A Phase 1a/1b Open-Label Dose Escalation and Expansion Study of Bcl-2 Inhibitor BGB-11417 in Patients With Mature B-Cell Malignancies
Overview
- Phase
- Phase 1
- Intervention
- Sonrotoclax
- Conditions
- Mature B-Cell Malignancies
- Sponsor
- BeiGene
- Enrollment
- 437
- Locations
- 44
- Primary Endpoint
- Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs)
- Status
- Active, not recruiting
- Last Updated
- last year
Overview
Brief Summary
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.
Investigators
Eligibility Criteria
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 investigator
Exclusion Criteria
- •Known current 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.
Arms & Interventions
Sonrotoclax Monotherapy Dose Finding: Part 1
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 sonrotoclax evaluated as monotherapy.
Intervention: Sonrotoclax
Sonrotoclax Monotherapy Expansion Cohorts: Part 2
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 sonrotoclax at the RP2D dose to further define the safety profile.
Intervention: Sonrotoclax
Sonrotoclax + Zanubrutinib Combination Therapy Dose Finding: Part 3
Participants with R/R MCL, R/R or treatment-naïve (TN) CLL/SLL will receive oral sonrotoclax in combination with zanubrutinib.
Intervention: Sonrotoclax
Sonrotoclax + Zanubrutinib Combination Therapy Dose Finding: Part 3
Participants with R/R MCL, R/R or treatment-naïve (TN) CLL/SLL will receive oral sonrotoclax in combination with zanubrutinib.
Intervention: Zanubrutinib
Sonrotoclax + Zanubrutinib Combination Therapy Dose Expansion: Part 4
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 sonrotoclax in combination with zanubrutinib at an RP2D dose to further define the safety profile.
Intervention: Sonrotoclax
Sonrotoclax + Zanubrutinib Combination Therapy Dose Expansion: Part 4
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 sonrotoclax in combination with zanubrutinib at an RP2D dose to further define the safety profile.
Intervention: Zanubrutinib
Sonrotoclax + Zanubrutinib Combination Therapy Dose Escalation: Part 5
Participants with treatment naïve CLL/SLL will receive oral sonrotoclax in combination with obinutuzumab without and with zanubrutinib.
Intervention: Sonrotoclax
Sonrotoclax + Zanubrutinib Combination Therapy Dose Escalation: Part 5
Participants with treatment naïve CLL/SLL will receive oral sonrotoclax in combination with obinutuzumab without and with zanubrutinib.
Intervention: Zanubrutinib
Sonrotoclax + Zanubrutinib Combination Therapy Dose Escalation: Part 5
Participants with treatment naïve CLL/SLL will receive oral sonrotoclax in combination with obinutuzumab without and with zanubrutinib.
Intervention: Obinutuzumab
Sonrotoclax + Zanubrutinib Combination Therapy Dose Expansion: Part 6
Participants with treatment naïve CLL/SLL will receive oral sonrotoclax in combination with obinutuzumab without and with zanubrutinib at an RP2D dose to further define the safety profile.
Intervention: Sonrotoclax
Sonrotoclax + Zanubrutinib Combination Therapy Dose Expansion: Part 6
Participants with treatment naïve CLL/SLL will receive oral sonrotoclax in combination with obinutuzumab without and with zanubrutinib at an RP2D dose to further define the safety profile.
Intervention: Zanubrutinib
Sonrotoclax + Zanubrutinib Combination Therapy Dose Expansion: Part 6
Participants with treatment naïve CLL/SLL will receive oral sonrotoclax in combination with obinutuzumab without and with zanubrutinib at an RP2D dose to further define the safety profile.
Intervention: Obinutuzumab
Outcomes
Primary Outcomes
Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs)
Time Frame: Up to 30 days after the last dose of study drug, an average of 18 months
Number of Participants Experiencing Serious Adverse Events (SAEs)
Time Frame: 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 Sonrotoclax
Time Frame: Up to 30 days after the last dose of study drug, an average of 18 months
Part 1, Part 3: Maximum Tolerated Dose (MTD) of Sonrotoclax
Time Frame: Up to approximately 2 months
Part 1, Part 3, Part 5: RP2D of Sonrotoclax
Time Frame: Day 1 to last dose of study drug, an average of 18 months
Part 1, Part 3, Part 5: Number of participants experiencing tumor lysis syndrome (TLS) relevant events
Time Frame: Up to 30 days after the last dose of study drug, an average of 18 months
Part 1, Part 3, Part 5: Number of Participants Experiencing Dose-Limiting Toxicities (DLTs
Time Frame: Up to approximately 2 months
Secondary Outcomes
- Maximum Observed Plasma Concentration (Cmax) After a Single Dose of Sonrotoclax(Predose up to 12 hours postdose)
- Area Under the Concentration-Time Curve from Time 0 to the Last Quantifiable Concentration (AUC0-last) After a Single Dose of Sonrotoclax(Predose up to 12 hours postdose)
- Area Under the Concentration-Time Curve from Time 0 to Infinity (AUC0-∞) After a Single Dose of Sonrotoclax(Predose up to 12 hours postdose)
- Time Taken for Half the Initial Dose Administered to Be Eliminated from The Body (T1/2) of Sonrotoclax(Predose up to 12 hours postdose)
- Time to Maximum Plasma Concentration (Tmax) After a Single Dose of Sonrotoclax(Predose up to 12 hours postdose)
- Apparent Clearance (CL/F) After a Single Dose of Sonrotoclax(Predose up to 12 hours postdose)
- Apparent volume of distribution (Vz/F) After a Single Dose of Sonrotoclax(Predose up to 12 hours postdose)
- Steady State Area Under the Concentration-Time Curve of 0 - Last Day (AUCLast, ss) of Sonrotoclax(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 Sonrotoclax(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 Sonrotoclax(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 Sonrotoclax(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 Sonrotoclax administered after a high fat/calorie meal (HF-Fed)(Predose up to 12 hours postdose)
- Part 2: Cmax of Sonrotoclax 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(Up to 18 months)
- Part 2: Major Response Rate (MRR) for WM as Assessed by the Investigator(Up to 18 months)
- Part 6: Minimum residual disease (MRD) negativity as measured by next generation sequencing(Up to 18 months)