Study of BGB-10188 as Monotherapy, and in Combination With Zanubrutinib, and Tislelizumab

Study Overview
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Brief Summary
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The purpose of this study is to determine the maximum tolerated dose (MTD), recommended dose for expansion (RDFE), safety and tolerability of BGB-10188 as monotherapy in participants with relapsed/refractory (R/R) mature B-cell malignancies; in combination with zanubrutinib in participants with R/R follicular lymphoma (FL), R/R mantle cell lymphoma (MCL) or R/R diffuse large B-cell lymphoma (DLBCL); and in combination with tislelizumab in participants with advanced solid tumors.

Official Title
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A Phase 1/2, Dose Escalation and Expansion Study of BGB-10188, a Phosphatidylinositol 3-Kinase Delta (PI3Kδ) Inhibitor, Combined With Zanubrutinib in Patients With Mature B-Cell Malignancies and Combined With Tislelizumab in Patients With Solid Tumors

Conditions
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Mantle Cell Lymphoma, Diffuse Large B Cell Lymphoma, Advanced Solid Tumor, Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Follicular Lymphoma, Marginal Zone Lymphoma

Intervention / Treatment
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* Drug: BGB-10188
* Drug: Zanubrutinib
* Drug: Tislelizumab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Parts A, B and C Confirmed diagnosis of one of the following: Part A: R/R CLL/SLL, R/R MZL, R/R FL, R/R MCL or R/R DLBCL Part B: R/R FL, R/R MCL, or R/R DLBCL Part C: R/R FL, R/R MCL, or R/R DLBCL Participants with MZL, FL, MCL, DLBCL, or SLL must have at least one bi-dimensionally measurable nodal lesion >1.5 cm in the longest diameter or extranodal lesion that is > 1cm in the longest diameter by computed tomography (CT) scan or magnetic resonance imaging (MRI), as defined by the Lugano Classification. Parts D and E Part D: Histologically or cytologically confirmed unresectable locally advanced or metastatic solid tumors previously treated with standard systemic therapy (including prior chemotherapy, radiotherapy, target therapy and immunotherapy as locally, or guidance approved therapy) or for which treatment is not available or not tolerated. Enrollment will be limited to participants with advanced solid tumors for which there is clinical evidence of response to T-cell based immuno-oncology agents (eg, non-small cell lung cancer [NSCLC], small cell lung cancer [SCLC], head and neck squamous cell cancer, hepatocellular carcinoma, gastric or gastroesophageal junction carcinoma, nasopharyngeal carcinoma, renal cell carcinoma, cervical cancer, triple-negative breast cancer, ovarian cancer (OC), endometrial carcinoma, esophageal cancer, melanoma, urothelial carcinoma or participant with confirmed microsatellite instability-high [MSI-H] or mismatch repair deficient [dMMR] solid tumor, etc). Enrollment of tumor types beyond above situations requires sponsor's approval. Part E: Participants with histologically or cytologically confirmed epithelial OC (including fallopian or primary peritoneal cancer) previously treated with 1 to 3 lines of systemic anticancer treatment; must be platinum resistant and checkpoint inhibitor (CPI) naïve. Participants must have measurable disease as assessed by RECIST v1.1. Key Exclusion Criteria: Parts A, B and C History of allogeneic stem-cell transplantation or chimeric antigen receptor-T (CAR-T) cell therapy. For participants with DLBCL in Part A, classified as T-cell/histiocyte-rich large B-cell lymphoma, high-grade B-cell lymphoma with myelocytomatosis viral oncogene homolog and B-cell lymphoma (BCL)-2 and/or BCL-6 rearrangements, high grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, Epstein-Barr virus positive DLBCL, and transformed DLBCL. Parts A, B, C, D and E Prior exposure to PI3K inhibitor. For participants in Part B and Part C, prior exposure to BTK inhibitor and/or PI3K inhibitor. Any approved anticancer therapy, including hormonal therapy, or any investigational agent or participation in another clinical study with therapeutic intent within 14 days before first dose. Treatment with systemic immune-stimulatory agents (including, but not limited to, interferons and interleukin-2) within 2 weeks or 5 half-lives of the drug, whichever is later, before first dose. Known human immunodeficiency virus (HIV) infection, or serologic status reflecting active viral hepatitis B (HBV) or viral hepatitis C (HCV) infection as follows: HBsAg (+), or HBcAb (+) and HBV DNA detected, or Presence of HCV antibody. Participants with presence of HCV antibody are eligible if HCV ribonucleic acid (RNA) is undetectable 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: Part A: BGB-10188 Monotherapy Dose Escalation<br>BGB-10188 capsules administered orally once daily (QD) in 5 cohorts of escalating doses | Drug: BGB-10188<br>* Administered as specified in the treatment arm<br>|
| Experimental: Part B: BGB-10188 + Zanubrutinib Dose Escalation<br>BGB-10188 capsules administered orally QD at the latest cleared dose of BGB-10188 monotherapy (Part A) in combination with zanubrutinib 160mg (2*80mg capsules) administered orally twice daily (BID) | Drug: BGB-10188<br>* Administered as specified in the treatment arm<br>Drug: Zanubrutinib<br>* Administered as specified in the treatment arm<br>* Other names: Brukinsa;|
| Experimental: Part C: BGB-10188 + Zanubrutinib Dose Expansion<br>BGB-10188 capsules administered orally QD at RDFE of part B in combination with zanubrutinib 160mg (2*80mg capsules) administered orally BID | Drug: BGB-10188<br>* Administered as specified in the treatment arm<br>Drug: Zanubrutinib<br>* Administered as specified in the treatment arm<br>* Other names: Brukinsa;|
| Experimental: Part D: BGB-10188 + Tislelizumab Infusion Dose Escalation<br>BGB-10188 capsules administered orally QD in up to 6 cohorts of escalating doses in combination with tislelizumab 200mg IV infusion administered every 3 weeks (Q3W) | Drug: BGB-10188<br>* Administered as specified in the treatment arm<br>Drug: Tislelizumab<br>* Administered as specified in the treatment arm<br>* Other names: BGB-A317;|
| Experimental: Part E: BGB-10188 + Tislelizumab Infusion Dose Expansion<br>BGB-10188 capsules administered orally QD at two doses in combination with tislelizumab 200mg IV infusion administered Q3W | Drug: BGB-10188<br>* Administered as specified in the treatment arm<br>Drug: Tislelizumab<br>* Administered as specified in the treatment arm<br>* Other names: BGB-A317;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: The recommended dose for expansion (RDFE) of BGB-10188 monotherapy |  | Up to 8 Weeks | 
| Part B: RDFE of BGB-10188 in combination with zanubrutinib |  | Up to 8 Weeks | 
| Part D: RDFE of BGB-10188 in combination with tislelizumab |  | Up to 8 Weeks | 
| Part C and E: Overall response rate (ORR) | ORR is defined as the proportion of participants achieving a partial response (PR) or better | Up to approximately 5 years and 6 months | 
| Parts A, B, D, and E: Number of participants experiencing Treatment Emergent Adverse Events (TEAEs) |  | Up to approximately 5 years and 6 months | 
| Parts A, B, D, and E: Number of participants experiencing Severe Adverse Events (SAEs) |  | Up to approximately 5 years and 6 months | 
| Parts A, B, D and E: Number of participants experiencing Adverse Events (AEs) Leading to Discontinuation |  | Up to approximately 5 years and 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts A, B, and D: Overall response rate (ORR) | ORR is defined as the proportion of participants achieving a partial response (PR) or better | Up to approximately 5 years and 6 months | 
| Parts B, C, D, and E: Duration of response (DOR) | DOR is defined as the time from the first response documentation to the date that progression is documented after treatment initiation or death, whichever occurs first | Up to approximately 5 years and 6 months | 
| Parts B, C, D, and E: Time to response (TTR) | TTR is defined as the time from treatment initiation to the first documentation of response | Up to approximately 5 years and 6 months | 
| Parts C and E: Progression-free survival (PFS) | PFS is defined as the time from treatment initiation to the first documentation of progression or death due to any cause, whichever happens first | Up to approximately 5 years and 6 months | 
| Parts D and E: Disease control rate (DCR) |  | Up to approximately 5 years and 6 months | 
| Parts A, B, C, D, and E: Observed maximum plasma concentration during a sample interval (Cmax) of BGB-10188 |  | Predose up to 7 days postdose | 
| Parts A, B, C, D, and E: Area under the plasma concentration-time curve (AUC) of BGB-10188 |  | Predose up to 7 days postdose | 
| Part C: Number of participants experiencing Treatment Emergent Adverse Events (TEAEs) |  | Up to approximately 5 years and 6 months | 
| Part C: Number of participants experiencing Severe Adverse Events (SAEs) |  | Up to approximately 5 years and 6 months | 
| Part C: Number of participants experiencing Adverse Events (AEs) Leading to Treatment Discontinuation |  | Up to approximately 5 years and 6 months | 
| Part E: Clinical Benefit Rate (CBR) | CBR is defined as proportion of participants with best overall response, as defined by RECIST v1.1, of a CR, PR, or at least 24 weeks of stable disease | Up to approximately 5 years and 6 months | 
| Part E: CA-125 Response Rate | CA-125 response rate is defined as the proportion of participants achieving a CA-125 response according to the Gynecological Cancer Center Intergroup criteria; a response has occurred if there is at least a 50% reduction in CA-125 levels from baseline | Up to approximately 5 years and 6 months |