Study of Surzebiclimab (BGB-A425) and Alcestobart (LBL-007) in Combination With Tislelizumab in Advanced Solid Tumors
Status and phase
Completed
Phase 2
Phase 1
Conditions
Locally Advanced or Metastatic Solid Tumors for Phase 1, Dose Escalation and Phase 2 Safety Lead-in
HNSCC for Phase 2 Dose Expansion
NSCLC for Phase 2 Dose Expansion
Treatments
Drug: Surzebiclimab
Drug: Tislelizumab
Drug: Alcestobart
Study type
Interventional
Funder types
Industry
Identifiers
Details and patient eligibility
About
This was an open-label, multicenter, nonrandomized Phase 1 and 2 clinical trial evaluating various combinations of surzebiclimab (BGB-A425) and/or alcestobart (LBL-007) with tislelizumab.
Full description
Blocking antibodies targeting programmed cell death protein-1 (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 was apparent that additional immuno-regulatory mechanism(s) underlie tumor immune escape. Indeed, research shows that the T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) pathway cooperates with PD-1 to maximize the suppression of effector tumor infiltrating lymphocytes (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 participants.
TIM-3, Lymphocyte activation gene-3 (LAG-3), 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 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 (i.e., 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 was strong scientific rationale that simultaneous targeting of these checkpoint blockers, could potentially increase therapeutic benefit and might help to overcome the resistance arising due to anti-PD-(L)-1 therapy. Hence, this study evaluated the safety and preliminary efficacy of surzebiclimab (anti TIM-3), alcestobart (Anti-LAG-3) in combination with tislelizumab (anti PD-1) in patients with advanced solid tumors.
This was an open-label, multicenter, nonrandomized Phase 1 and Phase 2 clinical trial. Phase 1 determined the recommended phase 2 dose (RP2D) for the combination of surzebiclimab and tislelizumab. Phase 2 safety lead-in determined the RP2D for the combination of surzebiclimab, tislelizumab and/or alcestobart. Phase 2 dose expansion continued to evaluate the safety but also focus on the efficacy of the doublet or triplet treatment combination in select tumor types.
Enrollment
147 patients
Sex
All
Ages
18+ years old
Volunteers
No Healthy Volunteers
Inclusion and exclusion criteria
Key Inclusion Criteria:
- Participants were aged >=18 years.
- Adequate organ function.
- Eastern Cooperative Oncology Group (ECOG) performance status <=1.
- Must have been able to provide a recently obtained archival tumor tissue or fresh tumor biopsy.
- The phase 1 dose escalation and phase 2 safety lead-in enrolled participants with histologically/cytologically confirmed advanced/metastatic solid tumors who had previously received standard systemic therapy per local guidelines, unless it was not available, not tolerated or determined not appropriate based on investigators judgement, and had at least 1 evaluable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
- The phase 2 dose expansion enrolled participants with recurrent/metastatic HNSCC (Cohorts 1 and 4) and advanced/metastatic NSCLC (Cohorts 2 and 5), with disease progression that occurred >=10 weeks from the initiation of anti-PD-1/PD-L1 treatment for locally advanced or metastatic disease and had at least 1 measurable lesion outside of the central nervous system per RECIST v1.1.
Key Exclusion Criteria:
- A history of severe hypersensitivity reactions to other monoclonal antibodies.
- Active autoimmune disease or a history of autoimmune diseases that might relapse or a history of life-threatening toxicity related to prior immune therapy.
- Any condition that required systemic treatment with either corticosteroids or other immunosuppressive medication <=14 days before administration of study drug.
- A history of interstitial lung disease, noninfectious pneumonitis or uncontrolled lung diseases.
- Prior therapy targeting TIM-3 and/or LAG-3.
- The phase 2 dose expansion NSCLC cohorts excluded participants with known sensitizing epidermal growth factor receptor (EGFR) mutation, v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation, anaplastic lymphoma kinase (ALK) fusion, or c-ros oncogene 1 (ROS1) fusion.
NOTE: Other protocol defined Inclusion/Exclusion criteria might apply.
Trial design
Primary purpose
Treatment
Allocation
Non-Randomized
Interventional model
Parallel Assignment
Masking
None (Open label)
147 participants in 20 patient groups
Phase 1 (Dose Escalation): Surzebiclimab 2 Milligrams (mg) + Tislelizumab
Experimental group
Description:
Participants received surzebiclimab 2 mg intravenous (IV) infusion on day 1 of each cycle. In the first cycle, tislelizumab 200 mg was administered intravenously on Day 8. If tolerated, participants received surzebiclimab 2 mg along with tislelizumab sequentially on Day 29 and every 21 days (i.e., once every 21 days) thereafter until they were no longer considered to receive clinical benefit, unacceptable toxicity, or withdrawal of informed consent. Cycle 1 consisted of 28 days, and each cycle from Cycle 2 onwards consisted of 21 days.
Treatment:
Drug: Tislelizumab
Drug: Surzebiclimab
Phase 1 (Dose Escalation): Surzebiclimab 6 mg + Tislelizumab
Experimental group
Description:
Participants received surzebiclimab 6 mg IV infusion on day 1 of each cycle. In the first cycle, tislelizumab 200 mg was administered intravenously on Day 8. If tolerated, participants received surzebiclimab 6 mg along with tislelizumab sequentially on Day 29 and every 21 days (i.e., once every 21 days) thereafter until they were no longer considered to receive clinical benefit, unacceptable toxicity, or withdrawal of informed consent. Cycle 1 consisted of 28 days, and each cycle from Cycle 2 onwards consisted of 21 days.
Treatment:
Drug: Tislelizumab
Drug: Surzebiclimab
Phase 1 (Dose Escalation): Surzebiclimab 20 mg + Tislelizumab
Experimental group
Description:
Participants received surzebiclimab 20 mg IV infusion on day 1 of each cycle. In the first cycle, tislelizumab 200 mg was administered intravenously on Day 8. If tolerated, participants received surzebiclimab 20 mg along with tislelizumab sequentially on Day 29 and every 21 days (i.e., once every 21 days) thereafter until they were no longer considered to receive clinical benefit, unacceptable toxicity, or withdrawal of informed consent. Cycle 1 consisted of 28 days, and each cycle from Cycle 2 onwards consisted of 21 days.
Treatment:
Drug: Tislelizumab
Drug: Surzebiclimab
Phase 1 (Dose Escalation): Surzebiclimab 60 mg + Tislelizumab
Experimental group
Description:
Participants received surzebiclimab 60 mg IV infusion on day 1 of each cycle. In the first cycle, tislelizumab 200 mg was administered intravenously on Day 8. If tolerated, participants received surzebiclimab 60 mg along with tislelizumab sequentially on Day 29 and every 21 days (i.e., once every 21 days) thereafter until they were no longer considered to receive clinical benefit, unacceptable toxicity, or withdrawal of informed consent. Cycle 1 consisted of 28 days, and each cycle from Cycle 2 onwards consisted of 21 days.
Treatment:
Drug: Tislelizumab
Drug: Surzebiclimab
Phase 1 (Dose Escalation): Surzebiclimab 200 mg + Tislelizumab
Experimental group
Description:
Participants received surzebiclimab 200 mg IV infusion on day 1 of each cycle. In the first cycle, tislelizumab 200 mg was administered intravenously on Day 8. If tolerated, participants received surzebiclimab 200 mg along with tislelizumab sequentially on Day 29 and every 21 days (i.e., once every 21 days) thereafter until they were no longer considered to receive clinical benefit, unacceptable toxicity, or withdrawal of informed consent. Cycle 1 consisted of 28 days, and each cycle from Cycle 2 onwards consisted of 21 days.
Treatment:
Drug: Tislelizumab
Drug: Surzebiclimab
Phase 1 (Dose Escalation): Surzebiclimab 400 mg + Tislelizumab
Experimental group
Description:
Participants received surzebiclimab 400 mg IV infusion on day 1 of each cycle. In the first cycle, tislelizumab 200 mg was administered intravenously on Day 8. If tolerated, participants received surzebiclimab 400 mg along with tislelizumab sequentially on Day 29 and every 21 days (i.e., once every 21 days) thereafter, until they were no longer considered to receive clinical benefit, unacceptable toxicity, or withdrawal of informed consent. Cycle 1 consisted of 28 days, and each cycle from Cycle 2 onwards consisted of 21 days.
Treatment:
Drug: Tislelizumab
Drug: Surzebiclimab
Phase 1 (Dose Escalation): Surzebiclimab 800 mg + Tislelizumab
Experimental group
Description:
Participants received surzebiclimab 800 mg IV infusion on day 1 of each cycle. In the first cycle, tislelizumab 200 mg was administered intravenously on Day 8. If tolerated, participants received surzebiclimab 800 mg along with tislelizumab sequentially on Day 29 and every 21 days (i.e., once every 21 days) thereafter until they were no longer considered to receive clinical benefit, unacceptable toxicity, or withdrawal of informed consent. Cycle 1 consisted of 28 days, and each cycle from Cycle 2 onwards consisted of 21 days.
Treatment:
Drug: Tislelizumab
Drug: Surzebiclimab
Phase 1 (Dose Escalation): Surzebiclimab 1600 mg + Tislelizumab
Experimental group
Description:
Participants received surzebiclimab 1600 mg IV infusion on day 1 of each cycle. In the first cycle, tislelizumab 200 mg was administered intravenously on Day 8. If tolerated, participants received surzebiclimab 400 mg along with tislelizumab sequentially on Day 29 and every 21 days (i.e., once every 21 days) thereafter until they were no longer considered to receive clinical benefit, unacceptable toxicity, or withdrawal of informed consent. Cycle 1 consisted of 28 days, and each cycle from Cycle 2 onwards consisted of 21 days.
Treatment:
Drug: Tislelizumab
Drug: Surzebiclimab
Phase 1 (Dose Escalation): Surzebiclimab 60 mg
Experimental group
Description:
Participants received one dose of surzebiclimab 60 mg IV infusion on Day 1 of Cycle 1 and discontinued the study treatment. Cycle 1 consisted of 28 days.
Treatment:
Drug: Surzebiclimab
Phase 1 (Dose Escalation): Surzebiclimab 1600 mg
Experimental group
Description:
Participants received one dose of surzebiclimab 1600 mg IV infusion on Day 1 of Cycle 1 and discontinued the study treatment. Cycle 1 consisted of 28 days.
Treatment:
Drug: Surzebiclimab
Phase 2 (Safety Lead-In): Cohort A: Alcestobart 300 mg + Tislelizumab
Experimental group
Description:
Participants received alcestobart 300 mg IV infusion on day 1 of each cycle along with tislelizumab 200 mg IV once every 21 days until they were no longer considered to receive clinical benefit, unacceptable toxicity, or withdrawal of informed consent. Each cycle consisted of 21 days.
Treatment:
Drug: Alcestobart
Drug: Tislelizumab
Phase 2 (Safety Lead-In): Cohort A: Alcestobart 600 mg + Tislelizumab
Experimental group
Description:
Participants received alcestobart 600 mg IV infusion on day 1 of each cycle along with tislelizumab 200 mg IV once every 21 days until they were no longer considered to receive clinical benefit, unacceptable toxicity, or withdrawal of informed consent. Each cycle consisted of 21 days.
Treatment:
Drug: Alcestobart
Drug: Tislelizumab
Phase 2 (Safety Lead-In): Cohort A: Alcestobart 1200 mg + Tislelizumab
Experimental group
Description:
Participants received alcestobart 1200 mg IV infusion on day 1 of each cycle along with tislelizumab 200 mg IV once every 21 days until they were no longer considered to receive clinical benefit, unacceptable toxicity, or withdrawal of informed consent. Each cycle consisted of 21 days.
Treatment:
Drug: Alcestobart
Drug: Tislelizumab
Phase 2 (Safety Lead-In): Cohort B: Alcestobart 300 mg + BGB-A425 + Tislelizumab
Experimental group
Description:
Participants received alcestobart 300 mg IV infusion on day 1 of each cycle along with surzebiclimab 600 mg IV and tislelizumab 200 mg IV once every 21 days until they were no longer considered to receive clinical benefit, unacceptable toxicity, or withdrawal of informed consent. Each cycle consisted of 21 days.
Treatment:
Drug: Alcestobart
Drug: Tislelizumab
Phase 2 (Safety Lead-In): Cohort B: Alcestobart 600 mg + Surzebiclimab + Tislelizumab
Experimental group
Description:
Participants received alcestobart 600 mg IV infusion on day 1 of each cycle along with surzebiclimab 600 mg IV and tislelizumab 200 mg IV once every 21 days until they were no longer considered to receive clinical benefit, unacceptable toxicity, or withdrawal of informed consent. Each cycle consisted of 21 days.
Treatment:
Drug: Alcestobart
Drug: Tislelizumab
Drug: Surzebiclimab
Phase 2 (Safety Lead-In): Cohort B: Alcestobart 900 mg + Surzebiclimab + Tislelizumab
Experimental group
Description:
Participants received alcestobart 900 mg IV infusion on day 1 of each cycle along with surzebiclimab 600 mg IV and tislelizumab 200 mg IV once every 21 days until they were no longer considered to receive clinical benefit, unacceptable toxicity, or withdrawal of informed consent. Each cycle consisted of 21 days.
Treatment:
Drug: Alcestobart
Drug: Tislelizumab
Drug: Surzebiclimab
Phase 2 (Dose Expansion): Cohort 1: HNSCC: Surzebiclimab 600 mg + Tislelizumab
Experimental group
Description:
Participants with head and neck squamous cell carcinoma (HNSCC) received surzebiclimab 600 mg IV infusion on day 1 of each cycle along with tislelizumab 200 mg IV once every 21 days until they were no longer considered to receive clinical benefit, unacceptable toxicity, or withdrawal of informed consent. Each cycle consisted of 21 days.
Treatment:
Drug: Tislelizumab
Drug: Surzebiclimab
Phase 2 (Dose Expansion): Cohort 2: NSCLC: Surzebiclimab 600 mg + Tislelizumab
Experimental group
Description:
Participants with non-small cell lung cancer (NSCLC) received surzebiclimab 600 mg IV infusion on day 1 of each cycle along with tislelizumab 200 mg IV once every 21 days until they were no longer considered to receive clinical benefit, unacceptable toxicity, or withdrawal of informed consent. Each cycle consisted of 21 days.
Treatment:
Drug: Tislelizumab
Drug: Surzebiclimab
Phase 2 (Dose Expansion): Cohort 4: HNSCC Surzebiclimab 600 mg + Alcestobart 600 mg + Tislelizumab
Experimental group
Description:
Participants with HNSCC received surzebiclimab 600 mg IV infusion on day 1 of each cycle along with alcestobart 600 mg IV and tislelizumab 200 mg IV once every 21 days until they were no longer considered to receive clinical benefit, unacceptable toxicity, or withdrawal of informed consent. Each cycle consisted of 21 days.
Treatment:
Drug: Alcestobart
Drug: Tislelizumab
Drug: Surzebiclimab
Phase 2 (Dose Expansion): Cohort 5: NSCLC: Surzebiclimab 600 mg + Alcestobart 600 mg + Tislelizumab
Experimental group
Description:
Participants with NSCLC received surzebiclimab 600 mg IV infusion on day 1 of each cycle along with alcestobart 600 mg IV and tislelizumab 200 mg IV once every 21 days until they were no longer considered to receive clinical benefit, unacceptable toxicity, or withdrawal of informed consent. Each cycle consisted of 21 days.
Treatment:
Drug: Alcestobart
Drug: Tislelizumab
Drug: Surzebiclimab
Trial contacts and locations
45
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Central trial contact
BeiGene
Data sourced from clinicaltrials.gov
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