Clinical trial NCT03744468: Study of BGB-A425 and LBL-007 in Combination With Tislelizumab in Advanced Solid Tumors
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
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
Lead sponsor: BeiGene
Sponsor class: INDUSTRY
First posted: 2018-11-16
Enrollment: 114
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
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 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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Phase 1 Dose Escalation and Phase 2 Safety lead-in: Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: Approximately 2 years
measure: Phase 1 Dose Escalation: Maximum Tolerated Dose (MTD)
timeFrame: Approximately 2 years
measure: Phase 2 Dose Expansion: Objective Response Rate (ORR)
timeFrame: Approximately 2 years
Secondary outcomes:
measure: Phase 1 and Phase 2 : Duration of Response (DOR)
timeFrame: Phase 1 or 2 Expansion - Approximately 2-3 years each
measure: Phase 1 and Phase 2 : Disease control rate (DCR)
timeFrame: Phase 1 or 2 Expansion - Approximately 2-3 years each
measure: Phase 1 and Phase 2 : Progression free survival
timeFrame: Phase 2 Expansion - Approximately 3 years
measure: Pharmacokinetic (PK) Parameter: Minimum Concentration (Cmin) of BGB-425 and LBL-007
timeFrame: Phase 1 and Phase 2- Approximately 2-3 years each
measure: PK Parameter: Area Under the Curve (AUC), 0 to 21 days of BGB-425 and LBL-007
timeFrame: Phase 1 and Phase 2- Approximately 2-3 years each
measure: PK Parameter: Maximum Concentration (Cmax) of BGB-425 and LBL-007
timeFrame: Phase 1 and Phase 2- Approximately 2-3 years each
measure: PK Parameter: Clearance (CL) of BGB-425 and LBL-007
timeFrame: Phase 1 and Phase 2- Approximately 2-3 years each
measure: PK Parameter: Volume of Distribution (Vz) of BGB-425 and LBL-007
timeFrame: Phase 1 and Phase 2- Approximately 2-3 years each
measure: PK Parameter: terminal half-life (t1/2) of BGB-425 and LBL-007
timeFrame: Phase 1 and Phase 2- Approximately 2-3 years each
measure: Percentage of participants with anti-BGB-A425 and LBL-007 antibodies
timeFrame: Phase 1 and Phase 2- Approximately 2-3 years each
measure: Phase 2 Dose Expansion: Number of participants with TEAEs and SAEs including physical examinations, electrocardiograms and laboratory assessments
timeFrame: Phase 1 and Phase 2- Approximately 2-3 years each
Other outcomes:
Locations:
city: Orange
country: United States
facility: Chao Family Comprehensive Cancer Center
state: California
city: Aurora
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Lexington
country: United States
facility: University of Kentucky Markey Cancer Center
state: Kentucky
city: New York
country: United States
facility: Weill Cornell Medical College Newyork Presbyterian Hospital
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina At Chapel Hill
state: North Carolina
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Houston
country: United States
facility: The University of Texas Md Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Ut Health San Antonio Mays Cancer Center
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Fairfax
country: United States
facility: Schar Cancer Institute
state: Virginia
city: Liverpool
country: Australia
facility: Sydney Southwest Private Hospital
state: New South Wales
city: Birtinya
country: Australia
facility: Sunshine Coast Hospital and Health Service
state: Queensland
city: Southport
country: Australia
facility: Gold Coast University Hospital
state: Queensland
city: Elizabeth Vale
country: Australia
facility: Lyell McEwin Hospital
state: South Australia
city: North Adelaide
country: Australia
facility: Calvary North Adelaide Hospital
state: South Australia
city: Box Hill
country: Australia
facility: Box Hill Hospital
state: Victoria
city: Malvern
country: Australia
facility: Cabrini Research and Education Institute
state: Victoria
city: Melbourne
country: Australia
facility: Peter Maccallum Cancer Centre
state: Victoria
city: St Albans
country: Australia
facility: Western Health Sunshine Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Hollywood Private Hospital
state: Western Australia
city: Nedlands
country: Australia
facility: Linear Clinical Research
state: Western Australia
city: Bordeaux
country: France
facility: Centre de Lutte Contre Le Cancer Institut Bergonie
city: Caen
country: France
facility: Centre de Lutte Contre Le Cancer Francois Baclesse
city: Bologna
country: Italy
facility: Irccs Azienda Ospedaliero Universitaria Bologna
city: Milano
country: Italy
facility: Fondazione Irccs Istituto Nazionale Dei Tumori
city: Torino
country: Italy
facility: Istituto Di Candiolo Irccs
city: Cheongjusi
country: Korea, Republic of
facility: Chungbuk National University Hospital
state: Chungcheongbukdo
city: Suwonsi
country: Korea, Republic of
facility: The Catholic University of Korea, St Vincents Hospital
state: Gyeonggi-do
city: Suwonsi
country: Korea, Republic of
facility: Ajou University Hospital
state: Gyeonggi-do
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Medical Center
state: Incheon Gwang'yeogsi
city: Seoul
country: Korea, Republic of
facility: Severance Hospital Yonsei University Health System
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul St Marys Hospital
state: Seoul Teugbyeolsi
city: Donggu
country: Korea, Republic of
facility: Ulsan University Hospital
state: Ulsan Gwang'yeogsi
city: Bydgoszcz
country: Poland
facility: Centrum Onkologiiim Prof F Lukaszczyka Wbydgoszczy
city: Warszawa
country: Poland
facility: Narodowy Instytut Onkologii Im Marii Skodowskiej Curie Pastwowy Instytut Badawczy
city: Barcelona
country: Spain
facility: Institut Catala Doncologia
city: Barcelona
country: Spain
facility: Ico Hug Trias I Pujol
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario Hm Madrid Sanchinarro
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Del Rocio
Study officials:
affiliation: BeiGene
name: Study Director
role: STUDY_DIRECTOR
References: