Clinical trial NCT02407990: Study of the Safety, Pharmacokinetics and Antitumor Activities of BGB-A317 in Participants With Advanced Tumors
Official title: A Phase 1A/1B, Open Label, Multiple Dose, Dose Escalation and Expansion Study to Investigate the Safety, Pharmacokinetics and Antitumor Activities of the Anti-PD-1 Monoclonal Antibody BGB-A317 in Subjects With Advanced Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced Cancer
Lead sponsor: BeiGene
Sponsor class: INDUSTRY
First posted: 2015-04-03
Enrollment: 451
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study evaluated the safety, tolerability, pharmacokinetic profile and treatment effect of a new drug known as BGB-A317 in participants with advanced tumors.


Eligibility criteria: Key Inclusion Criteria:

1. Participants must have had a histologically or cytologically confirmed advanced or metastatic tumor for which no effective standard therapy was available.

   1. For Phase 1A: no specific restriction
   2. For Phase 1B: histology specified below:

   i. non-small cell lung cancer (participants with documented epidermal growth factor receptor mutation or anaplastic lymphoma kinase rearrangement should have been excluded) ii. ovarian cancer iii. gastric cancer iv. hepatocellular carcinoma (HCC, Barcelona-Clinic Liver Cancer stage C, stage B not amenable to locoregional therapy or refractory to locoregional therapy, and not amenable to a curative treatment approach, and Child-Pugh A) v. head and neck squamous cell carcinoma vi. esophageal carcinoma vii. triple negative breast cancer viii. cholangiocarcinoma ix. renal cell cancer, bladder cancer, melanoma, Merkel-cell carcinoma, sarcoma, gastrointestinal stromal tumor, or cutaneous squamous cell carcinoma. Or any other solid tumors with known microsatellite instability-high or mismatch repair deficient status, such as colorectal cancer or pancreatic cancer
2. Participants with previously treated brain metastasis (es) that were asymptomatic or radiographically/clinically stable and not requiring steroids medications for 4 weeks prior to enrollment were permitted.
3. Participants must have had archival tumor tissues or agreed to a tumor biopsy for analysis of predictive biomarkers such as programmed death-ligand 1 (PD-L1). (Fresh tumor biopsies were strongly recommended at baseline for biomarker analysis in participants with readily accessible tumor lesions and who consented to the biopsies).
4. Participants must have had measurable disease as defined per Response Evaluation Criteria in Solid Tumor Version 1.1.
5. Eastern Cooperative Oncology Group performance status of ≤ 1.
6. Participants must have had adequate organ function as indicated by the following laboratory values:

   * Absolute neutrophil count ≥ 1,500 /microliter
   * Platelets ≥ 100,000 / milliliter (mL)
   * Hemoglobin ≥ 9 grams/deciliter or ≥ 5.6 millimoles/liter
   * Serum creatinine ≤ 1.5 X upper limit of normal (ULN)
   * Serum total bilirubin ≤ 1.5 X ULN
   * Aspartate aminotransferase (serum glutamic oxaloacetic transaminase) and alanine aminotransferase (serum glutamic pyruvic transaminase) ≤ 2.5 X ULN or ≤ 5 X ULN for participants with liver metastases
   * International normalized ratio or prothrombin time ≤ 1.5 X ULN
   * Activated partial thromboplastin time ≤ 1.5 X ULN

Key Exclusion Criteria:

1. History of severe hypersensitivity reactions to other Monoclonal antibodies.
2. Prior malignancy active within the previous 2 years except for tumor for which a participant was enrolled in the study, and locally curable cancers that had been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix or breast.
3. Prior therapies targeting PD-1 or PD-L1.
4. Participants who failed to meet enrollment criteria for other PD-1 or PD-L1 trials solely due to low or negative predictive biomarkers.
5. Participants with active autoimmune diseases or history of autoimmune diseases should have been excluded.
6. Participants should have been excluded if they had a condition requiring systemic treatment with either corticosteroids (\> 10 milligrams daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration.
7. Had history of interstitial lung disease or non-infectious pneumonitis except for those induced by radiation therapies.
8. Known history of human immunodeficiency virus.
9. Active infection requiring therapy, positive tests for hepatitis B surface antigen or hepatitis C ribonucleic acid except in participant with HCC, who met the following criteria:

   * Hepatitis B virus (HBV) viral load \< 200 international units/mL (approximately 1000 combined positive score/mL)
   * Participants with active HBV infection needed to be on anti-HBV suppression ≥ 3 months, throughout treatment and for 6 months after
   * Participants hepatitis C virus (HCV)-positive after successful treatment (defined as sustained virologic response \[SVR\] 12 or SVR 24) were allowed as long as 4 weeks had passed between completion of HCV therapy and start of study drug
10. Use of any vaccines against infectious diseases (for example, influenza, varicella) within 4 weeks (28 days) of initiation of study therapy and 60 days after the last administration of the study medication.

Note: Other protocol defined Inclusion/Exclusion criteria may have applied.

Primary outcomes:
measure: Phase 1A: Number of Participants Experiencing Adverse Events (AEs)
timeFrame: Day -28 through 5 years and 2 months
measure: Phase 1A: Number Of Participants With Abnormal Physical Examination Values
timeFrame: Day 1 and Day 15 of each cycle through 30 (+/- 7) days after last dose (up to 5 years and 2 months)
measure: Phase 1A: Number Of Participants Experiencing Dose-dependent Toxicity Through Ophthalmology Findings
timeFrame: Day 15 of cycle 1, Day 1 of Cycle 2 and all additional cycles, and 30 (+/- 7) days after last dose (up to 5 years and 2 months)
measure: Phase 1A: Number Of Participants With Abnormal Electrocardiograms
timeFrame: Days 1 and 15 of cycle 1; Day 1 of cycle 2 and all additional cycles; Day 1 of cycle 4; 30 (+/- 7) days after last dose (up to 5 years and 2 months)
measure: Phase 1A: Number Of Participants With Abnormal Laboratory Values
timeFrame: Day -28 (predose), Days 1, 8, and 15 of cycle 1; Days 1 and 15 of cycle 2 and additional cycles; Days 1 and 15 of cycle 4; 30 (+/- 7) days after last dose (up to 5 years and 2 months)
measure: Phase 1A: Number Of Participants Experiencing Severe AEs
timeFrame: Day -28 through 5 years and 2 months
measure: Phase 1B: Objective Response Rate (ORR)
timeFrame: Day -28 through 5 years and 2 months
Secondary outcomes:
measure: Phase 1A: Area Under The Plasma Concentration-time Curve Within the Dosing Interval (AUC0-tau) For Tislelizumab
timeFrame: Cycle 1 Day 1-1 hour pre-dose, End of infusion, 1, 5, 6, 24, and 72 hours post-dose; Day 15 and Cycle 2 Day 1 Pre-dose
measure: Phase 1A: Maximum Observed Plasma Concentration (Cmax) For Tislelizumab
timeFrame: Cycle 1 Day 1-1 hour pre-dose, End of infusion, 1, 5, 6, 24, and 72 hours post-dose; Day 15 and Cycle 2 Day 1 Pre-dose
measure: Phase 1A: Time To Maximum Concentration (Tmax) For Tislelizumab
timeFrame: Cycle 1 Day 1-1 hour pre-dose, End of infusion, 1, 5, 6, 24, and 72 hours post-dose; Day 15 and Cycle 2 Day 1 Pre-dose
measure: Phase 1A: Half-life (T½) For Tislelizumab
timeFrame: Cycle 1 Day 1-1 hour pre-dose, End of infusion, 1, 5, 6, 24, and 72 hours post-dose; Day 15 and Cycle 2 Day 1 Pre-dose
measure: Phase 1A - Part 3: Clearance (Cl) For Tislelizumab
timeFrame: Cycle 1 Day 1-1 hour pre-dose, End of infusion, 1, 5, 6, 24, and 72 hours post-dose; Day 15 and Cycle 2 Day 1 Pre-dose
measure: Phase 1A/1B: Number Of Participants With Anti-drug Antibodies (ADAs)
timeFrame: Day 1 of Cycles 1 through 15
measure: Phase 1A: ORR
timeFrame: Day -28 through 5 years and 2 months
measure: Phase 1A: CR Rate
timeFrame: Day -28 through 5 years and 2 months
measure: Phase 1A: PR Rate
timeFrame: Day -28 through 5 years and 2 months
measure: Phase 1A: Stable Disease (SD) Rate
timeFrame: Day -28 through 5 years and 2 months
measure: Phase 1A: Progression-free Survival (PFS)
timeFrame: Day -28 through 5 years and 2 months
measure: Phase 1A: Overall Survival (OS)
timeFrame: Day -28 through 5 years and 2 months
measure: Phase 1A: Duration Of Response (DOR)
timeFrame: Day -28 through 5 years and 2 months
measure: Phase 1B: Number of Participants Experiencing AEs
timeFrame: Day -28 through 5 years and 2 months
measure: Phase 1B: Steady State Plasma Trough Concentration Of Tislelizumab
timeFrame: Pre-dose, Day 1 Cycle 5 and every other Cycle in the first 6 months, every 4 cycles in the next 6 months, once every 6 months up to end of treatment (up to 5 years and 2 months)
measure: Phase 1B: PFS
timeFrame: Day -28 through 5 years and 2 months
measure: Phase 1B: Disease Control Rate (DCR)
timeFrame: Day -28 through 5 years and 2 months
measure: Phase 1B: Clinical Benefit Rate (CBR)
timeFrame: Day -28 through 5 years and 2 months
measure: Phase 1B: Number Of Participants With Abnormal Physical Examination Values
timeFrame: Day -28 (predose), Days 1, 4, 8, and 15 of cycle 1; Day 1 of cycle 2; through 30 (+/- 7) days after last dose up to 5 years and 2 months
measure: Phase 1B: Number Of Participants Experiencing Dose-dependent Toxicity Through Ophthalmology Findings
timeFrame: Day -28 (predose), Day 1 of cycle 2 and additional cycles, and 30 (+/- 7) days after last dose up to 5 years and 2 months
measure: Phase 1B: Number Of Participants With Abnormal Electrocardiograms
timeFrame: Day -28 (predose), Days 1 and 15 of cycle 1; Day 1 of cycle 2 and additional cycles; 30 (+/- 7) days after last dose up to 5 years and 2 months
measure: Phase 1B: Number Of Participants With Abnormal Laboratory Values
timeFrame: Day -28 (predose), Days 1, 8, and 15 of cycle 1; Day 1 of cycle 2 and additional cycles; 30 (+/- 7) days after last dose up to 5 years and 2 months
measure: Phase 1B: Number Of Participants Experiencing Severe AEs
timeFrame: Day -28 through 5 years and 2 months
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Houston
country: United States
facility: Oncology Consultants, P.A.
state: Texas
city: Camperdown
country: Australia
facility: Chris O'Brien Lifehouse
state: New South Wales
city: Sydney
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: Southport
country: Australia
facility: Tasman Oncology Research Ltd
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Woodville South
country: Australia
facility: The Queen Elizabeth Hospital
state: South Australia
city: Clayton
country: Australia
facility: Monash Health
state: Victoria
city: East Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Health Hospital
state: Victoria
city: Malvern
country: Australia
facility: Cabrini Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Nucleus Network
state: Victoria
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Linear Clinical Research/Sir Charles Gairdner Hospital
state: Western Australia
city: Seongnam
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
state: Kyeonggi-do
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Grafton
country: New Zealand
facility: Auckland City Hospital
city: Hamilton
country: New Zealand
facility: Waikato
city: Wellington
country: New Zealand
facility: Wellington Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Chang Gung Memorial Hospital
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taoyuan
country: Taiwan
facility: Linkou Chang Gung Memorial Hospital
city: Taoyuan
country: Taiwan
facility: Chang Gung Memorial Hospital, Sachin
Study officials:
affiliation: BeiGene
name: Study Director
role: PRINCIPAL_INVESTIGATOR
References:
citation: Desai J, Deva S, Lee JS, Lin CC, Yen CJ, Chao Y, Keam B, Jameson M, Hou MM, Kang YK, Markman B, Lu CH, Rau KM, Lee KH, Horvath L, Friedlander M, Hill A, Sandhu S, Barlow P, Wu CY, Zhang Y, Liang L, Wu J, Paton V, Millward M. Phase IA/IB study of single-agent tislelizumab, an investigational anti-PD-1 antibody, in solid tumors. J Immunother Cancer. 2020 Jun;8(1):e000453. doi: 10.1136/jitc-2019-000453.