A Study of the Safety and Efficacy of Atezolizumab Admini... | NCT02715531

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Arm A (Hepatocellular Carcinoma [HCC], All subtypes)	Experimental	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.	Drug: Atezolizumab Drug: Bevacizumab
Arm B (Gastric Cancer)	Experimental	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.	Drug: 5-FU Drug: Atezolizumab Drug: Bevacizumab Drug: Leucovorin Drug: Oxaliplatin Drug: Capecitabine
Arm C (Metastatic Pancreatic Cancer)	Experimental	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.

Interventions

Name	Type	Description	Arm Group Labels	Other Names
5-FU	Drug	5-FU (400 mg/m^2) will be administered as an IV bolus, followed by 2400 mg/m^2 by continuous IV infusion over 46 (± 1) hours, q2w.	Arm B (Gastric Cancer)

Measure	Description	Time Frame
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)		From screening to up to 90 days after the last dose of study drug (up to approximately 55 months)
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)		From screening to end of study (approximately 55 months)
Progression-Free Survival (PFS) as determined by the Independent Review Facility (IRF) according to RECIST v 1.1 (Arm F)		From randomization to the first occurrence of disease progression or death from any cause (whichever occurs first)

Measure	Description	Time Frame
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)

Eligibility Module

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)
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

Facility	Status	City	State	ZIP	Country	Contacts
Stanford Cancer Institute; Hematology		Palo Alto	California	94305	United States
University of Colorado Hospital

ID	Term
D005472	Fluorouracil
C000594389	atezolizumab
D000068258	Bevacizumab
D000093542	Gemcitabine
D002955	Leucovorin
C520255	130-nm albumin-bound paclitaxel
D000077150	Oxaliplatin
D000069287	Capecitabine
D002945	Cisplatin

ID	Term
D014498	Uracil
D011744	Pyrimidinones
D011743	Pyrimidines
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds
D061067	Antibodies, Monoclonal, Humanized
D000911	Antibodies, Monoclonal
D000906	Antibodies
D007136	Immunoglobulins
D007162	Immunoproteins
D001798	Blood Proteins
D011506	Proteins
D000602	Amino Acids, Peptides, and Proteins
D012712	Serum Globulins
D005916	Globulins
D003841	Deoxycytidine
D003562	Cytidine
D011741	Pyrimidine Nucleosides
D005575	Formyltetrahydrofolates
D013763	Tetrahydrofolates
D005492	Folic Acid
D011622	Pterins
D011621	Pteridines
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring
D003067	Coenzymes
D045762	Enzymes and Coenzymes
D056831	Coordination Complexes
D009930	Organic Chemicals
D003853	Deoxyribonucleosides
D009705	Nucleosides
D009706	Nucleic Acids, Nucleotides, and Nucleosides
D017606	Chlorine Compounds
D007287	Inorganic Chemicals
D017672	Nitrogen Compounds
D017671	Platinum Compounds