A Phase 1b/2 Study of Sonrotoclax (BGB-11417) as Monotherapy and in Various Combinations With Dexamethasone Plus Carfilzomib, Dexamethasone Plus Daratumumab, and Dexamethasone Plus Pomalidomide in Multiple Myeloma

BeiGene

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Relapsed/Refractory Multiple Myeloma

Treatments: Drug: Pomalidomide; Drug: Carfilzomib; Drug: Dexamethasone; Drug: Sonrotoclax; Drug: Daratumumab

Study type: Interventional

Funder types: Industry

Identifiers

NCT04973605

BGB-11417-105

2021-003614-39 (EudraCT Number)

2023-507751-30-00 (EU Trial (CTIS) Number)

U1111-1277-5444 (Other Identifier)

Details and patient eligibility

About

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.

Enrollment: 167 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2

2. A confirmed diagnosis of multiple myeloma (must have an M-component in serum and/or urine)

3. 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

4. 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.

   1. In Part 1 should have relapsed or progressive disease and have had ≥ 3 prior lines of therapy including a proteasome inhibitor, an IMiD, and an anti-CD38 monoclonal antibody, and no more available approved therapies.
   2. Participants in Part 2 should have relapsed or progressive disease and have had ≥ 1 prior line of therapy
   3. Prior treatment with carfilzomib is allowed but the patient must not be considered carfilzomib refractory by the investigator.

5. Positivity for t(11;14) translocation must be confirmed 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.

6. Adequate organ function defined as:

   1. Hemoglobin ≥ 8.0 g/dL within 7 days before first dose of study treatment, (transfusions, in accordance with institutional guidelines, are permitted)
   2. Platelet count ≥ 75,000/μL, within 7 days before first dose of study treatment, independent of growth factor support and transfusions
   3. Absolute neutrophil count (ANC) ≥ 1000/mm^3 within 7 days before first dose of study treatment
   4. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x upper limit of normal (ULN) and total bilirubin ≤ 2.0 x ULN N (total bilirubin must be < 3 x ULN for patients with Gilbert's syndrome)

Exclusion criteria

1. Participant has any of the following conditions:

   1. Non secretory MM (Serum free light chains < 10 mg/dL)
   2. Solitary plasmacytoma
   3. Active plasma cell leukemia (ie, either 20% of peripheral white blood cells or > 2.0 x 109/L circulating plasma cells by standard differential)
   4. Waldenström macroglobulinemia
   5. Amyloidosis.
   6. Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS) syndrome
   7. Chronic respiratory disease that requires continuous oxygen

2. Significant cardiovascular disease, including but not limited to:

   1. Myocardial infarction ≤ 6 months before screening
   2. Ejection fraction ≤ 50%
   3. Unstable angina≤ 3 months before screening
   4. New York Heart Association Class III or IV congestive heart failure
   5. History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, or torsades de pointes)
   6. Heart rate-corrected QT interval > 480 milliseconds based on Fridericia's formula
   7. History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place
   8. Uncontrolled hypertension at screening, defined as systolic blood pressure > 170 mmHg and diastolic blood pressure > 105 mmHg by ≥ 2 consecutive measurements. Prior therapy with sonrotoclax or other agents inhibiting BCL2 activity (eg, venetoclax)

3. Known infection with human immunodeficiency virus (HIV)

4. Serologic status reflecting active viral hepatitis B (HBV) or viral hepatitis C (HCV) infection as follows:

   1. 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.
   2. 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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167 participants in 2 patient groups

Part 1 Dose Escalation

Experimental group

Description:

Dose-escalation and de-escalation to determine maximum tolerated dose (MTD)

Treatment:

Drug: Daratumumab

Drug: Sonrotoclax

Drug: Dexamethasone

Drug: Pomalidomide

Drug: Carfilzomib

Part 2 Cohort Expansion

Experimental group

Description:

There will be 5 expansion cohorts to further evaluate the safety and efficacy of BGB-11417

Treatment:

Drug: Sonrotoclax

Drug: Dexamethasone

Drug: Carfilzomib