Phase 1 Study of BGB-21447, a Bcl-2 Inhibitor, in Mature B-Cell Malignancies

Study Overview
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Brief Summary
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This is a Phase 1 study testing the safety and tolerability of BGB-21447 monotherapy in participants with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The study aims to determine the maximum tolerated dose, recommended Phase 2 dose, and pharmacokinetic profile of the drug. Additionally, preliminary antitumor activity will be characterized. The study includes three cohorts and will also evaluate the safety and tolerability of a ramp-up dosing schedule.

Official Title
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A Phase 1 Open-Label Dose-Escalation Study of Bcl-2 Inhibitor BGB-21447 in Patients With Mature B-Cell Malignancies

Conditions
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Relapsed Non-Hodgkin Lymphoma, Refractory Non-Hodgkin Lymphoma, Relapsed Chronic Lymphocytic Leukemia, Refractory Chronic Lymphocytic Leukemia, Relapsed Follicular Lymphoma, Relapsed Marginal Zone Lymphoma, Diffuse Large B Cell Lymphoma, Relapsed Small Lymphocytic Lymphoma, Refractory Marginal Zone Lymphoma, Refractory Follicular Lymphoma, Refractory Small Lymphocytic Lymphoma

Intervention / Treatment
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* Drug: BGB-21447


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria 1. Confirmed diagnosis per WHO guidelines of one of the following: Cohort A: Relapsed/refractory (R/R) Diffuse large B-cell lymphoma (DLBCL)(excluding high-grade B-cell lymphomas with translocations of MYC and Bcl-6 and/or Bcl-2; primary cutaneous DLBCL, leg type; gray zone lymphoma; and primary mediastinal large B-cell lymphoma) R/R Follicular lymphoma (FL): R/R Marginal zone lymphoma (MZL Transformed B-Cell non-Hodgkin lymphoma (NHL) Cohorts B and C: R/R CLL/SLL diagnosis that meets the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria Measurable disease by computed tomography (CT) and/or magnetic resonance imaging (MRI). Exclusion Criteria: Prior malignancy (other than the disease under study) within the past 2 years, except for curatively treated basal or squamous skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast, or localized Gleason score ≤ 6 prostate cancer Known central nervous system involvement by lymphoma/leukemia Known history or currently suspected Richter's syndrome Prior autologous stem cell transplant < 3 months before the first dose of study drug. Or prior chimeric antigen receptor T-cell (CAR-T) therapy < 3 months before the first dose of study drug Prior allogeneic stem cell transplant. Major surgery < 4 weeks before the first dose of study treatment Use of the following substances prior to the first dose of the study drug: Any biologic and/or immunologic-based therapy(ies) ≤ 28 days before the first dose of study drug Any systemic chemotherapy or radiation therapy ≤ 14 days before the first dose of study drug Any targeted small molecule agents ≤ 14 days before the first dose of study drug Corticosteroid given with antineoplastic intent ≤ 7 days before the first dose of study drug. Short course of systemic corticosteroid treatment for control of lymphomarelated symptoms is allowed prior to enrollment, provided it is tapered off within 5 days after initiation of study treatment. Any treatment with a strong/moderate cytochrome P450 (CYP)3A inhibitor or inducer ≤ 14 days (or 5 half-lives for inhibitors, whichever is longer) before the first dose of study drug OR requiring long-term use of strong CYP3A inhibitors or inducers NOTE: Other 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: Dose escalation in participants with R/R Non-Hodgkin lymphoma<br>Participants will receive BGB-21447 once a day, starting with a small dose and increasing to higher doses one at a time. | Drug: BGB-21447<br>* BGB-21447 will be administered orally<br>|
| Experimental: Cohort B: Dose escalation in R/R CLL/SLL participants with low tumor burden<br>Participants will receive BGB-21447 once a day, starting with a small doses and increasing to higher doses one at a time. | Drug: BGB-21447<br>* BGB-21447 will be administered orally<br>|
| Experimental: Cohort C: Dose confirmation in R/R CLL/SLL participants with high tumor burden<br>Participants will receive BGB-21447 dose as determine in determined in cohort B. | Drug: BGB-21447<br>* BGB-21447 will be administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with dose limiting toxicities (DLTs) | Number of participants with dose limiting toxicities, defined as [see text in SAP or protocol for specific definition] | Up to approximately four years | 
| Number of participants with adverse events (AEs) | Number of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) assessed and graded based upon the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0). | Up to approximately four years | 
| Number of participants with Tumor Lysis Syndrome (TLS) | TLS will be determined via laboratory values and assessed by the investigator. In laboratory tumor lysis syndrome, 2 or more metabolic abnormalities must be present during the 24-hour period within 3 days before the start of study drug treatment or up to 7 days afterward. Clinical tumor lysis syndrome requires the presence of laboratory tumor lysis syndrome plus an increased creatinine level, seizures, cardiac dysrhythmia, or death. | Up to approximately four years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed plasma concentration (Cmax) of BGB-21447 |  | Up to approximately four years | 
| Pre-dose trough concentration (Ctrough) of BGB-21447 |  | Up to approximately four years | 
| Area under the curve from time 0 to the last sampling time point within the dose interval (AUClast) of BGB-21447 |  | Up to approximately four years | 
| Area under the curve from time 0 extrapolated to infinity (AUCinf) of BGB-21447 |  | Up to approximately four years | 
| Time to reach maximum observed plasma concentration (Tmax) of BGB-21447 |  | Up to approximately four years | 
| Apparent terminal elimination half life (t1/2) of BGB-21447 |  | Up to approximately four years | 
| Apparent oral clearance (CL/F) of BGB-21447 |  | Up to approximately four years | 
| Apparent volume of distribution (Vz/F) of BGB-21447 |  | Up to approximately four years | 
| Steady state maximum observed plasma concentration (Cmax) of BGB-21447 |  | Up to approximately four years | 
| Steady state pre-dose trough concentration (Ctrough) of BGB-21447 |  | Up to approximately four years | 
| Steady state area under the curve from time 0 to the last sampling time point within the dose interval (AUClast) of *drug name* |  | Up to approximately four years | 
| Steady state area under the curve from time 0 extrapolated to infinity (AUCinf) of BGB-21447 |  | Up to approximately four years | 
| Steady state time to reach maximum observed plasma concentration (Tmax) of BGB-21447 |  | Up to approximately four years | 
| Steady state apparent terminal elimination half life (t1/2) of BGB-21447 |  | Up to approximately four years | 
| Steady state apparent oral clearance (CL/F) of BGB-21447 |  | Up to approximately four years | 
| Steady state apparent volume of distribution (Vz/F) of BGB-21447 |  | Up to approximately four years | 
| Duration of Response (DOR) | defined as the time from the first response documentation to the date that progression is documented after treatment initiation or death due to any cause, whichever occurs first. | Up to approximately four years | 
| Time to response (TTR) | defined as the time from treatment initiation to the first documentation of response. | Up to approximately four years | 
| Progression-free survival (PFS) | defined as the time from treatment initiation to the first documented disease progression or death due to any cause, whichever occurs first. | Up to approximately four years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NHL, MZL, Refractory Chronic Lymphocytic Leukemia, RCLL, Relapsed Follicular Lymphoma, Refractory Follicular Lymphoma, Relapsed Marginal Zone Lymphoma, Refractory Marginal Zone Lymphoma, RFL, RMZL, Relapsed Chronic Lymphocytic Leukemia, small lymphocytic lymphoma., Follicular Lymphoma, Marginal Zone Lymphoma, Relapsed Non-Hodgkin Lymphoma, refractory non-Hodgkin lymphoma, CLL, SLL, FL, Relapsed Small Lymphocytic Lymphoma, Refractory Small Lymphocytic Lymphoma, RSLL