A Study Investigating the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of BGB-30813

Study Overview
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Brief Summary
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This is a First in Human (FIH) Phase 1, multicenter, open label, dose escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of BGB-30813 as monotherapy and in combination with tislelizumab in participants with advanced or metastatic solid tumors. The study will be conducted in 2 parts: Phase 1a dose escalation and Phase 1b dose expansion.

Detailed Description
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This study will test whether taking BGB-30813 alone or with tislelizumab can help treat patients with cancer that has spread throughout the body or is locally advanced. The two main goals of the study are to ensure that the treatments are safe by monitoring side effects and to determine the number of patients who respond well to treatment either partially or completely. The combination of BGB-30813 with other drugs that target immune checkpoints may work together to stop or prevent cancer activity. Approximately 209 patients will participate. In the first part of the study, patients will be given different doses of BGB-30813 either alone or with tislelizumab to find the dose that is best tolerated. BGB-30813 will be given orally and tislelizumab will be given through a vein. In the second part of the study, the selected dose of BGB-30813, either alone or with tislelizumab, will be given to a larger number of patients from different parts of the world to see if the treatments can improve the signs and symptoms of their cancer. Treatments will continue until patients are no longer considered to be receiving benefits, have unacceptable side effects, or withdraw consent.

Official Title
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A Phase 1a/1b Study Investigating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Antitumor Activity of the DGKζ Inhibitor BGB-30813, Alone or in Combination With the Anti-PD-1 Monoclonal Antibody Tislelizumab in Patients With Advanced or Metastatic Solid Tumors

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: BGB-30813
* Drug: Tislelizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Phase 1a (Dose Escalation): Participants with histologically or cytologically confirmed advanced, metastatic, and unresectable solid tumors who have previously received available standard systemic therapy or for whom treatment is not available or not tolerated and who have not received any prior therapy targeting diacylglycerol kinase ζ (DGK) Eligible tumor types are immune sensitive solid tumors such as NSCLC, HNSCC, small cell lung cancer, hepatocellular carcinoma, esophageal cancer, gastric or gastroesophageal carcinoma, nasopharyngeal carcinoma, triple-negative breast cancer, urothelial carcinoma, renal cell carcinoma, cervical cancer, endometrial carcinoma, cutaneous squamous cell carcinoma, melanoma, Merkel cell carcinoma, mesothelioma, microsatellite instability (MSI)-high, tumor mutation burden (TMB)-high, or mismatch repair deficient solid tumors Prior checkpoint inhibitor (CPI) therapy is allowed Phase 1b (Dose Expansion): Participants with selected advanced or metastatic solid tumors including NSCLC, HNSCC, and additional potential tumor types to be defined based on emerging data ≥ 1 measurable lesion per RECIST v1.1 Eastern Cooperative Group Oncology Performance (ECOG) Performance Status score ≤ 1 Females of childbearing potential must be willing to use a highly effective method of birth control for the duration of the study Adequate organ function as indicated by the following laboratory values up to first dose of study treatment: Hemoglobin≥ 90 grams per liter (g/L), Absolute neutrophil count ≥ 1.5 x 109/L , Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN) (< 3 x ULN for participants with Gilbert syndrome ), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN Exclusion Criteria: Previous therapy targeting DGK Active leptomeningeal disease or uncontrolled symptomatic central nervous system (CNS) metastasis Active autoimmune diseases or history of autoimmune diseases that may relapse Any active malignancy ≤ 2 years before the first dose of study treatment except for the specific cancer under investigation in this study and any locally recurring cancer that has been treated with curative intent Systemic anticancer therapy, including chemotherapy ≤ 21 days or 5 half-lives (whichever is shorter) before the first dose of study drugs Note: Other 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: Phase 1a: Dose Escalation Part A: BGB-30813 Monotherapy<br> | Drug: BGB-30813<br>* Specified dose administered on specified days<br>|
| Experimental: Phase 1a: Dose Escalation Part B: BGB-30813 + Tislelizumab<br> | Drug: BGB-30813<br>* Specified dose administered on specified days<br>Drug: Tislelizumab<br>* Specified dose administered on specified days<br>* Other names: BGB-A317;|
| Experimental: Phase 1b: Dose Expansion BGB-30813 in Combination with Tislelizumab<br> | Drug: BGB-30813<br>* Specified dose administered on specified days<br>Drug: Tislelizumab<br>* Specified dose administered on specified days<br>* Other names: BGB-A317;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1a: Dose Escalation: Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Dose-Limiting Toxicities (DLTs) |  | Up to Approximately 23 months | 
| Phase 1a : Dose Escalation: The Maximum Tolerated Dose (MTD) and Maximum Administered Dose (MAD) and Recommended dose(s) for Expansion (RDFE[s]) of BGB-30813 Alone or in Combination with Tislelizumab | The MTD or MAD is defined as the highest dose at which 30% of participants experience a DLT or the highest dose administered, respectively. The RDFE(s) of BGB-30813 alone or in combination with tislelizumab, determined based upon the MTD or MAD and other relevant data. | Up to approximately 23 months | 
| Phase 1b: Dose Expansion: Overall Response Rate (ORR) as Determined by the Investigator | ORR is defined as the percentage of participants who had confirmed complete response (CR) or partial response (PR) as determined from tumor assessments by the investigator per RECIST version 1.1 | Up to approximately 2 years and 11 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1a: Dose Escalation: ORR as Determined by the Investigator | ORR is defined as the percentage of participants who had confirmed CR or PR as determined from tumor assessments by the investigator per RECIST version 1.1 | Up to approximately 23 months | 
| Phase 1a: Maximum Observed Plasma Concentration (Cmax) Of BGB-30813 and Metabolite BGB-33481 Alone and in Combination with Tislelizumab |  | From Cycle 1 Day 1 up to Cycle 9 Day 1 | 
| Phase 1a: Dose Escalation: Observed Plasma Trough Concentration (Ctrough) Of BGB-30813 and Metabolite BGB-33481 Alone and in Combination with Tislelizumab |  | From Cycle 1 Day 1 up to Cycle 9 Day 1 | 
| Phase 1a: Dose Escalation: Area Under the concentration-time curve (AUC) Of BGB-30813 and Metabolite BGB-33481 Alone and in Combination with Tislelizumab |  | From Cycle 1 Day 1 up to Cycle 9 Day 1 | 
| Phase 1a: Dose Escalation: Half-life (t1/2) Of BGB-30813 and Metabolite BGB-33481 Alone and in Combination with Tislelizumab |  | From Cycle 1 Day 1 up to Cycle 9 Day 1 | 
| Phase 1b: Dose Expansion: Number of Participants Experiencing TEAEs, and SAEs |  | Up to approximately 2 years and 11 months | 
| Phase 1b: Dose Expansion: Duration of Response (DOR) | DOR is defined as the time from the first determination of an overall response assessed by the investigator using RECIST v1.1, until the first documentation of disease progression or death, whichever comes first. | Up to approximately 2 years and 11 months | 
| Phase 1b: Dose Expansion: Disease Control Rate (DCR) | DCR is defined as the percentage of participants with best overall response (BOR) of complete Response (CR), Partial Response (PR), or stable disease assessed by the investigator using RECIST v1.1. | Up to approximately 2 years and 11 months | 
| Phase 1b: Dose Expansion: Progression Free Survival (PFS) | PFS is defined as the time from the date of the first dose of study drugs to the date of the first documentation of disease progression assessed by the investigator using RECIST v1.1 or death, whichever occurs first. | Up to approximately 2 years and 11 months | 
| Phase 1b: Dose Expansion: Clinical Benefit Rate (CBR) | CBR is defined as the percentage of participants with BOR of confirmed CR, PR, or stable disease lasting ≥ 24 weeks | Up to approximately 2 years and 11 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DGKζ Inhibitor, BGB-30813, Anti-PD-1 Monoclonal Antibody, Tislelizumab, Advanced or Metastatic Solid Tumors, Diacylglycerol kinase, BGB-A317, NSCLC, Immunotherapy, HNSCC