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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 : October 13, 2021
Sponsor:
Information provided by (Responsible Party):
BeiGene

Tracking Information
First Submitted Date  ICMJE October 17, 2018
First Posted Date  ICMJE November 16, 2018
Last Update Posted Date October 13, 2021
Actual Study Start Date  ICMJE November 13, 2018
Estimated Primary Completion Date July 1, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 4, 2021)
  • 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
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: November 15, 2018)
  • Phase 1 Dose Escalation [ Time Frame: Approximately 1.5 years ]
    Safety and tolerability of BGB-A425 in combination with tislelizumab using Common Terminology Criteria for Adverse Events (CTCAE v.5.0) in patients with advanced solid tumors.
  • Phase 2 Dose Expansion [ Time Frame: Approximately 1.5 years ]
    Recommended Phase 2 dose (RP2D) of BGB-A425 in combination with tislelizumab [ Phase 1 Dose Escalation - Approximately 1.5 years ]; 3. Anti-tumor activity of BGB-A425 in combination with tislelizumab in patients 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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 4, 2021)
  • 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.
  • 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.
  • 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.
  • PK Parameter: Area Under the Curve (AUC), 0 to 21 days [ Time Frame: Phase 1 and Phase 2- Approximately 2-3 years each ]
  • Pharmacokinetic (PK) Parameter: Minimum Concentration (Cmin) [ Time Frame: Phase 1 and Phase 2- Approximately 2-3 years each ]
  • PK Parameter: Maximum Concentration (Cmax) [ Time Frame: Phase 1 and Phase 2- Approximately 2-3 years each ]
  • PK Parameter: Clearance (CL) [ Time Frame: Phase 1 and Phase 2- Approximately 2-3 years each ]
  • PK Parameter: Volume of Distribution (Vz) [ Time Frame: Phase 1 and Phase 2- Approximately 2-3 years each ]
  • PK Parameter: terminal half-life (t1/2) [ Time Frame: Phase 1 and Phase 2- Approximately 2-3 years each ]
  • Immunogenicity as assessed by the presence of anti-drug antibodies [ Time Frame: Phase 1 and Phase 2- Approximately 2-3 years each ]
  • 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 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: November 15, 2018)
  • Duration of response (DOR) [ Time Frame: Phase 1 or 2 Expansion - Approximately 1.5 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.
  • Disease control rate (DCR) [ Time Frame: Phase 1 or 2 Expansion - Approximately 1.5 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.
  • 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.
  • PK Parameter [ Time Frame: Phase 1 and Phase 2- Approximately 1.5 year each ]
    PK Parameter: AUC, 0 to 21 days
  • PK Parameter [ Time Frame: Phase 1 and Phase 2- Approximately 1.5 year each ]
    PK Parameter: Minimum Concentration (Cmin)
  • PK Parameter [ Time Frame: Phase 1 and Phase 2- Approximately 1.5 year each ]
    PK Parameter: Maximum Concentration (Cmax)
  • PK Parameter [ Time Frame: Phase 1 and Phase 2- Approximately 1.5 year each ]
    PK Parameter: Clearance (CL)
  • PK Parameter [ Time Frame: Phase 1 and Phase 2-Approximately 1.5 year each ]
    PK Parameter: Volume of Distribution (Vz)
  • PK Parameter [ Time Frame: Phase 1 and Phase 2- Approximately 1.5 year each ]
    PK Parameter: terminal half-life (t1/2)
  • Immunogenicity [ Time Frame: Phase 1 and Phase 2- Approximately 1.5 year each ]
    Immunogenicity as assessed by the presence of anti-drug antibodies
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of BGB-A425 in Combination With Tislelizumab in Advanced Solid Tumors
Official Title  ICMJE 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
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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE 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
Condition  ICMJE Locally Advanced or Metastatic Solid Tumors for Phase 1 HNSCC, NSCLC and RCC for Phase 2
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • Experimental: Phase 1 Dose Escalation
    Dose escalation of BGB-A425 in combination with tislelizumab in participants with advanced solid tumors
    Interventions:
    • Drug: BGB-A425
    • Drug: tislelizumab
  • 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.
    Interventions:
    • Drug: BGB-A425
    • Drug: tislelizumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 15, 2018)
162
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 1, 2024
Estimated Primary Completion Date July 1, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: BeiGene 1 (877) 828-5568 clinicaltrials@beigene.com
Listed Location Countries  ICMJE Australia,   Korea, Republic of,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03744468
Other Study ID Numbers  ICMJE BGB-900-102
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Responsible Party BeiGene
Study Sponsor  ICMJE BeiGene
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Emily Liu BeiGene
PRS Account BeiGene
Verification Date October 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP