A Study of Atezolizumab With or Without Bevacizumab in Combination With Cisplatin Plus Gemcitabine in Patients With Untreated, Advanced Biliary Tract Cancer

Study Overview
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Brief Summary
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This study will evaluate the efficacy and safety of atezolizumab with bevacizumab in combination with cisplatin and gemcitabine(CisGem), compared with atezolizumab in combination with CisGem, in participants with advanced biliary tract cancer (BTC) who have not received prior systemic therapy. Treatment will consist of a chemotherapy combination phase followed by a cancer immunotherapy (CIT)/placebo phase.

Official Title
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A Phase II, Randomized, Double-Blind Placebo-Controlled Study of Atezolizumab With or Without Bevacizumab in Combination With Cisplatin Plus Gemcitabine in Patients With Untreated, Advanced Biliary Tract Cancer

Conditions
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Biliary Tract Cancer

Intervention / Treatment
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* Drug: Atezolizumab
* Drug: Bevacizumab
* Other: Placebo
* Drug: Cisplatin
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Considered to be eligible to receive platinum-based chemotherapy, in the investigator's judgment Documentation of recurrent/metastatic or locally advanced unresectable disease based on computed tomography (CT) or magnetic resonance imaging (MRI) scans Histologically or cytologically confirmed diagnosis of iCCA, eCCA, or GBC No prior systemic therapy for advanced BTC At least one measurable untreated lesion (per RECIST v1.1) Adequate biliary drainage with no evidence of ongoing infection Eastern Cooperative Oncology Group Performance Status of 0 or 1 Life expectancy of > 3 months Adequate hematologic and end-organ function For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating eggs For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm Exclusion Criteria: Recurrent disease <=6 months after curative surgery or <= 6 months after the completion of adjuvant therapy Prior local regional therapy such as radioembolization Combined or mixed hepatocellular/cholangiocarcinoma Clinically significant hepatic encephalopathy within the 12 months prior to Day 1 of Cycle 1 National Cancer Institute Common Terminoogy Criteria for Adverse Events Grade >= 2 peripheral neuropathy Prior bleeding event due to untreated or incompletely treated esophageal and/or gastric varices within 6 months prior to Day 1 of Cycle 1 Pregnant or breastfeeding, or intending to become pregnant during the study or within 5 months after the final dose of atezolizumab or within 6 months after the final dose of bevacizumab, cisplatin or gemcitabine Active or history of autoimmune disease or immune deficiency History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan History of malignancy other than BTC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death Symptomatic, untreated, or actively progressing CNS metastases For patients with lung metastases, if one of the following criteria applies: Large, centrally located pulmonary metastases; Clear tumor infiltration into the thoracic great vessels seen on imaging; Clear cavitation of pulmonary lesions seen on imaging Active tuberculosis Co-infection with HBV and HCV Treatment with systemic immunostimulatory agents or immunosuppressive medication Inadequately controlled arterial hypertension History of hypertensive crisis or hypertensive encephalopathy Significant vascular disease Evidence of bleeding diathesis or significant coagulopathy Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture Chronic daily treatment with a non-steroidal anti-inflammatory drug (NSAID) Preexisting renal impairment, myelosuppression, or hearing impairment

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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Atezo+Bev+CisGem, followed by Atezo+Bev<br>Participants will receive atezolizumab intravenously on Day 1 of each 21-day cycle until unacceptable toxicity or loss of clinical benefit as determined by the investigator after an integrated assessment of radiographic and biochemical data, and clinical status. Participants will receive bevacizumab intravenously on Day 1 of each 21-day cycle. Participants will receive cisplatin intravenously followed by gemcitabine on Days 1 and 8 of each 21-day cycle for Cycles 1-8. | Drug: Atezolizumab<br>* Atezolizumab will be administered intravenously at a fixed dose of 1200 mg on Day 1 of each 21-day cycle.<br>* Other names: Tecentriq;Drug: Bevacizumab<br>* Bevacizumab will be administered at a dose of 15 mg/kg intravenously on Day 1 of each 21-day cycle after atezolizumab.<br>* Other names: Avastin;Drug: Cisplatin<br>* Cisplatin will be administered intravenously at a dose of 25 mg/m^2 on Days 1 and 8 of each 21-day cycle for Cycles 1-8.<br>Drug: Gemcitabine<br>* Gemcitabine will be administered intravenously at a dose of 1000 mg/m^2 on Days 1 and 8 of each 21-day cycle for Cycles 1-8.<br>|
| Active Comparator: Arm B: Atezo+PBO+CisGem, followed by Atezo+PBO<br>Participants will receive atezolizumab intravenously on Day 1 of each 21-day cycle until unacceptable toxicity or loss of clinical benefit as determined by the investigator after an integrated assessment of radiographic and biochemical data, and clinical status. Participants will receive placebo matching bevacizumab intravenously on Day 1 of each 21-day cycle. Participants will receive cisplatin intravenously followed by gemcitabine on Days 1 and 8 of each 21-day cycle for Cycles 1-8. | Drug: Atezolizumab<br>* Atezolizumab will be administered intravenously at a fixed dose of 1200 mg on Day 1 of each 21-day cycle.<br>* Other names: Tecentriq;Other: Placebo<br>* Placebo matching bevacizumab will be administered intravenously on Day 1 of each 21-day cycle after atezolizumab.<br>Drug: Cisplatin<br>* Cisplatin will be administered intravenously at a dose of 25 mg/m^2 on Days 1 and 8 of each 21-day cycle for Cycles 1-8.<br>Drug: Gemcitabine<br>* Gemcitabine will be administered intravenously at a dose of 1000 mg/m^2 on Days 1 and 8 of each 21-day cycle for Cycles 1-8.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS is defined as the time from randomization to the first occurrence of disease progression as determined by the investigator according to RECIST v1.1 or death from any cause (whichever occurs first) | Randomization to the first occurrence of disease progression as determined by the investigator according to RECIST v1.1 or death from any cause (whichever occurs first)(up to approximately 14 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time from randomization to death from any cause. | Randomization to death from any cause (up to approximately 3-5 years) | 
| Confirmed Objective Response Rate (ORR) | Confirmed ORR is defined as the proportion of participants with Complete Response (CR) or Partial Response (PR) on two consecutive occasions >=4 weeks apart, as determined by the investigator according to RECIST v1.1. | Randomization up to approximately 14 months | 
| Duration of Response (DOR) | DOR is defined as the time from the first occurrence of a confirmed objective response to disease progression as determined by the investigator according to RECIST v1.1 or death from any cause (whichever occurs first). | First occurrence of a confirmed objective response to disease progression as determined by the investigator according to RECIST v1.1 or death from any cause (whichever occurs first)(up to approximately 14 months) | 
| Disease Control Rate (DCR) | DCR is defined as the proportion of participants with a CR or a PR on two consecutive occasions >= 4 weeks apart or SD with a minimum duration of 9weeks, as determined by the investigator according to RECIST v1.1 | Randomization up to approximately 14 months | 
| Time to Confirmed Deterioration (TTCD) | TTCD in patient-reported physical functioning, role functioning, and quality of life, as measured by the respective scales of the EORTC QLQ-C30 and/or EORTC IL77, and defined as the time from randomization to the first clinically meaningful deterioration that is either maintained for two consecutive assessments or followed by death from any cause within 3 weeks. | Randomization to the first clinically meaningful deterioration (up to approximately 14 months) | 
| Percentage of Participants With Adverse Events |  | Randomization up to approximately 3-5 years | 
| Serum Concentration of Atezolizumab | Serum concentration of atezolizumab at specified timepoints. | Pre-Dose on Day 1 of Cycles 1, 2, 3, 4, 8, 12, and 16, and Post Dose Day 1 of Cycle 1 (cycle length=21 days) | 
| Prevalence of ADAs to Atezolizumab |  | Baseline | 
| Incidence of ADAs to Atezolizumab |  | At pre-defined intervals from administration of study drug up to approximately 14 months |