Atezolizumab and Bevacizumab in Treating Patients With Rare Solid Tumors

Inclusion Criteria:

• Signed informed consent form

• Ability to comply with the study protocol, in the investigator's judgment

• Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1; previously irradiated lesions can be considered asmeasurable disease only if progressive disease has been unequivocally documented atthat site since radiation; the pleural mesothelioma cohort will require measurabledisease according to modified RECIST

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L without granulocytecolony-stimulating factor support, obtained within 14 days prior to initiation ofstudy treatment

• Lymphocyte count >= 0.5 x 10^9/L, obtained within 14 days prior to initiation ofstudy treatment

• Platelet count >= 100 x 10^9/L without transfusion, obtained within 14 days prior toinitiation of study treatment

• White blood cell (WBC) count >= 2500/ul, obtained within 14 days prior to initiationof study treatment

• Hemoglobin >= 90 g/L (patients may be transfused to meet this criterion), obtainedwithin 14 days prior to initiation of study treatment

• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkalinephosphatase (ALP) =< 2.5 x upper limit of normal (ULN), obtained within 14 daysprior to initiation of study treatment, with the following exceptions: patients withdocumented liver metastases: AST and ALT =< 5 x ULN; patients with documented liveror bone metastases: alkaline phosphatase (ALP) =< 5 x ULN

• Serum bilirubin 1.5 x ULN, obtained within 14 days prior to initiation of studytreatment

• Serum creatinine =< 1.5 x ULN, obtained within 14 days prior to initiation of studytreatment

• Serum albumin >= 2.5 g/dL, obtained within 14 days prior to initiation of studytreatment

• For patients not receiving therapeutic anticoagulation: international normalizedratio (INR) or activated partial thromboplastin time (aPTT) =< 1.5 x ULN, obtainedwithin 14 days prior to initiation of study treatment

• For patients receiving therapeutic anticoagulation: stable anticoagulant regimen

• For women of childbearing potential: agreement to remain abstinent (refrain fromheterosexual intercourse) or use a contraceptive method with a failure rate of < 1%per year during the treatment period and for 6 months after the last dose of studytreatment

• A woman is considered to be of childbearing potential if she is postmenarchal, hasnot reached a postmenopausal state (>= 12 continuous months of amenorrhea with noidentified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus); examples of contraceptive methods with a failurerate of < 1% per year include bilateral tubal ligation, male sterilization, hormonalcontraceptives that inhibit ovulation, hormone-releasing intrauterine devices, andcopper intrauterine devices; the reliability of sexual abstinence should beevaluated in relation to the duration of the clinical trial and the preferred andusual lifestyle of the patient; periodic abstinence (e.g., calendar, ovulation,symptothermal, or postovulation methods) and withdrawal are not acceptable methodsof contraception

• Appendiceal adenocarcinoma basket

• Metastatic appendiceal adenocarcinoma

• Not considered candidate for curative surgery

• Nasopharyngeal carcinoma basket

• Metastatic or locally recurrent disease not amenable to curative intenttreatment

• Any number of prior therapies, including 0

• Human papilloma virus-associated cancers

• Histologically proven squamous carcinoma of the anal canal, penile, vaginal,vulva, or refractory cervical cancer with progression or intolerance to atleast one treatment regimen including cisplatin, oxaliplatin or carboplatinwill be enrolled; human papilloma virus (HPV) confirmation is not required

• Patients must have metastatic disease not amenable to surgical resection

• If human immunodeficiency virus (HIV)+ positive, all patients infected withhuman immunodeficiency virus (HIV) and CD4+ T cell count > 400 cells/mm^3 maybe eligible for study

• Patients co-infected with hepatitis B virus and/or hepatitis C virus may beincluded in this study provided that their liver function tests remain withinthe limits listed above; patients must be followed by a hepatologist during thecourse of this study

• Merkel cell carcinoma basket

• Metastatic or locally recurrent disease not amenable to curative intenttreatment

• Prior treatment with CD137 agonists or immune checkpoint blockade therapies,including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies

• Any number of prior therapies

• Neuroendocrine tumors, pancreatic basket

• Grade 1 or grade 2 (or described as low grade, intermediate grade, welldifferentiated, or moderately differentiated) according to reviewingpathologist

• Progressive disease over the preceding 12 months

• Any number of prior therapies, including 0

• Patients using a somatostatin analogue for symptom control must be on stabledoses for 56 days prior to enrollment

• Neuroendocrine tumors, extrapancreatic basket

• Grade 1 or grade 2 (or described as low grade, intermediate grade, welldifferentiated, or moderately differentiated; typical or atypical carcinoid iforiginating in lung) according to reviewing pathologist

• Progressive disease over the preceding 12 months

• Any number of prior therapies, including 0

• Patients using a somatostatin analogue for symptom control must be on stabledoses for 56 days prior to enrollment

• Peritoneal mesothelioma basket

• Refractory or intolerant to platinum and pemetrexed systemic therapy

• Any number of prior therapies

• Pleural mesothelioma basket

• Metastatic or locally recurrent disease not amenable to curative intenttreatment

• Refractory to platinum and pemetrexed systemic therapy

• Any number of prior therapies

Exclusion Criteria:

• Treatment for the studied cancer within 28 days prior to initiation of studytreatment

• Treatment with investigational therapy within 28 days prior to initiation of studytreatment

• History of severe allergic, anaphylactic, or other hypersensitivity reactions tochimeric or humanized antibodies or fusion proteins

• Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovarycells

• Known allergy or hypersensitivity to any component of the atezolizumab formulation

• Known allergy or hypersensitivity to any component of the bevacizumab formulation

• Active or history of autoimmune disease or immune deficiency, including, but notlimited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipidantibody syndrome, Wegener granulomatosis, Sjogren's syndrome, Guillain-Barresyndrome, or multiple sclerosis, with the following exceptions: patients with ahistory of autoimmune-related hypothyroidism who are on thyroid replacement hormoneare eligible for the study; patients with controlled type 1 diabetes mellitus whoare on an insulin regimen are eligible for the study; patients with eczema,psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestationsonly (e.g., patients with psoriatic arthritis are excluded) are eligible for thestudy provided all of following conditions are met:

• Rash must cover < 10% of body surface area

• Disease is well controlled at baseline and requires only low-potency topicalcorticosteroids

• No occurrence of acute exacerbations of the underlying condition requiringpsoralen plus ultraviolet A radiation, methotrexate, retinoids, biologicagents, oral calcineurin inhibitors, or high potency or oral corticosteroidswithin the previous 12 months

• Prior allogeneic stem cell or solid organ transplantation

• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitisobliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence ofactive pneumonitis on screening chest computed tomography (CT) scan; (history ofradiation pneumonitis in the radiation field [fibrosis] is permitted)

• Positive HIV test at screening (except in cohort 3, HPV-associated cancers)

• Except in cohort 3, HPV-associated cancers, active hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive hepatitis B surface antigen (HBsAg)test at screening; patients with a past or resolved HBV infection, defined as havinga negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) testand negative HBV deoxyribonucleic acid (DNA) test at screening, are eligible for thestudy

• Except in cohort 3, HPV-associated cancers active hepatitis C virus (HCV) infection,defined as having a positive HCV antibody test followed by a positive HCV RNA testat screening; the HCV RNA test will be performed only for patients who have apositive HCV antibody test

• Active tuberculosis

• Severe infection within 4 weeks prior to initiation of study treatment, including,but not limited to, hospitalization for complications of infection, bacteremia, orsevere pneumonia

• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiationof study treatment; patients receiving prophylactic antibiotics (e.g., to prevent aurinary tract infection or chronic obstructive pulmonary disease exacerbation) areeligible for the study

• Significant cardiovascular disease, such as New York Heart Association cardiacdisease (class II or greater), myocardial infarction, or cerebrovascular accidentwithin 3 months prior to initiation of study treatment, unstable arrhythmia, orunstable angina

• Major surgical procedure other than for diagnosis within 4 weeks prior to initiationof study treatment, or anticipation of need for a major surgical procedure duringthe course of the study

• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation ofstudy treatment, or anticipation of need for such a vaccine during the course of thestudy, or up to 5 months following the anticipated last dose of atezolizumab

• Malignancies other than the disease under study within 5 years prior to cycle 1, day 1, with the exception of those with a negligible risk of metastasis or death andwith expected curative outcome (such as adequately treated carcinoma in situ of thecervix, basal or squamous cell skin cancer, or ductal carcinoma in situ treatedsurgically with curative intent) or undergoing active surveillance perstandard-of-care management (e.g., chronic lymphocytic leukemia Rai stage 0)

• Any other disease, metabolic dysfunction, physical examination finding, or clinicallaboratory finding that contraindicates the use of an investigational drug, mayaffect the interpretation of the results, or may render the patient at high riskfrom treatment complications

• Except for cohort 4, Merkel cell carcinoma, prior treatment with CD137 agonists orimmune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, andanti-PD-L1 therapeutic antibodies

• Treatment with systemic immunostimulatory agents (including, but not limited to,interferon and interleukin 2 [IL-2]) within 4 weeks or five half-lives of the drug (whichever is longer) prior to initiation of study treatment

• Treatment with systemic immunosuppressive medication (including, but not limited to,corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, andanti-TNF-· agents) within 2 weeks prior to initiation of study treatment, oranticipation of need for systemic immunosuppressive medication during the course ofthe study, with the following exceptions: patients who received low-doseimmunosuppressant medication are eligible for the study; patients who receivedmineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructivepulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatichypotension or adrenal insufficiency are eligible for the study

• Pregnant or breastfeeding, or intending to become pregnant during the study; womenof childbearing potential must have a negative serum pregnancy test result within 14days prior to initiation of study treatment

• Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHgand/or diastolic blood pressure > 100 mmHg); anti-hypertensive therapy to maintain asystolic blood pressure < 150 mmHg and/or diastolic blood pressure < 100 mmHg ispermitted

• Prior history of hypertensive crisis or hypertensive encephalopathy

• History of stroke or transient ischemic attack within 6 months prior to cycle 1, day 1

• Significant vascular disease (e.g., aortic aneurysm requiring surgical repair orrecent peripheral arterial thrombosis) within 6 months prior to cycle 1, day 1

• Patients with a baseline electrocardiography (ECG) demonstrating a corrected QT (QTc) > 460 ms

• Evidence of bleeding diathesis or clinically significant coagulopathy (in theabsence of therapeutic anticoagulation)

• Current or recent (within 10 calendar days prior to cycle 1, day 1) use ofdipyramidole, ticlopidine, clopidogrel, or cilostazol

• Core biopsy or other minor surgical procedure, excluding placement of a vascularaccess device, within 7 calendar days prior to the first dose of bevacizumab

• History of abdominal or tracheoesophageal fistula or gastrointestinal perforationwithin 6 months prior to cycle 1, day 1

• Clinical signs or symptoms of gastrointestinal obstruction or requirement forroutine parenteral hydration, parenteral nutrition, or tube feeding

• Evidence of abdominal free air not explained by paracentesis or recent surgicalprocedure

• 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-hoururine collection; all patients with >= 2+ protein on dipstick urinalysis at baselinemust undergo a 24-hour urine collection for protein

• Appendiceal adenocarcinoma basket

• Complete or partial bowel obstruction

• Epstein-Barr virus-associated nasopharyngeal carcinoma basket:

• None

• Human papilloma virus-associated cancers basket

• None

• Merkel cell carcinoma basket:

• None

• Neuroendocrine tumors, pancreatic basket:

• Grade 3, poorly differentiated neuroendocrine carcinoma

• Large cell or small cell histology

• Neuroendocrine tumors, extrapancreatic basket:

• Grade 3, poorly differentiated neuroendocrine carcinoma

• Large cell or small cell histology

• Peritoneal mesothelioma basket:

• None

• Pleural mesothelioma basket:

• None