A Study of the Safety and Efficacy of Atezolizumab Administered in Combination With Bevacizumab and/or Other Treatments in Participants With Solid Tumors

Roche

Status and phase: Completed; Phase 1

Conditions: Solid Tumor

Treatments: Drug: Cisplatin; Drug: Capecitabine; Drug: Gemcitabine; Drug: Oxaliplatin; Drug: Leucovorin; Drug: Bevacizumab; Drug: Atezolizumab; Drug: Nab-Paclitaxel; Drug: 5-FU

Study type: Interventional

Funder types: Industry

Identifiers

NCT02715531

GO30140

Details and patient eligibility

About

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.

Enrollment: 243 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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)
• Willing to undergo fresh liver biopsy if provided archival tissue was taken greater than (>) 6 months from Cycle 1 Day 1
• Child-Pugh Score of up to B7
• Serum bilirubin </= 3 times upper limit of normal (x ULN)
• International normalized ratio (INR) and activated partial thromboplastin time (aPTT) </= 2 x ULN
• Albumin >2.8 grams per deciliter (g/dL)
• Documented virology status of hepatitis, as confirmed by screening hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), and/or anti-hepatitis C virus (anti-HCV)
• Antiviral therapy per local standard-of-care if active hepatitis B virus (HBV)

Inclusion Criteria Specific to Arm A (Patients must also meet all of the following specific inclusion criteria to be eligible for enrollment in Arm A:)

• Child-Pugh score of up to B7
• Willing to undergo biopsy if archival tissue is not available or if archival tissue was taken >6 months from Cycle 1, Day 1
• Anti-viral therapy per local standard-of-care if active hepatitis B virus (HBV).

Inclusion Criteria Specific to Arm F (Patients must also meet all of the following specific inclusion criteria to be eligible for enrollment in Arm F:)

• LIfe expectancy >=3 months, as determined by the investigator
• Child-Pugh score A
• Platelet count ≥ 75x109/L (75,000/uL) without transfusion
• Availability at the site of tumor specimens in paraffin blocks (preferred) or 16 unstained slides, with an associated pathology report, prior to study entry
• Anti-viral therapy per local standard-of-care if active hepatitis B virus (HBV).

Inclusion Criteria Specific to Gastric Cancer (Arm B) (Patients must also meet all of the following specific inclusion criteria to be eligible for enrollment in Arm B:)

• Histologically or cytologically confirmed locally advanced or metastatic adenocarcinoma of the stomach or GEJ in participants who have not received prior systemic therapy for metastatic disease
• Absence of HER2 expression documented as in situ hybridization (ISH) negative on previously collected and assessed tumor tissue upon initial diagnosis of disease

Inclusion criteria specific to metastatic pancreatic cancer (Arm C) (Patients must also meet all of the following specific inclusion criteria to be eligible for enrollment in Arm C:)

• Histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas
• No previous radiotherapy, surgery, chemotherapy, or investigational therapy for the treatment of metastatic disease

Inclusion Criteria Specific to mEC (Arm E) (Patients must also meet all of the following specific inclusion criteria to be eligible for enrollment in Arm E:)

• Histologically or cytologically confirmed locally mEC or metastatic adenocarcinoma of the GEJ Siewert Classification Type I in participants who have not received prior systemic therapy for primary and metastatic disease or chemoradiation therapy for primary disease
• Absence of HER2 expression documented as ISH-negative on previously collected and assessed tumor tissue upon initial diagnosis of disease
• Willing to undergo biopsy if archival tissue is not available or if archival tissue was taken >6 months from Cycle 1 Day 1

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
• Severe infections within 4 weeks prior to Day 1
• Signs or symptoms of significant infection within 2 weeks prior to Day 1
• Received oral or IV antibiotics within 2 weeks prior to Cycle 1 Day 1
• Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac disease (Class II or greater), myocardial infarction within 3 months prior to Day 1, unstable arrhythmias, or unstable angina
• History of stroke, reversible ischemic neurological defect or transient ischemic attack within 6 months prior to Day 1
• Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or anticipation that such a live attenuated vaccine will be required during the study
• Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's and/or Medical Monitor's judgment, precludes the participants safe participation in and completion of the study
• Malignancies other than pancreatic carcinoma within 2 years prior to study start, with the exception of those with a negligible risk of metastasis or death treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent)

Exclusion Criteria Related to Medications

• Prior treatment with anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4), anti-programmed death-1 (anti-PD-1), or anti-programmed death ligand-1 (anti-PD-L1) therapeutic antibody
• Treatment with systemic immunostimulatory agents within 6 weeks or five half-lives of the drug, whichever is longer, prior to screening
• Treatment with systemic corticosteroids or other immunosuppressive medications within 2 weeks prior to Cycle 1, Day 1
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
• Participants with prior allogeneic bone marrow transplantation or prior solid organ transplantation
• Known allergies to oxaliplatin (or other platinum agents), leucovorin, 5-FU, nab-paclitaxel (or other taxanes) or gemcitabine

Exclusion Criteria Specific to Bevacizumab-Containign Arms (Arms A, B, and F) (Patients who meet any of the following criteria will be excluded from enrollment into bevacizumab-containing Arms A, B, and F:)

• Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 3 days prior to the first dose of bevacizumab or vanucizumab
• History of abdominal or tracheoesophageal fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess within 6 months prior to Day 1
• History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction within 6 months prior to Day 1 of Cycle 1
• Clinical signs or symptoms of GI obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding
• Evidence of abdominal free air that is not explained by paracentesis or recent surgical procedure
• Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture
• Proteinuria, as demonstrated by urine dipstick or > 1.0 g of protein in a 24-hour urine collection
• Metastatic disease that involves major airways or blood vessels, or centrally located mediastinal tumor masses of large volume. HCC participants (Arm A and F) with vascular invasion of the portal or hepatic veins may be enrolled
• History of intra-abdominal inflammatory process within 6 months prior to Day 1 of Cycle 1
• Radiotherapy within 28 days and abdominal/pelvic radiotherapy within 60 days prior to Day 1 of Cycle 1
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 of Cycle 1
• Chronic daily treatment with a nonsteroidal anti-inflammatory drug (NSAID)

Exclusions specific to Arms A and F (HCC) (Patients who meet any of the following specific exclusion criteria will be excluded from enrollment in Arms A and F:)

• Participants with untreated or incompletely treated varices with bleeding or high-risk for bleeding
• Treatment with any HCV anti-viral therapy within 4 weeks prior to Cycle 1 Day 1
• Moderate or severe ascites
• Hepatic encephalopathy

Exclusion Criteria Specific to Arm B (Gastric Cancer) (Patients who meet any of the following specific exclusion criteria will be excluded from enrollment in Arm B:)

• HER2 expression as defined by ISH positive and/or 3+ by immunohistochemistry (IHC)
• Prior treatment with an oxaliplatin-containing regimen
• Previous antiangiogenic therapy
• Ongoing treatment for epilepsy

Exclusion Criteria Specific to Arm C (Metastatic Pancreatic Cancer) (Patients who meet any of the following specific exclusion criteria will be excluded from enrollment in Arm C:)

• Patients with only locally advanced disease
• Presence of islet cell neoplasms

Exclusions Specific to Arm E (Metastatic Esophageal Cancer) (Patients who meet any of the following specific exclusion criteria will be excluded from enrollment in Arm E:)

• HER2 expression as defined by ISH positive and/or 3+ by immunohistochemistry
• Prior chemotherapy treatment, including radio-sensitization in pre- and post-operative settings

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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243 participants in 5 patient groups

Arm A (Hepatocellular Carcinoma [HCC], All subtypes)

Experimental group

Description:

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.

Treatment:

Drug: Bevacizumab

Drug: Atezolizumab

Arm B (Gastric Cancer)

Experimental group

Description:

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.

Treatment:

Drug: Oxaliplatin

Drug: Leucovorin

Drug: 5-FU

Drug: Bevacizumab

Drug: Atezolizumab

Drug: Capecitabine

Arm C (Metastatic Pancreatic Cancer)

Experimental group

Description:

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.

Treatment:

Drug: Nab-Paclitaxel

Drug: Atezolizumab

Drug: Gemcitabine

Arm E (Randomized Metastatic Esophageal Cancer)

Experimental group

Description:

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.

Treatment:

Drug: Oxaliplatin

Drug: Leucovorin

Drug: 5-FU

Drug: Atezolizumab

Drug: Cisplatin

Arm F (Randomized HCC)

Experimental group

Description:

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.

Treatment:

Drug: Bevacizumab

Drug: Atezolizumab