A Phase Ia/Ib Open-Label Dose Escalation and Expansion Study of Bcl-2 Inhibitor BGB-11417 in Patients with Mature B-Cell Malignancies

Study Identifier:
BGB-11417-101
CT.gov Identifier:
NCT04277637
EudraCT Identifier:
2020-004641-37
EU Trial (CTIS) Number:
2024-515592-35-00
Study Contact Information:
N/A
Recruitment Complete

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Study Summary

To investigate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of BGB-11417 in patients with mature B-cell malignancies. To determine the safety, tolerability; Recommended Phase 2 Dose (RP2D), optimal ramp-up dosing schedule; and to evaluate preliminary activity of BGB-11417 monotherapy. To determine the safety, tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose of BGB-11417 in pts with R/R B-cell malignancies. Adverse events (AEs) are reported per Common Terminology Criteria for AEs v5.0. Dose-limiting toxicity (DLT; assessed from ramp-up through day 21 at intended daily dose), evaluated by Bayesian logistic regression model, will be used to determine the maximum tolerated dose (MTD). To study the the safety and efficacy data from patients with treatment-naïve (TN) CLL/SLL who received the combination of sonrotoclax and zanubrutinib. Dose-limiting toxicity (DLT), predefined in the protocol for each dose cohort, was evaluated during dose ramp-up through day 21 at the intended dose. Responses were assessed per Lugano criteria 2014. Adverse events (AEs) were reported per CTCAE v5.0 and tumor lysis syndrome (TLS) was assessed per Howard (2011) criteria. To report the safety, tolerability, and efficacy of sonrotoclax monotherapy in patients with relapsed/refractory (R/R) CLL/SLL without a history of prior venetoclax treatment. TLS was assessed per Howard 2011 criteria.

Study endpoints include safety per NCI-CTCAE v5.0, overall response rate (ORR) per iwCLL guidelines, and MRD status as assessed by ERIC approved flow cytometry (FC) assay and NGS, depending on the timepoint. Tumor lysis syndrome (TLS) is assessed per Howard (2011) criteria.

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
  • Leukemia
  • Lymphoma, Non-Hodgkin's
    • Phase
    The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
    I
    Sex
    Female & Male
    Age
    18+ years
    Study Drug
  • Drug: Experimental: 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); Waldenstroms macroglobulinemia (WM); and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) will receive oral sonrotoclax evaluated as monotherapy. Drug: Sonrotoclax Film-coated tablets administered once daily at a dose as specified in the treatment arm Experimental: 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. Drug: Sonrotoclax Film-coated tablets administered once daily at a dose as specified in the treatment arm Experimental: Sonrotoclax + Zanubrutinib Combination Therapy Dose Finding: Part 3 Participants with R/R MCL, R/R or treatment-naive (TN) CLL/SLL will receive oral sonrotoclax in combination with zanubrutinib. Drug: Sonrotoclax Film-coated tablets administered once daily at a dose as specified in the treatment arm Drug: Zanubrutinib 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) Experimental: 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-naive (TN) CLL/SLL will receive oral sonrotoclax in combination with zanubrutinib at an RP2D dose to further define the safety profile. Drug: Sonrotoclax Film-coated tablets administered once daily at a dose as specified in the treatment arm Drug: Zanubrutinib 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) Experimental: Sonrotoclax + Zanubrutinib Combination Therapy Dose Escalation: Part 5 Participants with treatment naive CLL/SLL will receive oral sonrotoclax in combination with obinutuzumab without and with zanubrutinib. Drug: Sonrotoclax Film-coated tablets administered once daily at a dose as specified in the treatment arm Drug: Zanubrutinib 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) Drug: Obinutuzumab Given as an intravenous infusion administered per label. Experimental: Sonrotoclax + Zanubrutinib Combination Therapy Dose Expansion: Part 6 Participants with treatment naive CLL/SLL will receive oral sonrotoclax in combination with obinutuzumab without and with zanubrutinib at an RP2D dose to further define the safety profile. Drug: Sonrotoclax Film-coated tablets administered once daily at a dose as specified in the treatment arm Drug: Zanubrutinib 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) Drug: Obinutuzumab Given as an intravenous infusion administered per label. Patients received zanubrutinib (320 mg QD or 160 mg BID) 8-12 weeks before starting sonrotoclax using a ramp-up schedule starting from 1 mg to the intended target dosage of 160 mg or 320 mg QD (doubling weekly [W] or 30% increase every day 5 d/week [D]) to mitigate risk of tumor lysis syndrome (TLS). Patients were treated until progression, unacceptable toxicity, or could elect to stop. TLS was assessed per Howard (2011) criteria; mitigation included mandatory oral hydration and antihyperuricemics. Patients received zanubrutinib (standard dose: 320 mg QD or 160 mg BID) 8-12 weeks before starting sonrotoclax in a dose escalation cohort (target sonrotoclax doses: 80, 160, 320, or 640mg QD) according to a ramp-up schedule designed to mitigate potential risk of tumor lysis syndrome (TLS).This was followed by 2 sonrotoclax expansion cohorts at 160 mg and 320 mg. Patients were treated untilprogression or unacceptable toxicity. EHA 2024: Patients with R/R WM(≥1 prior therapy) received sonrotoclax (planned dose escalation: 80, 160, 320, or640 mg QD) with a ramp-up schedule to the intended dose to mitigate potential risk of tumor lysis syndrome(TLS). Patients were treated until progression or unacceptable toxicity. ASH 2024: Patients received zanubrutinib (320 mg once daily [QD] or 160 mg twice daily) for 8-12 weeks, then added sonrotoclax using a ramp-up schedule (weekly or daily) to the target doses (160 or 320 mg QD) to mitigate risk of tumor lysis syndrome (TLS). Patients were treated until progression, unacceptable toxicity, or could elect to stop after 96 weeks (24 cycles) of treatment. EHA 2025: Subject received sonrotoclax (planned doses: 80, 160, and 320 mg QD) with ramp-up to the target dose, and mandatory hydration and antihyperuricemic prophylaxis to mitigate potential risk of tumor lysis syndrome (TLS). All patients were treated until disease progression or unacceptable toxicity. Patients with R/R WM (≥1 prior therapy) received sonrotoclax (80, 160, 320, or 640 mg QD) with a ramp-up schedule to the intended dose to mitigate potential risk of tumor lysis syndrome (TLS). Patients were treated until progression or unacceptable toxicity. Pts with R/R MCL (≥1 prior therapy) received zanu (320mg QD or 160mg BID) 8-12 wk before sonrotoclax (80, 160, 320, or 640mg QD) until progressive disease (PD) or unacceptable toxicity, with ramp-up to the target dose to mitigate tumor lysis syndrome (TLS) risk. Dose expansion occurred at 160 and 320mg. Pts received zanu (320 mg QD or 160 mg BID) 8-12 wk before starting sonro (40, 80, 160, 320, or 640 mg QD) with ramp-up to the target dose to prevent tumor lysis syndrome (TLS). Pts were treated until disease progression or unacceptable toxicity. Pts with R/R MCL (≥ 1 prior treatment [tx]) received zanu (320 mg QD or 160 mg BID) 8-12 wk before sonro (80, 160, 320, or 640 mg QD) until progressive disease (PD) or unacceptable toxicity, with ramp-up to the target dose to mitigate tumor lysis syndrome (TLS) risk. Dose expansion occurred at 160 and 320 mg.
    • Study Status
    Indicates the current recruitment status or the expanded access status
    Recruitment Complete

    Requirements information
    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:
    • 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, 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
    • 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:
    • Serum amylase ≤ 1.5 x upper limit of normal (ULN)
    • Serum lipase ≤ 1.5 x ULN
    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.
    • Pts with previous progression on a BTKi or prior BCL2 inhibitor exposure were excluded from this cohort

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    Study Locations

    Location
    Investigator
    Status
    Condition(s) Treated at Site
    Location
    START Madrid, Spain (FJD)
    Madrid, Spain, 28040
    Investigator
    Daniel Morillo Giles
    Status
    Recruitment Complete
    Condition(s) Treated at Site
    Leukemia
    Lymphoma, Non-Hodgkin's