent line of therapy. i. Relapsed MM is defined as previously treated MM that progresses and requires initiation of salvage therapy but does not meet the criteria for refractory MM. ii. Refractory MM is defined as disease that is nonresponsive (failure to achieve minimal response or development of progressive disease) while on primary or salvage therapy or progresses within 60 days of last therapy. Participants in Part 1 should have failed all other available options including having had ≥ 3 prior lines of therapy including a proteasome inhibitor, IMiD agent, and an anti-CD38 monoclonal antibody. Participants in Part 2 should have had and failed ≥ 1 but ≤ 7 prior lines of therapy and will have had prior treatment with both a proteasome inhibitor and an IMiD agent. Note: A line of therapy consists of greater ≥ 1 complete cycle of a single agent, a regimen consisting of combination of several drugs, or a planned sequential therapy of various regimens. Induction therapy with consolidation and maintenance following stem cell transplant is considered a single line of therapy. Prior treatment with carfilzomib is allowed but the patient must not be considered carfilzomib refractory and not have had carfilzomib within the past 6 months Positivity for t(11;14) by validated fluorescence in situ hybridization (FISH) testing assay in a pre-defined laboratory a. fresh bone marrow aspirate sample must be collected at screening and sent to central laboratory for t(11;14) FISH testing. Adequate organ function defined as: Hemoglobin ≥ 8.0 g/dL, within 7 days before first dose of study treatment, independent of growth factor support and transfusions Platelet count ≥ 75,000/μL, within 7 days before first dose of study treatment, independent of growth factor support and transfusions Absolute neutrophil count (ANC) ≥ 1000/mm3 [ANC = (% of segmented neutrophils + % of segmented bands) x total WBC count within 7 days before first dose of study treatment ALT and AST ≤ 3 x upper limit of normal (ULN) and total bilirubin ≤ 2.0 x ULN Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 45 mL/min/1.73 m2 calculated by the MDRD-6 formula. Exclusion Criteria: Participant has any of the following conditions: Non secretory MM (Serum free light chains < 10 mg/dL) Solitary plasmacytoma Active plasma cell leukemia (ie, either 20% of peripheral white blood cells or > 2.0 x 109/L circulating plasma cells by standard differential) Waldenström macroglobulinemia Amyloidosis. Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS) syndrome Uncontrolled diabetes (HbA1c > 7% or 53 mmol/mol or requiring insulin at study entry Chronic respiratory disease that requires continuous oxygen Significant cardiovascular disease, including but not limited to: Myocardial infarction ≤ 6 months before screening Ejection fraction ≤ 50% Unstable angina≤ 3 months before screening New York Heart Association Class III or IV congestive heart failure History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, or torsades de pointes) Heart rate-corrected QT interval > 480 milliseconds based on Fridericia's formula History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place Uncontrolled hypertension at screening, defined as systolic blood pressure > 170 mmHg and diastolic blood pressure > 105 mmHg by ≥ 2 consecutive measurements Known infection with human immunodeficiency virus (HIV) Serologic status reflecting active viral hepatitis B (HBV) or viral hepatitis C (HCV) infection as follows: Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Participants with presence of HBcAb, but absence of HBsAg, are eligible if HBV DNA is undetectable (limitation of sensitivity < 20 IU/mL) ,), and if they are willing to undergo monthly monitoring for HBV reactivation. Presence of HCV antibody. Participants with presence of HCV antibody are eligible if HCV RNA is undetectable (limitation of sensitivity < 15 IU/mL). 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Dose Escalation<br>Dose-escalation and de-escalation to determine maximum tolerated dose (MTD) | Drug: BGB-11417<br>* Administered orally daily<br>* Other names: Sonrotoclax;Drug: Dexamethasone<br>* Once weekly either orally or intravenously<br>Drug: Carfilzomib<br>* Administered intravenously weekly<br>|
| Experimental: Part 2 Cohort Expansion<br>There will be 5 expansion cohorts to further evaluate the safety and efficacy of BGB-11417 | Drug: BGB-11417<br>* Administered orally daily<br>* Other names: Sonrotoclax;Drug: Dexamethasone<br>* Once weekly either orally or intravenously<br>Drug: Carfilzomib<br>* Administered intravenously weekly<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number Of Participants Experiencing Dose-limiting Toxicities (DLTs) | DLTs will be based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 and will be defined as any of following events: Grade 3 or higher toxicity assessed by the investigator as related to BGB-11417 treatment; and Grade 4 or higher regimen-related organ toxicities | 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 Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) with adverse events leading to discontinuation, and AEs graded according NCI-CTCAE Version 5 |  | Up to 24 months after last dose of study drug | 
| Part 2: Overall response rate (ORR) | Defined as the proportion of patients who achieved a stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) per International Myeloma Working Group (IMWG) criteria | Approximately 4 years | 
| Part 2: Very good partial response (VGPR) or better response rate | Defined as the proportion of patients with a documented VGPR or better (including sCR, CR, and VGPR) | Upon study termination (Baseline up to first documentation of disease progression [PD] or death from any cause [approximately 4 years] | 
| Part 2: Complete Response (CR) or better | defined as the proportion of patients with a documented CR or sCR | Upon study termination (Baseline up to first documentation of disease progression [PD] or death from any cause [approximately 4 years]) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Area under the plasma concentration-time curve (AUC) |  | At the end of Cycle 1 (each cycle is 28 days) | 
| Part 1: Maximum observed plasma concentration (Cmax) |  | At the end of Cycle 1 (each cycle is 28 days) | 
| Part 1: Time to reach Cmax (tmax) |  | At the end of Cycle 1 (each cycle is 28 days) | 
| Part 1: After steady-state: AUC last,ss |  | At the end of Cycle 1 (each cycle is 28 days) | 
| Part 1: After steady-state: Cmax, ss |  | At the end of Cycle 1 (each cycle is 28 days) | 
| Part 1: After steady-state: trough plasma concentration (Ctrough) ss |  | At the end of Cycle 1 (each cycle is 28 days) | 
| Part 1: After steady-state: time to reach Cmax (tmax,ss) |  | At the end of Cycle 1 (each cycle is 28 days) | 
| Part 2: Time to response (TTR) as assessed by investigator | TTR is defined as the time from start of treatment to first documentation of response of Partial Response (PR) or better | Upon study termination (Baseline up to first documentation of disease progression [PD] or death from any cause [approximately 4 years]) | 
| Part 2: Duration of response (DOR) as assessed by investigator | DOR is defined as the time from the date of the first documented response (PR or better) after treatment initiation until the date of first documented disease progression or death due to MM, whichever occurs first. DOR will be analyzed using the same methods as the PFS analysis, but only for patients who have achieved an overall response of at least PR. The distribution of DOR will be summarized by the Kaplan-Meier method. | Upon study termination (Baseline up to first documentation of disease progression [PD] or death from any cause [approximately 4 years]) | 
| Part 2: Progression-free survival (PFS) as assessed by investigator | PFS is defined as time from start of treatment to the first documentation of disease progression or death, whichever occurs first | Upon study termination (Baseline up to first documentation of disease progression [PD] or death from any cause [approximately 4 years]) | 
| Part 2: Overall survival (OS) as assessed by investigator | OS defined as the time from start of treatment to the date of death due to any cause | Upon study termination (Baseline up to approximately 4 years) |