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

BeiGene

Status and phase: Active, not recruiting; Phase 1

Conditions: Mature B-Cell Malignancies

Treatments: Drug: Obinutuzumab; Drug: Sonrotoclax; Drug: Zanubrutinib

Study type: Interventional

Funder types: Industry

Identifiers

NCT04277637

2024-515592-35-00 (EU Trial (CTIS) Number)

2020-004641-37 (EudraCT Number)

BGB-11417-101

Details and patient eligibility

About

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.

Enrollment: 437 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Key Inclusion Criteria:

• Confirmed diagnosis of one of the following:

NHL Cohorts:

1. 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

2. 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

3. 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)

4. 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:

5. 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:

6. 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

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:

  1. 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
  2. DLBCL, FL, MZL, MCL, or 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
  3. WM: serum immunoglobulin (Ig) M level > 0.5 g/dL

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

• Adequate organ function

• Adequate pancreatic function indicated by:

  1. Serum amylase ≤ 1.5 x upper limit of normal (ULN)
  2. Serum lipase ≤ 1.5 x ULN

Key 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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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437 participants in 6 patient groups

Sonrotoclax Monotherapy Dose Finding: Part 1

Experimental group

Description:

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.

Treatment:

Drug: Sonrotoclax

Sonrotoclax Monotherapy Expansion Cohorts: Part 2

Experimental group

Description:

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.

Treatment:

Drug: Sonrotoclax

Sonrotoclax + Zanubrutinib Combination Therapy Dose Finding: Part 3

Experimental group

Description:

Participants with R/R MCL, R/R or treatment-naïve (TN) CLL/SLL will receive oral sonrotoclax in combination with zanubrutinib.

Treatment:

Drug: Zanubrutinib

Drug: Sonrotoclax

Sonrotoclax + Zanubrutinib Combination Therapy Dose Expansion: Part 4

Experimental group

Description:

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.

Treatment:

Drug: Zanubrutinib

Drug: Sonrotoclax

Sonrotoclax + Zanubrutinib Combination Therapy Dose Escalation: Part 5

Experimental group

Description:

Participants with treatment naïve CLL/SLL will receive oral sonrotoclax in combination with obinutuzumab without and with zanubrutinib.

Treatment:

Drug: Zanubrutinib

Drug: Sonrotoclax

Drug: Obinutuzumab

Sonrotoclax + Zanubrutinib Combination Therapy Dose Expansion: Part 6

Experimental group

Description:

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.

Treatment:

Drug: Zanubrutinib

Drug: Sonrotoclax

Drug: Obinutuzumab