Study of BGB-A425 and LBL-007 in Combination With Tislelizumab in Advanced Solid Tumors

Study Overview
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Brief Summary
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This is an open-label, multicenter, nonrandomized Phase 1 and 2 clinical trial evaluating various combinations of BGB-A425 and/or LBL-007 with tislelizumab.

Detailed Description
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Blocking antibodies targeting PD-1 have achieved remarkable results in the treatment of many types of tumors. However, based upon the rate of primary and secondary resistance to PD-1 blockade, it is apparent that additional immuno-regulatory mechanism(s) underlie tumor immune escape. Indeed, research shows that the TIM-3 pathway cooperates with PD-1 to maximize the suppression of effector TILs as well as promote resistance to anti-PD-1 therapy. Therefore, TIM-3 represents an ideal target with the potential to significantly improve and/or extend the therapeutic benefit of anti-PD-1 therapy to a greater number of patients. TIM3, LAG3, and PD-1 function as immune checkpoint receptors in the overlapping regulation of immune tolerance and have been shown to be co-overexpressed on the tumor infiltrating lymphocytes (TILs) from the participant samples of various solid tumors. Furthermore, emerging clinical data and preclinical data demonstrate co-expression of Tim-3, LAG-3, PD-1 often yield T cells' exhausted immunophenotype (ie, cytokine expression, proliferation etc.). Cancer cells take advantage of PD-1, TIM-3, and LAG-3 in inhibiting immune cells' function, and escape the immune surveillance. Based upon the overlapping expression profiles and immuno-regulatory functions, TIM-3 and LAG-3 mediated adaptive resistance, there is strong scientific rationale that simultaneous targeting of these checkpoint blockers, could potentially increase therapeutic benefit and may help to overcome the resistance arising due to anti-PD-(L)-1 therapy. Hence, this study will evaluate the safety and preliminary efficacy of BGB-A425 (anti TIM-3), LBL-007 (Anti-LAG-3) in combination with tislelizumab (anti PD-1) in patients with advanced solid tumors This is an open-label, multicenter, nonrandomized Phase 1 and Phase 2 clinical trial. Phase 1 will determine the recommended phase 2 dose (RP2D) for the combination of BGB-A425 and Tislelizumab. Phase 2 safety lead-in will determine the RP2D for the combination of BGB-A425, Tislelizumab and/or LBL-007. Phase 2 dose expansion will continue to evaluate the safety but also focus on the efficacy of the doublet or triplet treatment combination in select tumor types.

Official Title
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Phase 1-2 Study Investigating Safety, Tolerability, Pharmacokinetics and Preliminary Antitumor Activity of Various Combinations of BGB-A425 and LBL-007 With Tislelizumab in Patients With Advanced Solid Tumors

Conditions
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Locally Advanced or Metastatic Solid Tumors for Phase 1,Dose Escalation and Phase 2 Safety Lead-in, HNSCC, NSCLC and RCC Participants for Phase 2

Intervention / Treatment
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* Drug: BGB-A425
* Drug: Tislelizumab
* Drug: LBL-007


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Has Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1. Adequate organ function Phase 1 Dose Escalation + Phase 2 Safety Lead-In: Participants with histologically or cytologically confirmed advanced, metastatic, unresectable solid tumors who have previously received standard systemic therapy or for which treatment is not available, not tolerated or refused. Phase 2 Dose-Expansion: Participants with one of the following histologically or cytologically confirmed solid tumors: For HNSCC participants in cohort 1,4 and 6 (PD-L1 positive): Recurrent/metastatic head and neck squamous cell cancer of the oral cavity, oropharynx, hypopharynx, and/or larynx whose tumor is not amenable to local therapy with curative intent (ie, surgery or radiation therapy with or without chemotherapy • For NSCLC participants in Cohort 2, 5 and 7 (PD-L1 positive): Locally recurrent Stage IIIB, stage IIIC or Stage IV squamous or non-squamous non-small cell lung cancer • For RCC participants in Cohort 3: Locally advanced unresectable or metastatic and histologically confirmed renal cell carcinoma with a clear cell histology Key Exclusion Criteria: NSCLC patients with known EGFR mutation, BRAF mutation, ALK fusion, or ROS1 fusion Active leptomeningeal disease or uncontrolled, untreated brain metastasis. Active autoimmune diseases or history of autoimmune diseases that may relapse. Interstitial lung disease, noninfectious pneumonitis or uncontrolled lung diseases Uncontrolled diabetes or significant cardiac issues Infections requiring systemic antibacterial, antifungal, or antiviral therapy History of severe hypersensitivity reactions to other monoclonal antibodies History of HIV infection or untreated chronic hepatitis B or chronic hepatitis B virus carriers Major surgical procedure within 28 days before study drug administration Chemotherapy, radiotherapy, immunotherapy or any investigational therapies within 28 days (PH 2 Safety Lead-In) or 14 days (PH 2 Dose Expansion) or 5 half-lives of (whichever is shorter) of first administration of study drug(s). With infections (including tuberculosis infection, etc) requiring systemic antibacterial, antifungal, or antiviral therapy ≤ 14 days prior to the first dose of study drug(s), or a requirement for chronic prophylactic treatment with antibiotics. Concurrent participation in another therapeutic clinical trial Received prior therapies targeting TIM-3and/or LAG3 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
Interventional Model Description: This is an open-label, multicenter, nonrandomized Phase 1 and Phase 2 clinical trial. Phase 1 will determine the recommended phase 2 dose (RP2D) for the combination of BGB-A425 and Tislelizumab. Phase 2 safety lead-in will determine the RP2D for the combination of BGB-A425, Tislelizumab and/or LBL-007. Phase 2 dose expansion will continue to evaluate the safety but also focus on the efficacy of the double or triplet treatment combination in select tumor types.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Dose Escalation<br>Dose escalation of BGB-A425 in combination with Tislelizumab in participants with advanced solid tumors | Drug: BGB-A425<br>* Humanized IgG1-variant monoclonal antibody against TIM-3<br>Drug: Tislelizumab<br>* Humanized, IgG4-variant monoclonal antibody against PD-1<br>* Other names: BGB-A317;|
| Experimental: Phase 2 Safety Lead-in<br>Dose escalation for Cohort A (LBL-007 + Tislelizumab) and Cohort B (BGB-A425 + LBL-007 + Tislelizumab) in participants with advanced solid tumors | Drug: BGB-A425<br>* Humanized IgG1-variant monoclonal antibody against TIM-3<br>Drug: Tislelizumab<br>* Humanized, IgG4-variant monoclonal antibody against PD-1<br>* Other names: BGB-A317;Drug: LBL-007<br>* Human anti LAG-3 IgG4-kappa antibody<br>|
| Experimental: Phase 2 Dose Expansion<br>Further explore the safety and clinical activity of BGB-A425 and LBL-007 in combination with Tislelizumab in participants with NSCLC, HNSCC and RCC | Drug: BGB-A425<br>* Humanized IgG1-variant monoclonal antibody against TIM-3<br>Drug: Tislelizumab<br>* Humanized, IgG4-variant monoclonal antibody against PD-1<br>* Other names: BGB-A317;Drug: LBL-007<br>* Human anti LAG-3 IgG4-kappa antibody<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 Dose Escalation and Phase 2 Safety lead-in: Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | A TEAE is defined as an AE that had an onset date or a worsening in severity from baseline (pretreatment) on or after the first dose of study drug up to 30 days following study drug discontinuation or initiation of new anticancer therapy, whichever comes first. An SAE is any untoward medical occurrence that at any dose results in death or is life threatening. | Approximately 2 years | 
| Phase 1 Dose Escalation: Maximum Tolerated Dose (MTD) | The MTD or MAD is defined as the highest dose at which < 33% of the participants experience a dose limiting toxicity (DLT) | Approximately 2 years | 
| Phase 2 Dose Expansion: Objective Response Rate (ORR) | ORR is determined from the investigator derived tumor assessments per RECIST v1.1 | Approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 and Phase 2 : Duration of Response (DOR) | Duration of response (DOR) will be determined from investigator derived tumor assessments per Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1. | Phase 1 or 2 Expansion - Approximately 2-3 years each | 
| Phase 1 and Phase 2 : Disease control rate (DCR) | Disease control rate (DCR) will be determined from investigator derived tumor assessments per Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1. | Phase 1 or 2 Expansion - Approximately 2-3 years each | 
| Phase 1 and Phase 2 : Progression free survival | Progression free survival will be determined from investigator derived tumor assessments per RECIST 1.1. | Phase 2 Expansion - Approximately 3 years | 
| Pharmacokinetic (PK) Parameter: Minimum Concentration (Cmin) of BGB-425 and LBL-007 |  | Phase 1 and Phase 2- Approximately 2-3 years each | 
| PK Parameter: Area Under the Curve (AUC), 0 to 21 days of BGB-425 and LBL-007 |  | Phase 1 and Phase 2- Approximately 2-3 years each | 
| PK Parameter: Maximum Concentration (Cmax) of BGB-425 and LBL-007 |  | Phase 1 and Phase 2- Approximately 2-3 years each | 
| PK Parameter: Clearance (CL) of BGB-425 and LBL-007 |  | Phase 1 and Phase 2- Approximately 2-3 years each | 
| PK Parameter: Volume of Distribution (Vz) of BGB-425 and LBL-007 |  | Phase 1 and Phase 2- Approximately 2-3 years each | 
| PK Parameter: terminal half-life (t1/2) of BGB-425 and LBL-007 |  | Phase 1 and Phase 2- Approximately 2-3 years each | 
| Percentage of participants with anti-BGB-A425 and LBL-007 antibodies |  | Phase 1 and Phase 2- Approximately 2-3 years each | 
| Phase 2 Dose Expansion: Number of participants with TEAEs and SAEs including physical examinations, electrocardiograms and laboratory assessments |  | Phase 1 and Phase 2- Approximately 2-3 years each |