Study of the Safety, Pharmacokinetics and Antitumor Activities of BGB-A317 in Participants With Advanced Tumors

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

Official Title
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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

Conditions
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Advanced Cancer

Intervention / Treatment
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* Biological: BGB-A317
* Biological: BGB-A317


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Participants must have had a histologically or cytologically confirmed advanced or metastatic tumor for which no effective standard therapy was available. For Phase 1A: no specific restriction 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 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. 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). Participants must have had measurable disease as defined per Response Evaluation Criteria in Solid Tumor Version 1.1. Eastern Cooperative Oncology Group performance status of ≤ 1. 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: History of severe hypersensitivity reactions to other Monoclonal antibodies. 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. Prior therapies targeting PD-1 or PD-L1. Participants who failed to meet enrollment criteria for other PD-1 or PD-L1 trials solely due to low or negative predictive biomarkers. Participants with active autoimmune diseases or history of autoimmune diseases should have been excluded. 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. Had history of interstitial lung disease or non-infectious pneumonitis except for those induced by radiation therapies. Known history of human immunodeficiency virus. 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 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BGB-A317 Phase 1A<br> | Biological: BGB-A317<br>* In the dose escalation part, the dose levels were escalated following a modified 3+3 dose escalation scheme. In the scheduled exploration part, participants were assigned to doses and dose schedules. In the fixed dose exploration part, participants were assigned to dose group(s) not to exceed the maximum tolerated dose. In the dose expansion part, participants were assigned to different groups based on their tumor type.<br>|
| Experimental: BGB-A317 Phase 1B<br> | Biological: BGB-A317<br>* Participants were assigned to different groups based on their tumor types<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1A: Number of Participants Experiencing Adverse Events (AEs) | An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE could have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of an investigational product. All AEs were monitored per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE version [v] 4.03 2010). | Day -28 through 5 years and 2 months | 
| Phase 1A: Number Of Participants With Abnormal Physical Examination Values | A complete physical examination, vital signs (systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse rate, temperature, and respiratory rate), and weight were performed pre-specified time points for Phase 1A. During the treatment period, symptom-directed physical examinations were performed. If there were no complaints and no abnormal findings from the previous visit for a particular organ system, a physical examination of that organ system was not required. | Day 1 and Day 15 of each cycle through 30 (+/- 7) days after last dose (up to 5 years and 2 months) | 
| Phase 1A: Number Of Participants Experiencing Dose-dependent Toxicity Through Ophthalmology Findings | Ophthalmological examinations (such as eyesight/visual acuity, fundoscopy, slit lamp microscopy, and optical coherence tomography [or equivalent diagnostic test]) were performed at pre-specified time points for Phase 1A. Eye exam, visual acuity test, and optical coherence tomography (or equivalent diagnostic test) will be assessed by an appropriate specialist at Screening. Participants dosed underwent subsequent ophthalmologic examinations, a specified in the protocol, by an appropriate specialist during study treatment. | 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) | 
| Phase 1A: Number Of Participants With Abnormal Electrocardiograms | Electrocardiograms were obtained at pre-specified time points. Significant QT interval corrected for heart rate (QTc) prolongation was defined as an interval ≥ 500 milliseconds (msec) or an interval which increases by ≥ 60 msec over baseline. | 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) | 
| Phase 1A: Number Of Participants With Abnormal Laboratory Values | Clinical chemistry, hematology, coagulation, and urinalysis were performed at pre-specified time points for Phase 1A. If warranted, additional testing was done, or the relevant tests done more frequently in accordance with institutional guidelines. All participants who had any Grade 3 or Grade 4 laboratory abnormalities at withdrawal from the study were followed up until they had returned to Grade 1 or Grade 2, unless these were not likely to improve due to the underlying disease. Participants experiencing decreases (low) and increases (high) to ≥ Grade 3 are reported. | 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) | 
| Phase 1A: Number Of Participants Experiencing Severe AEs | All AEs were monitored per the NCI-CTCAE (v 4.03 2010). In addition to performing the CTCAE assessment, the intensity of each AE and serious adverse event (SAE) recorded was assigned to one of the following categories based on the Investigator's clinical judgment: Mild: an event that is easily tolerated by the participant, causing minimal discomfort and not interfering with everyday activities; moderate: An event that is sufficiently discomforting to interfere with normal everyday activities; severe: An event that prevents normal everyday activities. Severity was a category utilized for rating the intensity of an event and, accordingly, both AEs and SAEs could be assessed as severe. | Day -28 through 5 years and 2 months | 
| Phase 1B: Objective Response Rate (ORR) | The ORR was defined as the percentage of participants in the study whose best overall response was either complete response (CR) or partial response (PR) as assessed by investigators based on Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1. | Day -28 through 5 years and 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1A: Area Under The Plasma Concentration-time Curve Within the Dosing Interval (AUC0-tau) For Tislelizumab |  | 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 | 
| Phase 1A: Maximum Observed Plasma Concentration (Cmax) For Tislelizumab |  | 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 | 
| Phase 1A: Time To Maximum Concentration (Tmax) For Tislelizumab |  | 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 | 
| Phase 1A: Half-life (T½) For Tislelizumab |  | 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 | 
| Phase 1A - Part 3: Clearance (Cl) For Tislelizumab |  | 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 | 
| Phase 1A/1B: Number Of Participants With Anti-drug Antibodies (ADAs) | Immunogenicity was summarized by the number and percentage of participants who developed detectable treatment-emergent ADAs, which included positive ADAs and neutralizing antibodies (NAb). | Day 1 of Cycles 1 through 15 | 
| Phase 1A: ORR | The ORR was defined as the percentage of participants in the study whose best overall response was either CR or PR as assessed by investigators based on RECIST v 1.1. | Day -28 through 5 years and 2 months | 
| Phase 1A: CR Rate | The CR rate was based on RECIST v 1.1 and the results of Investigator evaluations. | Day -28 through 5 years and 2 months | 
| Phase 1A: PR Rate | The PR rate was based on RECIST v 1.1 and the results of Investigator evaluations. | Day -28 through 5 years and 2 months | 
| Phase 1A: Stable Disease (SD) Rate | The SD rate was based on RECIST v 1.1 and the results of Investigator evaluations. | Day -28 through 5 years and 2 months | 
| Phase 1A: Progression-free Survival (PFS) | PFS was defined as the time from the date of first study dose to disease progression or death whichever occurs first. Participants without an event (no disease progression or death) were censored at the date of last tumor assessment. Participants with no baseline or post-baseline tumor assessments were censored at Day 1. PFS was based on RECIST v 1.1 and the results of Investigator evaluations. | Day -28 through 5 years and 2 months | 
| Phase 1A: Overall Survival (OS) | OS was defined as the time interval between the date of the first study drug dose to the date of death for any cause. Kaplan-Meier methodology was used to estimate OS at various time points. The OS was based on RECIST v 1.1 and the results of Investigator evaluations. | Day -28 through 5 years and 2 months | 
| Phase 1A: Duration Of Response (DOR) | DOR for responders (CR or PR) was defined as the time interval between the date of the earliest qualifying response and the date of progressive disease or death for any cause, whichever occurred earlier. For participants who were alive without progression following the qualifying response, DOR was censored on the date of last evaluable tumor assessment or last follow-up for progression of disease. The DOR was based on RECIST v 1.1 and the results of Investigator evaluations. | Day -28 through 5 years and 2 months | 
| Phase 1B: Number of Participants Experiencing AEs | An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE could have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of an investigational product. All AEs were monitored per the NCI-CTCAE (v 4.03 2010). | Day -28 through 5 years and 2 months | 
| Phase 1B: Steady State Plasma Trough Concentration Of Tislelizumab |  | 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) | 
| Phase 1B: PFS | PFS was defined as the time from the date of first study dose to disease progression or death whichever occurs first. Participants without an event (no disease progression or death) were censored at the date of last tumor assessment. Participants with no baseline or post-baseline tumor assessments were censored at Day 1. PFS was based on RECIST v 1.1 and the results of Investigator evaluations. | Day -28 through 5 years and 2 months | 
| Phase 1B: Disease Control Rate (DCR) | The DCR was defined as the percentage of participants who achieve CR, PR, and SD based on RECIST v 1.1 in participants with select tumor types. | Day -28 through 5 years and 2 months | 
| Phase 1B: Clinical Benefit Rate (CBR) | The CBR was defined as the percentage of participants who achieved CR, PR, and durable SD [SD ≥24 weeks] based on RECIST v 1.1 in participants with select tumor types. | Day -28 through 5 years and 2 months | 
| Phase 1B: Number Of Participants With Abnormal Physical Examination Values | A complete physical examination, vital signs (SBP, DBP, pulse rate, temperature, and respiratory rate), and weight were performed pre-specified time points for Phase 1B. During the treatment period, symptom-directed physical examinations were performed. If there were no complaints and no abnormal findings from the previous visit for a particular organ system, a physical examination of that organ system was not required. | 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 | 
| Phase 1B: Number Of Participants Experiencing Dose-dependent Toxicity Through Ophthalmology Findings | Ophthalmological examinations (such as eyesight/visual acuity, fundoscopy, slit lamp microscopy, and optical coherence tomography [or equivalent diagnostic test]) were performed at pre-specified time points for Phase 1B. Eye exam, visual acuity test, and optical coherence tomography (or equivalent diagnostic test) will be assessed by an appropriate specialist at Screening. Participants dosed underwent subsequent ophthalmologic examinations, a specified in the protocol, by an appropriate specialist during study treatment. | 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 | 
| Phase 1B: Number Of Participants With Abnormal Electrocardiograms | Electrocardiograms were obtained at pre-specified time points. Significant QTc prolongation was defined as an interval ≥ 500 msec or an interval which increases by ≥ 60 msec over baseline. | 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 | 
| Phase 1B: Number Of Participants With Abnormal Laboratory Values | Clinical chemistry, hematology, coagulation, and urinalysis will be performed at pre-specified time points for Phase 1A and Phase 1B respectively. If warranted, additional testing was done, or the relevant tests done more frequently in accordance with institutional guidelines. All participants who had any Grade 3 or Grade 4 laboratory abnormalities at withdrawal from the study were followed up until they had returned to Grade 1 or Grade 2, unless these were not likely to improve due to the underlying disease. Participants experiencing decreases (low) and increases (high) to ≥ Grade 3 are reported. | 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 | 
| Phase 1B: Number Of Participants Experiencing Severe AEs | All AEs were monitored per the NCI-CTCAE (v 4.03 2010). In addition to performing the CTCAE assessment, the intensity of each AE and SAE recorded was assigned to one of the following categories based on the Investigator's clinical judgment: Mild: an event that is easily tolerated by the participant, causing minimal discomfort and not interfering with everyday activities; moderate: An event that is sufficiently discomforting to interfere with normal everyday activities; severe: An event that prevents normal everyday activities. Severity was a category utilized for rating the intensity of an event and, accordingly, both AEs and SAEs could be assessed as severe. | Day -28 through 5 years and 2 months |