Study of Bcl-2 Inhibitor BGB-11417 in Participants With Mature B-Cell Malignancies

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety, tolerability; and to define the maximum tolerated dose (MTD) and Recommended Phase 2 Dose (RP2D); and to evaluate the safety and tolerability of the ramp-up dosing schedule and at the RP2D of BGB-11417 monotherapy, and when given in combination with zanubrutinib and obinutuzumab.

Official Title
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A Phase 1a/1b Open-Label Dose Escalation and Expansion Study of Bcl-2 Inhibitor BGB-11417 in Patients With Mature B-Cell Malignancies

Conditions
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Mature B-Cell Malignancies

Intervention / Treatment
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* Drug: BGB-11417
* Drug: Zanubrutinib
* Drug: obinutuzumab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Confirmed diagnosis of one of the following: NHL Cohorts: MZL i. R/R extranodal, splenic, or nodal MZL defined as disease that relapsed after, or was refractory to, at least one prior therapy ii. Active disease requiring treatment FL i. R/R FL (Grade 1, 2 or 3a based on the WHO 2008 classification of tumors of hematopoietic and lymphoid tissue) and defined as disease that relapsed after, or was refractory to, at least 1 prior systemic therapy DLBCL i. R/R DLBCL (including all subtypes of DLBCL) defined as disease that relapsed after, or was refractory to, at least two prior systemic therapies and has either progressed following or is not a candidate for autologous stem cell transplant (due to comorbidities or non-responsiveness to salvage chemotherapy) Transformed indolent B-cell NHL i. Any lymphoma otherwise eligible for Part 1 that has transformed into a more aggressive lymphoma. Patients with transformation from CLL or SLL (Richter's transformation) are not eligible for Part 1 CLL/SLL Cohorts: CLL/SLL diagnosis that meets the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria i. Disease characterized as Treatment Naive (TN) or R/R disease defined as disease that relapsed after, or was refractory to, at least 1 prior therapy ii. Requiring treatment as defined by history MCL cohorts: WHO-defined MCL I. R/R MCL defined as disease that relapsed after, or was refractory to, at least 1 prior systemic therapy; ii. Requiring treatment in the opinion of the investigatorr WM cohorts: g. WHO-defined WM (clinical and definitive histologic diagnosis) i. R/R disease defined as disease that relapsed after, or was refractory to, at least 1 prior therapy; ii. Meeting at least 1 criterion for treatment according to consensus panel criteria from the Seventh International Workshop on Waldenström's Macroglobulinemia (Dimopoulos et al 2014) Measurable disease by computed tomography (CT)/magnetic resonance imaging (MRI), defined as: CLL: at least 1 lymph node > 1.5 cm in longest diameter and measurable in 2 perpendicular dimensions or clonal lymphocytes measured by flow cytometry DLBCL, FL, MZL, SLL: at least 1 lymph node > 1.5 cm in longest diameter OR 1 extranodal lesion > 1.0 cm in the longest diameter, measurable in at least 2 perpendicular dimensions. For MZL, isolated splenomegaly is considered measurable for this study Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 Adequate organ function Adequate pancreatic function indicated by: Serum amylase ≤ 1.5 x upper limit of normal (ULN) Serum lipase ≤ 1.5 x ULN Key Exclusion Criteria: Known central nervous system involvement by lymphoma/leukemia Known plasma cell neoplasm, prolymphocytic leukemia, history of or currently suspected Richter's syndrome Prior therapy ≥ 2 months with or progression on a B-cell lymphoma-2 (Bcl-2) inhibitor 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: BGB-11417 Monotherapy Dose Finding: Part 1<br>Participants with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) including follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma (MZL) or transformed NHL, mantle cell lymphoma (MCL); Waldenströms macroglobulinemia (WM); and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) will receive oral BGB-11417 until the maximum tolerated dose (MTD) (or maximum ascending dose (MAD)) and recommended phase 2 dose can be determined | Drug: BGB-11417<br>* Film-coated tablets administered once daily at a dose as specified in the treatment arm<br>* Other names: Sonrotoclax;|
| Experimental: BGB-11417 Monotherapy Expansion Cohorts: Part 2<br>Participants with R/R indolent NHL including FL, MZL; aggressive NHL including DLBCL, transformed NHL; CLL/SLL with low tumor burden or low creatine clearance; CLL/SLL with without high tumor burden or low creatine clearance will receive oral BGB-11417 at the RP2D dose to further define the safety profile | Drug: BGB-11417<br>* Film-coated tablets administered once daily at a dose as specified in the treatment arm<br>* Other names: Sonrotoclax;|
| Experimental: BGB-11417 + Zanubrutinib Combination Therapy Dose Finding: Part 3<br>Participants with R/R indolent NHL including FL, MZL; aggressive NHL including DLBCL, transformed NHL; R/R MCL; R/R or treatment-naïve (TN) CLL/SLL will receive oral BGB-11417 until RP2D can be determined in combination with zanubrutinib | Drug: BGB-11417<br>* Film-coated tablets administered once daily at a dose as specified in the treatment arm<br>* Other names: Sonrotoclax;Drug: Zanubrutinib<br>* 320 mg daily administered as two 80-mg capsules twice a day (160 mg twice a day) or as four 80-mg capsules once a day (320 mg once a day)<br>* Other names: BGB-3111;|
| Experimental: BGB-11417 + Zanubrutinib Combination Therapy Dose Expansion: Part 4<br>Participants with R/R indolent NHL including FL, MZL; aggressive NHL including DLBCL, transformed NHL; R/R MCL; R/R or treatment-naïve (TN) CLL/SLL will receive oral BGB-11417 at an RP2D dose to further define the safety profile in combination with zanubrutinib | Drug: BGB-11417<br>* Film-coated tablets administered once daily at a dose as specified in the treatment arm<br>* Other names: Sonrotoclax;Drug: Zanubrutinib<br>* 320 mg daily administered as two 80-mg capsules twice a day (160 mg twice a day) or as four 80-mg capsules once a day (320 mg once a day)<br>* Other names: BGB-3111;|
| Experimental: : BGB-11417 + Zanubrutinib Combination Therapy Dose Escalation: Part 5<br>Participants with treatment naïve CLL/SLL will receive oral BGB-11417 until RP2D can be determined in combination with obinutuzumab without and with zanubrutinib. | Drug: BGB-11417<br>* Film-coated tablets administered once daily at a dose as specified in the treatment arm<br>* Other names: Sonrotoclax;Drug: Zanubrutinib<br>* 320 mg daily administered as two 80-mg capsules twice a day (160 mg twice a day) or as four 80-mg capsules once a day (320 mg once a day)<br>* Other names: BGB-3111;|
| Experimental: BGB-11417 + Zanubrutinib Combination Therapy Dose Expansion: Part 6<br>Participants with treatment naïve CLL/SLL will receive oral BGB-11417 at an RP2D dose to further define the safety profile in combination with obinutuzumab without and with zanubrutinib | Drug: BGB-11417<br>* Film-coated tablets administered once daily at a dose as specified in the treatment arm<br>* Other names: Sonrotoclax;Drug: Zanubrutinib<br>* 320 mg daily administered as two 80-mg capsules twice a day (160 mg twice a day) or as four 80-mg capsules once a day (320 mg once a day)<br>* Other names: BGB-3111;Drug: obinutuzumab<br>* Given as an intravenous infusion administered per label.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) |  | Up to 30 days after the last dose of study drug, an average of 18 months | 
| Number of Participants Experiencing Serious Adverse Events (SAEs) |  | Up to 30 days after the last dose of study drug, an average of 18 months | 
| Number of Participants Experiencing Adverse Events (AEs) leading to discontinuation of BGB-11417 |  | Up to 30 days after the last dose of study drug, an average of 18 months | 
| Part 1, Part 3: Maximum Tolerated Dose (MTD) |  | Day 1 to 21 days target dose of the study drug, an average of 18 months | 
| Part 1, Part 3: Maximum RP2D of BGB-11417 |  | Day 1 to last dose of study drug, an average of 18 months | 
| Part 1, Part 3: Number of participants experiencing tumor lysis syndrome (TLS) relevant events |  | Up to 30 days after the last dose of study drug, an average of 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of BGB-11417 |  | Predose up to 12 hours postdose | 
| Area Under the Concentration-Time Curve from Time 0 to the Last Quantifiable Concentration (AUC0-last) of BGB-11417 |  | Predose up to 12 hours postdose | 
| Area Under the Concentration-Time Curve from Time 0 to Infinity (AUC0-∞) of BGB-11417 |  | Predose up to 12 hours postdose | 
| Time Taken for Half the Initial Dose Administered to Be Eliminated from The Body (T1/2) of BGB-11417 |  | Predose up to 12 hours postdose | 
| Time to Maximum Plasma Concentration (Tmax) of BGB-11417 |  | Predose up to 12 hours postdose | 
| Apparent Clearance (CL/F) of BGB-11417 |  | Predose up to 12 hours postdose | 
| Apparent volume of distribution (Vz/F) of BGB-11417 |  | Predose up to 12 hours postdose | 
| Steady State Area Under the Concentration-Time Curve of 0 - Last Day (AUCLast, ss) of BGB-11417 |  | Predose up to 12 hours postdose | 
| Part 3, Part 4: Steady State Area Under the Concentration-Time Curve of 0 - Last Day (AUCLast, ss) of zanubrutinib |  | Predose up to 12 hours postdose | 
| Steady State Maximum Observed Plasma Concentration (Cmax, ss) of BGB-11417 |  | Predose up to 12 hours postdose | 
| Part 3, Part 4: Steady State Maximum Observed Plasma Concentration (Cmax, ss) of zanubrutinib |  | Predose up to 12 hours postdose | 
| Steady State Trough Observed Plasma Concentration (Ctrough, SS) of BGB-11417 |  | Predose up to 12 hours postdose | 
| Part 3, Part 4: Steady State Trough Observed Plasma Concentration (Ctrough, SS) of zanubrutinib |  | Predose up to 12 hours postdose | 
| Steady State Time to Maximum Plasma Concentration (Tmax, ss) of BGB-11417 |  | Predose up to 12 hours postdose | 
| Part 3, Part 4: Steady State Time to Maximum Plasma Concentration (Tmax, ss) of zanubrutinib |  | Predose up to 12 hours postdose | 
| Part 2: AUC of BGB-11417 administered after a high fat/calorie meal (HF-Fed) |  | Predose up to 12 hours postdose | 
| Part 2: Cmax of BGB-11417 administered after a high fat/calorie meal (HF-Fed) |  | Predose up to 12 hours postdose | 
| Part 2, Part 4, Part 6: Overall Response Rate (ORR) as Assessed by the Investigator | ORR is defined as the proportion of participants who had confirmed complete response Complete Response (CR) or Partial Response (PR) | Up to 30 days after the last dose of study drug, an average of 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NHL, BCL2 Inhibitor, CLL, MCL, MZL, SLL, WM