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

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ClinicalTrials.gov Identifier: NCT03744468
Recruitment Status : Recruiting
First Posted : November 16, 2018
Last Update Posted : September 9, 2021
Sponsor:
Information provided by (Responsible Party):
BeiGene

Brief Summary:
BGB-A425 is a humanized, immunoglobulin gamma-1 (IgG1)-variant monoclonal antibody against TIM-3. Tislelizumab is a humanized, immunoglobulin G4 (IgG4)-variant monoclonal antibody against PD-1. This study tests the safety and anti-tumor effect of BGB-A425 in combination with tislelizumab in participants with advanced solid tumors.

Condition or disease Intervention/treatment Phase
Locally Advanced or Metastatic Solid Tumors for Phase 1 HNSCC, NSCLC and RCC for Phase 2 Drug: BGB-A425 Drug: tislelizumab Phase 1 Phase 2

Detailed Description:

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.

TIM-3 and PD-1 function as immune checkpoint receptors in the overlapping regulation of immune tolerance and have been shown to be overexpressed on the tumor infiltrating lymphocytes (TILs) from participant samples of various solid tumors including, but not limited to non-small cell lung cancer, head and neck squamous cell carcinoma, renal cell carcinoma, hepatocellular carcinoma, and gastric carcinoma. Subsequently, the activation of TIM-3 and PD-1 represent TILs from both participants or animals across solid tumor types with the most exhausted immunophenotype (ie, cytokine expression, proliferation etc.), which can be reversed with combined blockade of TIM-3 and PD 1. The overlap in expression and function indicates that TIM-3 and PD-1 cooperate to promote effector cell exhaustion which may impede an effective antitumor immune response. Based upon the overlapping expression profiles and immuno-regulatory functions, the improved in vivo antitumor effects, as well as the potential for TIM-3 mediated adaptive resistance, there is strong scientific rationale to evaluate the antitumor effects derived from the combined blockade of TIM-3 and PD-1 in advanced solid tumors. Accordingly, this study will evaluate the safety and preliminary efficacy of BGB-A425 (anti TIM-3) in combination with tislelizumab (anti PD-1) in participants 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 will continue to evaluate the safety but also focus on the efficacy of the combination in select tumor types.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 162 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention 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 will continue to evaluate the safety but also focus on the efficacy of the combination in select tumor types.
Masking: None (Open Label)
Masking Description: Open Label
Primary Purpose: Treatment
Official Title: Phase 1-2 Study Investigating Safety, Tolerability, Pharmacokinetics and Preliminary Antitumor Activity of Anti-TIM-3 Monoclonal Antibody BGB-A425 in Combination With Anti-PD-1 Monoclonal Antibody Tislelizumab in Patients With Advanced Solid Tumors
Actual Study Start Date : November 13, 2018
Estimated Primary Completion Date : July 1, 2023
Estimated Study Completion Date : January 1, 2024

Arm Intervention/treatment
Experimental: Phase 1 Dose Escalation
Dose escalation of BGB-A425 in combination with tislelizumab in participants with advanced solid tumors
Drug: BGB-A425
Humanized IgG1-variant monoclonal antibody against TIM-3

Drug: tislelizumab
Humanized, IgG4-variant monoclonal antibody against PD-1
Other Name: BGB-A317

Experimental: Phase 2 Dose Expansion
Further explore the safety and clinical activity of BGB-A425 in combination with tislelizumab in participants with NSCLC, HNSCC and RCC.
Drug: BGB-A425
Humanized IgG1-variant monoclonal antibody against TIM-3

Drug: tislelizumab
Humanized, IgG4-variant monoclonal antibody against PD-1
Other Name: BGB-A317




Primary Outcome Measures :
  1. Phase 1 Dose Escalation [ Time Frame: Approximately 2 years ]

    Safety and tolerability of BGB-A425 in combination with tislelizumab using Common Terminology Criteria for Adverse Events (CTCAE v.5.0) in participants with advanced solid tumors.

    maximum tolerated dose (MTD) or maximum administered dose (MAD) and recommended Phase 2 dose (RP2D) of BGB-A425 in combination with tislelizumab


  2. Phase 2 Dose Expansion [ Time Frame: Approximately 2 years ]
    Preliminary anti-tumor activity of BGB-A425 in combination with tislelizumab in participants with select advanced solid tumors, in terms of objective response rate (ORR) as assessed by the Investigators using Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1.


Secondary Outcome Measures :
  1. Duration of response (DOR) [ Time Frame: Phase 1 or 2 Expansion - Approximately 2-3 years each ]
    Duration of response (DOR) will be determined from investigator derived tumor assessments per Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1.

  2. Disease control rate (DCR) [ Time Frame: Phase 1 or 2 Expansion - Approximately 2-3 years each ]
    Disease control rate (DCR) will be determined from investigator derived tumor assessments per Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1.

  3. Progression free survival [ Time Frame: Phase 2 Expansion - Approximately 3 years ]
    Progression free survival will be determined from investigator derived tumor assessments per RECIST 1.1.

  4. PK Parameter: Area Under the Curve (AUC), 0 to 21 days [ Time Frame: Phase 1 and Phase 2- Approximately 2-3 years each ]
  5. Pharmacokinetic (PK) Parameter: Minimum Concentration (Cmin) [ Time Frame: Phase 1 and Phase 2- Approximately 2-3 years each ]
  6. PK Parameter: Maximum Concentration (Cmax) [ Time Frame: Phase 1 and Phase 2- Approximately 2-3 years each ]
  7. PK Parameter: Clearance (CL) [ Time Frame: Phase 1 and Phase 2- Approximately 2-3 years each ]
  8. PK Parameter: Volume of Distribution (Vz) [ Time Frame: Phase 1 and Phase 2- Approximately 2-3 years each ]
  9. PK Parameter: terminal half-life (t1/2) [ Time Frame: Phase 1 and Phase 2- Approximately 2-3 years each ]
  10. Immunogenicity as assessed by the presence of anti-drug antibodies [ Time Frame: Phase 1 and Phase 2- Approximately 2-3 years each ]
  11. Safety and tolerability: The safety of BGB-A425 in combination with tislelizumab will be assessed throughout the study by monitoring AEs and SAEs per NCI-CTCAE version 5.0, physical examinations, ECGs, and laboratory assessments as needed [ Time Frame: Phase 1 and Phase 2- Approximately 2-3 years each ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  1. Phase 1: Patients 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.
  2. Has Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1.
  3. Phase 2: Patients with one of the following histologically or cytologically confirmed solid tumors:

Cohort 1 (HNSCC, 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

Cohort 2 (NSCLC, PD-L1 positive):

Locally recurrent Stage IIIB, stage IIIC or Stage IV squamous or non-squamous non-small cell lung cancer

Cohort 3 (RCC):

Locally advanced unresectable or metastatic and histologically confirmed renal cell carcinoma with a clear cell histology

Key Exclusion Criteria:

  • Active leptomeningeal disease or uncontrolled, untreated brain metastasis.
  • Active autoimmune diseases or history of autoimmune diseases that may relapse.
  • 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. 6. Received prior therapies targeting TIM-3.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03744468


Contacts
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Contact: BeiGene 1 (877) 828-5568 clinicaltrials@beigene.com

Locations
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Sponsors and Collaborators
BeiGene
Investigators
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Study Director: Emily Liu BeiGene
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Responsible Party: BeiGene
ClinicalTrials.gov Identifier: NCT03744468    
Other Study ID Numbers: BGB-900-102
First Posted: November 16, 2018    Key Record Dates
Last Update Posted: September 9, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasms