Atezolizumab and Bevacizumab in Treating Patients With Rare Solid Tumors
Atezolizumab and Bevacizumab in Treating Patients With Rare Solid Tumors
This phase II trial studies how well atezolizumab and bevacizumab work in treating patients
 with rare solid tumors. Immunotherapy with monoclonal antibodies, such as atezolizumab and
 bevacizumab, may help the body's immune system attack the cancer, and may interfere with the
 ability of tumor cells to grow and spread.
PRIMARY OBJECTIVES:

 I. To evaluate the efficacy of atezolizumab when given in combination with bevacizumab (atezo
 bev).

 SECONDARY OBJECTIVES:

 I. To evaluate the efficacy of atezo bev. II. To evaluate the safety of atezo + bev.

 EXPLORATORY BIOMARKER OBJECTIVES:

 I. To identify biomarkers that are predictive of response to atezo bev (i.e., predictive
 biomarkers), are associated with progression to a more severe disease state (i.e., prognostic
 biomarkers), are associated with resistance to atezo bev, are associated with susceptibility
 to developing adverse events, can provide evidence of study treatment activity, or can
 increase the knowledge and understanding of disease biology.

 OUTLINE:

 Patients receive atezolizumab and bevacizumab intravenously (IV) over 60 minutes on day 1.
 Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up every 3 months.
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 as measurable disease
 only if progressive disease has been unequivocally documented at that site since
 radiation; the pleural mesothelioma cohort will require measurable disease 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 granulocyte colony-stimulating
 factor support, obtained within 14 days prior to initiation of study treatment

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

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

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

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

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

 -  Serum bilirubin 1.5 x ULN, obtained within 14 days prior to initiation of study
 treatment

 -  Serum creatinine =< 1.5 x ULN, obtained within 14 days prior to initiation of study
 treatment

 -  Serum albumin >= 2.5 g/dL, obtained within 14 days prior to initiation of study
 treatment

 -  For patients not receiving therapeutic anticoagulation: international normalized ratio
 (INR) or activated partial thromboplastin time (aPTT) =< 1.5 x ULN, obtained within 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 from
 heterosexual 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 study
 treatment

 -  A woman is considered to be of childbearing potential if she is postmenarchal, has not
 reached a postmenopausal state (>= 12 continuous months of amenorrhea with no
 identified cause other than menopause), and has not undergone surgical sterilization
 (removal of ovaries and/or uterus); examples of contraceptive methods with a failure
 rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal
 contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and
 copper intrauterine devices; the reliability of sexual abstinence should be evaluated
 in relation to the duration of the clinical trial and the preferred and usual
 lifestyle of the patient; periodic abstinence (e.g., calendar, ovulation,
 symptothermal, or postovulation methods) and withdrawal are not acceptable methods of
 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 intent treatment

 -  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 at least
 one treatment regimen including cisplatin, oxaliplatin or carboplatin will 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 with human
 immunodeficiency virus (HIV) and CD4+ T cell count > 400 cells/mm^3 may be
 eligible for study

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

 -  Merkel cell carcinoma basket

 -  Metastatic or locally recurrent disease not amenable to curative intent treatment

 -  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, well
 differentiated, or moderately differentiated) 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 stable
 doses for 56 days prior to enrollment

 -  Neuroendocrine tumors, extrapancreatic basket

 -  Grade 1 or grade 2 (or described as low grade, intermediate grade, well
 differentiated, or moderately differentiated; typical or atypical carcinoid if
 originating 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 stable
 doses 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 intent treatment

 -  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 study treatment

 -  Treatment with investigational therapy within 28 days prior to initiation of study
 treatment

 -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to
 chimeric or humanized antibodies or fusion proteins

 -  Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovary
 cells

 -  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 not
 limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
 erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
 antibody syndrome, Wegener granulomatosis, Sjogren's syndrome, Guillain-Barre
 syndrome, or multiple sclerosis, with the following exceptions: patients with a
 history of autoimmune-related hypothyroidism who are on thyroid replacement hormone
 are eligible for the study; patients with controlled type 1 diabetes mellitus who are
 on an insulin regimen are eligible for the study; patients with eczema, psoriasis,
 lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g.,
 patients with psoriatic arthritis are excluded) are eligible for the study 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 topical
 corticosteroids

 -  No occurrence of acute exacerbations of the underlying condition requiring
 psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents,
 oral calcineurin inhibitors, or high potency or oral corticosteroids within the
 previous 12 months

 -  Prior allogeneic stem cell or solid organ transplantation

 -  History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
 obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of
 active pneumonitis on screening chest computed tomography (CT) scan; (history of
 radiation 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 having a
 negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test and
 negative HBV deoxyribonucleic acid (DNA) test at screening, are eligible for the study

 -  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 test at
 screening; the HCV RNA test will be performed only for patients who have a positive
 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, or severe
 pneumonia

 -  Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
 of study treatment; patients receiving prophylactic antibiotics (e.g., to prevent a
 urinary tract infection or chronic obstructive pulmonary disease exacerbation) are
 eligible for the study

 -  Significant cardiovascular disease, such as New York Heart Association cardiac disease
 (class II or greater), myocardial infarction, or cerebrovascular accident within 3
 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina

 -  Major surgical procedure other than for diagnosis within 4 weeks prior to initiation
 of study treatment, or anticipation of need for a major surgical procedure during the
 course of the study

 -  Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study
 treatment, or anticipation of need for such a vaccine during the course of the study,
 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 and with
 expected curative outcome (such as adequately treated carcinoma in situ of the cervix,
 basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically
 with curative intent) or undergoing active surveillance per standard-of-care
 management (e.g., chronic lymphocytic leukemia Rai stage 0)

 -  Any other disease, metabolic dysfunction, physical examination finding, or clinical
 laboratory finding that contraindicates the use of an investigational drug, may affect
 the interpretation of the results, or may render the patient at high risk from
 treatment complications

 -  Except for cohort 4, Merkel cell carcinoma, prior treatment with CD137 agonists or
 immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-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, and
 anti-TNF-· agents) within 2 weeks prior to initiation of study treatment, or
 anticipation of need for systemic immunosuppressive medication during the course of
 the study, with the following exceptions: patients who received low-dose
 immunosuppressant medication are eligible for the study; patients who received
 mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive
 pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic
 hypotension or adrenal insufficiency are eligible for the study

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

 -  Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg
 and/or diastolic blood pressure > 100 mmHg); anti-hypertensive therapy to maintain a
 systolic blood pressure < 150 mmHg and/or diastolic blood pressure < 100 mmHg is
 permitted

 -  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 or
 recent 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 the absence
 of therapeutic anticoagulation)

 -  Current or recent (within 10 calendar days prior to cycle 1, day 1) use of
 dipyramidole, ticlopidine, clopidogrel, or cilostazol

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

 -  History of abdominal or tracheoesophageal fistula or gastrointestinal perforation
 within 6 months prior to cycle 1, day 1

 -  Clinical signs or symptoms of gastrointestinal obstruction or requirement for routine
 parenteral hydration, parenteral nutrition, or tube feeding

 -  Evidence of abdominal free air 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; all patients with >= 2+ protein on dipstick urinalysis at baseline
 must 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