Study of BGB-A425 and LBL-007 in Combination With Tislelizumab in Advanced Solid Tumors
- Conditions
- 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
- Interventions
- Registration Number
- NCT03744468
- Lead Sponsor
- BeiGene
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 114
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
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Phase 2 Safety Lead-in LBL-007 Dose escalation for Cohort A (LBL-007 + Tislelizumab) and Cohort B (BGB-A425 + LBL-007 + Tislelizumab) in participants with advanced solid tumors Phase 2 Dose Expansion BGB-A425 Further explore the safety and clinical activity of BGB-A425 and LBL-007 in combination with Tislelizumab in participants with NSCLC, HNSCC and RCC Phase 2 Dose Expansion LBL-007 Further explore the safety and clinical activity of BGB-A425 and LBL-007 in combination with Tislelizumab in participants with NSCLC, HNSCC and RCC Phase 1 Dose Escalation BGB-A425 Dose escalation of BGB-A425 in combination with Tislelizumab in participants with advanced solid tumors Phase 2 Safety Lead-in BGB-A425 Dose escalation for Cohort A (LBL-007 + Tislelizumab) and Cohort B (BGB-A425 + LBL-007 + Tislelizumab) in participants with advanced solid tumors Phase 2 Safety Lead-in Tislelizumab Dose escalation for Cohort A (LBL-007 + Tislelizumab) and Cohort B (BGB-A425 + LBL-007 + Tislelizumab) in participants with advanced solid tumors Phase 1 Dose Escalation Tislelizumab Dose escalation of BGB-A425 in combination with Tislelizumab in participants with advanced solid tumors Phase 2 Dose Expansion Tislelizumab Further explore the safety and clinical activity of BGB-A425 and LBL-007 in combination with Tislelizumab in participants with NSCLC, HNSCC and RCC
- Primary Outcome Measures
Name Time Method Phase 2 Dose Expansion: Objective Response Rate (ORR) Approximately 2 years ORR is determined from the investigator derived tumor assessments per RECIST v1.1
Phase 1 Dose Escalation: Maximum Tolerated Dose (MTD) Approximately 2 years The MTD or MAD is defined as the highest dose at which \< 33% of the participants experience a dose limiting toxicity (DLT)
Phase 1 Dose Escalation and Phase 2 Safety lead-in: Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Approximately 2 years 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.
- Secondary Outcome Measures
Name Time Method Phase 1 and Phase 2 : Progression free survival 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 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 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 PK Parameter: Maximum Concentration (Cmax) 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 1 and Phase 2 : Duration of Response (DOR) 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.
Pharmacokinetic (PK) Parameter: Minimum Concentration (Cmin) of BGB-425 and LBL-007 Phase 1 and Phase 2- Approximately 2-3 years each Phase 1 and Phase 2 : Disease control rate (DCR) 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.
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
Related Research Topics
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Trial Locations
- Locations (42)
Chao Family Comprehensive Cancer Center
🇺🇸Orange, California, United States
University of Colorado Cancer Center
🇺🇸Aurora, Colorado, United States
University of Chicago Medical Center
🇺🇸Chicago, Illinois, United States
University of Kentucky Markey Cancer Center
🇺🇸Lexington, Kentucky, United States
Weill Cornell Medical College Newyork Presbyterian Hospital
🇺🇸New York, New York, United States
University of North Carolina At Chapel Hill
🇺🇸Chapel Hill, North Carolina, United States
Fox Chase Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
The University of Texas Md Anderson Cancer Center
🇺🇸Houston, Texas, United States
Ut Health San Antonio Mays Cancer Center
🇺🇸San Antonio, Texas, United States
University of Virginia
🇺🇸Charlottesville, Virginia, United States
Schar Cancer Institute
🇺🇸Fairfax, Virginia, United States
Sydney Southwest Private Hospital
🇦🇺Liverpool, New South Wales, Australia
Sunshine Coast Hospital and Health Service
🇦🇺Birtinya, Queensland, Australia
Gold Coast University Hospital
🇦🇺Southport, Queensland, Australia
Lyell McEwin Hospital
🇦🇺Elizabeth Vale, South Australia, Australia
Calvary North Adelaide Hospital
🇦🇺North Adelaide, South Australia, Australia
Box Hill Hospital
🇦🇺Box Hill, Victoria, Australia
Cabrini Research and Education Institute
🇦🇺Malvern, Victoria, Australia
Peter Maccallum Cancer Centre
🇦🇺Melbourne, Victoria, Australia
Western Health Sunshine Hospital
🇦🇺St Albans, Victoria, Australia
Hollywood Private Hospital
🇦🇺Nedlands, Western Australia, Australia
Linear Clinical Research
🇦🇺Nedlands, Western Australia, Australia
Institut Catala Doncologia
🇪🇸Barcelona, Spain
Centre de Lutte Contre Le Cancer Institut Bergonie
🇫🇷Bordeaux, France
Centre de Lutte Contre Le Cancer Francois Baclesse
🇫🇷Caen, France
Irccs Azienda Ospedaliero Universitaria Bologna
🇮🇹Bologna, Italy
Fondazione Irccs Istituto Nazionale Dei Tumori
🇮🇹Milano, Italy
Istituto Di Candiolo Irccs
🇮🇹Torino, Italy
Chungbuk National University Hospital
🇰🇷Cheongjusi, Chungcheongbukdo, Korea, Republic of
The Catholic University of Korea, St Vincents Hospital
🇰🇷Suwonsi, Gyeonggi-do, Korea, Republic of
Ajou University Hospital
🇰🇷Suwonsi, Gyeonggi-do, Korea, Republic of
Gachon University Gil Medical Center
🇰🇷Incheon, Incheon Gwang'yeogsi, Korea, Republic of
Severance Hospital Yonsei University Health System
🇰🇷Seoul, Seoul Teugbyeolsi, Korea, Republic of
Asan Medical Center
🇰🇷Seoul, Seoul Teugbyeolsi, Korea, Republic of
The Catholic University of Korea, Seoul St Marys Hospital
🇰🇷Seoul, Seoul Teugbyeolsi, Korea, Republic of
Ulsan University Hospital
🇰🇷Donggu, Ulsan Gwang'yeogsi, Korea, Republic of
Centrum Onkologiiim Prof F Lukaszczyka Wbydgoszczy
🇵🇱Bydgoszcz, Poland
Narodowy Instytut Onkologii Im Marii Skodowskiej Curie Pastwowy Instytut Badawczy
🇵🇱Warszawa, Poland
Ico Hug Trias I Pujol
🇪🇸Barcelona, Spain
Hospital Clinico San Carlos
🇪🇸Madrid, Spain
Hospital Universitario Hm Madrid Sanchinarro
🇪🇸Madrid, Spain
Hospital Universitario Virgen Del Rocio
🇪🇸Sevilla, Spain