An Open-Label, Multicenter Phase Ib Study of The Safety and Efficacy of Atezolizumab (Anti-PD-L1 Antibody) Administered in Combination With Bevacizumab and/or Other Treatments in Patients With Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- Atezolizumab
- Conditions
- Solid Tumor
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 243
- Locations
- 30
- Primary Endpoint
- Percentage of Participants with Objective Response as Determined By The Independent Review Facility (IRF) According To Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (Arm A)
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
This study will evaluate the safety, efficacy, and pharmacokinetics of atezolizumab in combination with bevacizumab, bevacizumab + oxaliplatin, leucovorin and 5-fluorouracil (5-FU) (FOLFOX), vanucizumab, nab-paclitaxel + gemcitabine, FOLFOX, or 5-FU + cisplatin, in participants with solid tumors.
Investigators
Eligibility Criteria
Inclusion Criteria
- •General Inclusion criteria
- •Measurable disease per RECIST v1.1
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Adequate hematologic and end organ function
- •Resolution of any acute, clinically significant treatment-related toxicity from prior therapy to Grade less than or equal to (\</=) 1 prior to study entry, with the exception of alopecia
- •Ready to use reliable contraceptive procedures
- •Inclusion Criteria Specific to HCC (Arm A and Arm F):
- •Participants with advanced or metastatic and/or unresectable HCC
- •The participant has disease that is not amenable to a curative approach
- •No prior line of systemic therapy (includes participants who are sorafenib-naïve)
Exclusion Criteria
- •General Exclusion Criteria
- •Uncontrolled pleural effusion, pericardial effusion, or ascites
- •Uncontrolled tumor-related pain
- •Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy
- •Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, fatty liver, and inherited liver disease (exception for participants in Arm A and Arm F)
- •Known primary central nervous system (CNS) malignancy or untreated or active CNS metastases
- •Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or other recombinant human antibodies
- •Positive test for Human Immunodeficiency Virus (HIV)
- •Active hepatitis B (chronic or acute), or hepatitis C (exception for participants in Arm A and Arm F)
- •Active tuberculosis
Arms & Interventions
Arm A (Hepatocellular Carcinoma [HCC], All subtypes)
Participants with advanced or metastatic and/or unresectable HCC who have received no prior treatment are non-randomized and will receive atezolizumab and bevacizumab, every 3 weeks (q3w), each cycle of 21 days, as long as participants are experiencing clinical benefit in the opinion of the investigator.
Intervention: Atezolizumab
Arm A (Hepatocellular Carcinoma [HCC], All subtypes)
Participants with advanced or metastatic and/or unresectable HCC who have received no prior treatment are non-randomized and will receive atezolizumab and bevacizumab, every 3 weeks (q3w), each cycle of 21 days, as long as participants are experiencing clinical benefit in the opinion of the investigator.
Intervention: Bevacizumab
Arm B (Gastric Cancer)
Participants with previously untreated human epidermal growth factor receptor 2 (HER2)-negative adenocarcinoma of the stomach or gastroesophageal junction (GEJ) are non-randomized and will receive atezolizumab, bevacizumab, and FOLFOX (oxaliplatin, leucovorin, and 5-fluorouracil \[FU\]), every 2 weeks (q2w), each cycle of 28 days, as long as participants are experiencing clinical benefit in the opinion of the investigator. Oxaliplatin will be administered for up to 8 cycles. After 6 months, at discretion of investigator, capecitabine may be administered as maintenance therapy without oxaliplatin instead of infusional 5-FU and leucovorin, and biologic therapy may be given every 3 weeks (q3w). In the event that a patient experiences unacceptable toxicity after replacement of infusional 5-FU and leucovorin with capecitabine, the patient may be allowed to switch back to 5-FU and leucovorin following investigator discussion with the Medical Monitor.
Intervention: 5-FU
Arm B (Gastric Cancer)
Participants with previously untreated human epidermal growth factor receptor 2 (HER2)-negative adenocarcinoma of the stomach or gastroesophageal junction (GEJ) are non-randomized and will receive atezolizumab, bevacizumab, and FOLFOX (oxaliplatin, leucovorin, and 5-fluorouracil \[FU\]), every 2 weeks (q2w), each cycle of 28 days, as long as participants are experiencing clinical benefit in the opinion of the investigator. Oxaliplatin will be administered for up to 8 cycles. After 6 months, at discretion of investigator, capecitabine may be administered as maintenance therapy without oxaliplatin instead of infusional 5-FU and leucovorin, and biologic therapy may be given every 3 weeks (q3w). In the event that a patient experiences unacceptable toxicity after replacement of infusional 5-FU and leucovorin with capecitabine, the patient may be allowed to switch back to 5-FU and leucovorin following investigator discussion with the Medical Monitor.
Intervention: Atezolizumab
Arm B (Gastric Cancer)
Participants with previously untreated human epidermal growth factor receptor 2 (HER2)-negative adenocarcinoma of the stomach or gastroesophageal junction (GEJ) are non-randomized and will receive atezolizumab, bevacizumab, and FOLFOX (oxaliplatin, leucovorin, and 5-fluorouracil \[FU\]), every 2 weeks (q2w), each cycle of 28 days, as long as participants are experiencing clinical benefit in the opinion of the investigator. Oxaliplatin will be administered for up to 8 cycles. After 6 months, at discretion of investigator, capecitabine may be administered as maintenance therapy without oxaliplatin instead of infusional 5-FU and leucovorin, and biologic therapy may be given every 3 weeks (q3w). In the event that a patient experiences unacceptable toxicity after replacement of infusional 5-FU and leucovorin with capecitabine, the patient may be allowed to switch back to 5-FU and leucovorin following investigator discussion with the Medical Monitor.
Intervention: Bevacizumab
Arm B (Gastric Cancer)
Participants with previously untreated human epidermal growth factor receptor 2 (HER2)-negative adenocarcinoma of the stomach or gastroesophageal junction (GEJ) are non-randomized and will receive atezolizumab, bevacizumab, and FOLFOX (oxaliplatin, leucovorin, and 5-fluorouracil \[FU\]), every 2 weeks (q2w), each cycle of 28 days, as long as participants are experiencing clinical benefit in the opinion of the investigator. Oxaliplatin will be administered for up to 8 cycles. After 6 months, at discretion of investigator, capecitabine may be administered as maintenance therapy without oxaliplatin instead of infusional 5-FU and leucovorin, and biologic therapy may be given every 3 weeks (q3w). In the event that a patient experiences unacceptable toxicity after replacement of infusional 5-FU and leucovorin with capecitabine, the patient may be allowed to switch back to 5-FU and leucovorin following investigator discussion with the Medical Monitor.
Intervention: Leucovorin
Arm B (Gastric Cancer)
Participants with previously untreated human epidermal growth factor receptor 2 (HER2)-negative adenocarcinoma of the stomach or gastroesophageal junction (GEJ) are non-randomized and will receive atezolizumab, bevacizumab, and FOLFOX (oxaliplatin, leucovorin, and 5-fluorouracil \[FU\]), every 2 weeks (q2w), each cycle of 28 days, as long as participants are experiencing clinical benefit in the opinion of the investigator. Oxaliplatin will be administered for up to 8 cycles. After 6 months, at discretion of investigator, capecitabine may be administered as maintenance therapy without oxaliplatin instead of infusional 5-FU and leucovorin, and biologic therapy may be given every 3 weeks (q3w). In the event that a patient experiences unacceptable toxicity after replacement of infusional 5-FU and leucovorin with capecitabine, the patient may be allowed to switch back to 5-FU and leucovorin following investigator discussion with the Medical Monitor.
Intervention: Oxaliplatin
Arm B (Gastric Cancer)
Participants with previously untreated human epidermal growth factor receptor 2 (HER2)-negative adenocarcinoma of the stomach or gastroesophageal junction (GEJ) are non-randomized and will receive atezolizumab, bevacizumab, and FOLFOX (oxaliplatin, leucovorin, and 5-fluorouracil \[FU\]), every 2 weeks (q2w), each cycle of 28 days, as long as participants are experiencing clinical benefit in the opinion of the investigator. Oxaliplatin will be administered for up to 8 cycles. After 6 months, at discretion of investigator, capecitabine may be administered as maintenance therapy without oxaliplatin instead of infusional 5-FU and leucovorin, and biologic therapy may be given every 3 weeks (q3w). In the event that a patient experiences unacceptable toxicity after replacement of infusional 5-FU and leucovorin with capecitabine, the patient may be allowed to switch back to 5-FU and leucovorin following investigator discussion with the Medical Monitor.
Intervention: Capecitabine
Arm C (Metastatic Pancreatic Cancer)
Participants with previously untreated metastatic pancreatic cancer are non-randomized and will receive atezolizumab q2w starting on Day 1, Cycle 1 (each cycle of 28 days). Administration of nab-paclitaxel followed by gemcitabine will occur on Days 1, 8, and 15 of each cycle (3-weeks-on/1-week-off schedule). Treatment consisting of atezolizumab with gemcitabine and nab-paclitaxel may be continued as long as participants are experiencing clinical benefit in the opinion of the investigator.
Intervention: Atezolizumab
Arm C (Metastatic Pancreatic Cancer)
Participants with previously untreated metastatic pancreatic cancer are non-randomized and will receive atezolizumab q2w starting on Day 1, Cycle 1 (each cycle of 28 days). Administration of nab-paclitaxel followed by gemcitabine will occur on Days 1, 8, and 15 of each cycle (3-weeks-on/1-week-off schedule). Treatment consisting of atezolizumab with gemcitabine and nab-paclitaxel may be continued as long as participants are experiencing clinical benefit in the opinion of the investigator.
Intervention: Gemcitabine
Arm C (Metastatic Pancreatic Cancer)
Participants with previously untreated metastatic pancreatic cancer are non-randomized and will receive atezolizumab q2w starting on Day 1, Cycle 1 (each cycle of 28 days). Administration of nab-paclitaxel followed by gemcitabine will occur on Days 1, 8, and 15 of each cycle (3-weeks-on/1-week-off schedule). Treatment consisting of atezolizumab with gemcitabine and nab-paclitaxel may be continued as long as participants are experiencing clinical benefit in the opinion of the investigator.
Intervention: Nab-Paclitaxel
Arm E (Randomized Metastatic Esophageal Cancer)
Participants with squamous metastatic esophageal cancer (mEC) will be randomized (1:1) into Group E1 and Group E2. All participants with metastatic adenocarcinoma of esophageal carcinoma or GEJ Siewert Classification Type I will be enrolled into Group E3. In Groups E1 and E3, participants will receive atezolizumab and FOLFOX, q2w, each cycle of 28 days, as long as participants are experiencing clinical benefit in opinion of the investigator. Oxaliplatin will be administered for up to 8 cycles. In Group E2, participants will receive atezolizumab followed by cisplatin and 5-FU q3w. Cisplatin will be administered for up to 6 cycles. Treatment with atezolizumab in combination with 5-FU may be continued as long as participants experience clinical benefit in opinion of the investigator.
Intervention: 5-FU
Arm E (Randomized Metastatic Esophageal Cancer)
Participants with squamous metastatic esophageal cancer (mEC) will be randomized (1:1) into Group E1 and Group E2. All participants with metastatic adenocarcinoma of esophageal carcinoma or GEJ Siewert Classification Type I will be enrolled into Group E3. In Groups E1 and E3, participants will receive atezolizumab and FOLFOX, q2w, each cycle of 28 days, as long as participants are experiencing clinical benefit in opinion of the investigator. Oxaliplatin will be administered for up to 8 cycles. In Group E2, participants will receive atezolizumab followed by cisplatin and 5-FU q3w. Cisplatin will be administered for up to 6 cycles. Treatment with atezolizumab in combination with 5-FU may be continued as long as participants experience clinical benefit in opinion of the investigator.
Intervention: Atezolizumab
Arm E (Randomized Metastatic Esophageal Cancer)
Participants with squamous metastatic esophageal cancer (mEC) will be randomized (1:1) into Group E1 and Group E2. All participants with metastatic adenocarcinoma of esophageal carcinoma or GEJ Siewert Classification Type I will be enrolled into Group E3. In Groups E1 and E3, participants will receive atezolizumab and FOLFOX, q2w, each cycle of 28 days, as long as participants are experiencing clinical benefit in opinion of the investigator. Oxaliplatin will be administered for up to 8 cycles. In Group E2, participants will receive atezolizumab followed by cisplatin and 5-FU q3w. Cisplatin will be administered for up to 6 cycles. Treatment with atezolizumab in combination with 5-FU may be continued as long as participants experience clinical benefit in opinion of the investigator.
Intervention: Leucovorin
Arm E (Randomized Metastatic Esophageal Cancer)
Participants with squamous metastatic esophageal cancer (mEC) will be randomized (1:1) into Group E1 and Group E2. All participants with metastatic adenocarcinoma of esophageal carcinoma or GEJ Siewert Classification Type I will be enrolled into Group E3. In Groups E1 and E3, participants will receive atezolizumab and FOLFOX, q2w, each cycle of 28 days, as long as participants are experiencing clinical benefit in opinion of the investigator. Oxaliplatin will be administered for up to 8 cycles. In Group E2, participants will receive atezolizumab followed by cisplatin and 5-FU q3w. Cisplatin will be administered for up to 6 cycles. Treatment with atezolizumab in combination with 5-FU may be continued as long as participants experience clinical benefit in opinion of the investigator.
Intervention: Oxaliplatin
Arm E (Randomized Metastatic Esophageal Cancer)
Participants with squamous metastatic esophageal cancer (mEC) will be randomized (1:1) into Group E1 and Group E2. All participants with metastatic adenocarcinoma of esophageal carcinoma or GEJ Siewert Classification Type I will be enrolled into Group E3. In Groups E1 and E3, participants will receive atezolizumab and FOLFOX, q2w, each cycle of 28 days, as long as participants are experiencing clinical benefit in opinion of the investigator. Oxaliplatin will be administered for up to 8 cycles. In Group E2, participants will receive atezolizumab followed by cisplatin and 5-FU q3w. Cisplatin will be administered for up to 6 cycles. Treatment with atezolizumab in combination with 5-FU may be continued as long as participants experience clinical benefit in opinion of the investigator.
Intervention: Cisplatin
Arm F (Randomized HCC)
Participants with advanced or metastatic and/or unresectable HCC who have received no prior systemic treatment will be randomized (1:1) into Group F1 and Group F2. Participants will receive atezolizumab alone (Group F2) or combined with bevacizumab (Group F1) on a q3w schedule, with dosing on Day 1 of each 21 day Cycle. Treatment with atezolizumab with or without bevacizumab may be continued as long as participants are experiencing clinical benefit in the opinion of the investigator. Participants who are randomly assigned to Group F2 (atezolizumab monotherapy) and experience investigator-assessed unequivocal radiographic progression as per RECIST v1.1 will also be given the option to cross over to atezolizumab and bevacizumab combination therapy, provided they meet the criteria for crossover and Medical Monitor approval is obtained.
Intervention: Atezolizumab
Arm F (Randomized HCC)
Participants with advanced or metastatic and/or unresectable HCC who have received no prior systemic treatment will be randomized (1:1) into Group F1 and Group F2. Participants will receive atezolizumab alone (Group F2) or combined with bevacizumab (Group F1) on a q3w schedule, with dosing on Day 1 of each 21 day Cycle. Treatment with atezolizumab with or without bevacizumab may be continued as long as participants are experiencing clinical benefit in the opinion of the investigator. Participants who are randomly assigned to Group F2 (atezolizumab monotherapy) and experience investigator-assessed unequivocal radiographic progression as per RECIST v1.1 will also be given the option to cross over to atezolizumab and bevacizumab combination therapy, provided they meet the criteria for crossover and Medical Monitor approval is obtained.
Intervention: Bevacizumab
Outcomes
Primary Outcomes
Percentage of Participants with Objective Response as Determined By The Independent Review Facility (IRF) According To Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (Arm A)
Time Frame: From screening to end of study (approximately 55 months)
Number of Participants With At Least One Adverse Event, with Severity Determined According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)
Time Frame: From screening to up to 90 days after the last dose of study drug (up to approximately 55 months)
Progression-Free Survival (PFS) as determined by the Independent Review Facility (IRF) according to RECIST v 1.1 (Arm F)
Time Frame: From randomization to the first occurrence of disease progression or death from any cause (whichever occurs first)
Secondary Outcomes
- Percentage of Participants with Objective Response as Determined by the IRF according to RECIST v 1.1 (Arm F)(Baseline, every 8 weeks (± 1 week) for the first 12 months following Cycle 1 Day 1, and every 12 weeks (± 1 week) thereafter up to study completion (Cycle length=21-28 days; up to approximately 55 months))
- Percentage of Participants with Objective Response as Determined by the IRF according to HCC-Specific Modified RECIST (mRECIST) (Arm A and Arm F)(Baseline, every 8 weeks (± 1 week) for the first 12 months following Cycle 1 Day 1, and every 12 weeks (± 1 week) thereafter up to study completion (Cycle length=21-28 days; up to approximately 55 months))
- PFS Duration as Determined by The IRF According to RECIST v1.1 (Arm A)(From the first dose of study treatment to the first occurrence of disease progression or death from any cause, whichever comes first (up to approximately 55 months))
- PFS Duration as Determined by the IRF Acording to HCC-Specific mRECIST (Arm A and Arm F)(From the first dose of study treatment (Arm A) or randomization (Arm F) to the first occurrence of disease progression or death from any cause, whichever comes first (up to approximately 55 months))
- TTRP as Determined by The Investigator According to RECIST (Arm A and Arm F)(From the first dose of study treatment (Arm A) or randomization (Arm F) to the first occurrence of radiographic disease progression (up to approximately 55 months))
- Plasma Concentration of 5-FU (Arm B and Arm E)(Predose (0 h), immediately following bolus administration and 2 hours post-bolus dose on Day 1 of Cycles 1 and 3 (Cycle length=21-28 days; up to approximately 3 months))
- Plasma Concentration of Cisplatin (Group E2)(Predose (0 h) and 5-10 minutes before the end of infusion (infusion length=120 min) on Day 1 of Cycles 1 and 3 (Cycle length=21 days; up to approximately 3 months))
- Plasma Concentration of nab-Paclitaxel (Arm C)(Predose (0 h), 5-10 minutes before the end of infusion and 1 hour after the end of the infusion (infusion length=35 min) on Day 1 of Cycles 1 and 3 (Cycle length=28 days; up to approximately 3 months))
- Duration of Objective Response as Determined by the IRF according to RECIST v1.1 (Arm A and Arm F)(From the first occurrence of a documented objective response to disease progression or death from any cause, whichever comes first (up to approximately 55 months))
- Duration of Objective Response as Determined by the IRF According to HCC-Specific mRECIST (Arm A and Arm F)(From the first occurrence of a documented objective response to disease progression or death from any cause, whichever comes first (up to approximately 55 months))
- PFS Duration as Determined by the Investigator According To RECIST v 1.1 (Arm A and Arm F)(From the first dose of study treatment (Arm A) or randomization (Arm F) to the first occurrence of disease progression or death from any cause, whichever comes first (up to approximately 55 months))
- TTRP as Determined by The IRF According to HCC-Specific mRECIST (Arm A and Arm F)(From the first dose of study treatment (Arm A) or randomization (Arm F) to the first occurrence of radiographic disease progression (up to approximately 55 months))
- Plasma Concentration of Oxaliplatin (Arm B and Group E1)(Predose (0 h) and 5-10 min before the end of infusion (infusion length=120 min) on Day 1 of Cycles 1 and 3 (Cycle length=21-28 days; up to approximately 3 months))
- Duration of Objective Response as Determined by The Investigator According to RECIST v 1.1 (Arm A and Arm F)(From the first occurrence of a documented objective response to disease progression or death from any cause, whichever comes first (up to approximately 55 months))
- Percentage of Participants With Anti-Therapeutic Antibodies (ATAs)(Predose (0 h) on Day 1 of Cycles 1, 2, 3, 4, 8 and every 8 cycles until treatment discontinuation (up to 55 months); at 120 days after last dose (Cycle length =21-28 days; up to 55 months))
- Serum Concentrations of Atezolizumab (All Arms)(Predose (0 hour[h]), 30 minutes(min) postdose on Day 1 of Cycles(Cy) 1 and 3; Predose(0h) on Day 1 of Cy 2,4,8 and every 8 Cy until treatment discontinuation (up to 55 months); 120 days after last dose (Cy length=21-28 days; up to 55 months))
- Serum Concentrations of Bevacizumab (Arm A, Arm B and Group F1)(Predose (0 h) and 30 min postdose (infusion length=30-90 min) on Day 1 of Cy 1 and 3; at treatment discontinuation (up to 55 months); at 120 days after last dose (Cy length=21-28 days; up to 55 months))
- Plasma Concentration of Gemcitabine (Arm C)(Predose (0 h), 5-10 minutes before the end of infusion and 1 hour after the end of the infusion (infusion length=35 min) on Day 1 of Cycles 1 and 3 (Cycle length=28 days) (up to approximately 3 months))
- Percentage of Participants with Objective Response as Determined By The Investigator According To RECIST v 1.1 (Arm A and Arm F)(Baseline, every 8 weeks (± 1 week) for the first 12 months following Cycle 1 Day 1, and every 12 weeks (± 1 week) thereafter up to study completion (Cycle length=21-28 days; up to approximately 55 months))
- Overall Survival (OS) Duration (Arm A and Arm F)(Baseline up to study completion or death, whichever occurs first (up to approximately 55 months))
- Time to Radiological Progression (TTRP) as Determined by the IRF According to RECIST v1.1 (Arm A and Arm F)(From the first dose of study treatment (Arm A) or randomization (Arm F) to the first occurrence of radiographic disease progression (up to approximately 55 months))