Atezolizumab and Bevacizumab in Rare Solid Tumors

Study Drug Administration:

Each cycle is 21 days.

On Day 1 of each cycle, you will receive atezolizumab and bevacizumab by vein over about 60
minutes each.

Length of Treatment:

You may continue taking the study drugs for as long as the doctor thinks it is in your best
interest. You will no longer be able to take the study drugs if the disease gets worse, if
intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the follow-up visits.

Study Visits:

On Day 1 of every odd-numbered cycle (Cycles 1, 3, 5, and so on):

- You will have a physical exam.

- Blood (about 3 teaspoons) will be drawn for routine tests.

- Urine will be collected for routine tests.

On Day 1 of every even-numbered cycle (Cycles 2, 4, 6, and so on):

- You will have a physical exam.

- Blood (about 4 teaspoons) will be drawn for routine testing.

- During Cycle 2, blood (about 2 teaspoons) will be drawn before your dose of study drugs
for biomarker testing.

- During Cycle 2, you will have an image-guided core biopsy to check the status of the
disease and for biomarker testing.

On Day 8 of Cycles 1 and Cycle 2:

- You will have a physical exam.

- Blood (about 2 teaspoons) will be drawn for routine testing.

Every 9-12 weeks, you will have an MRI or CT scan.

At any time the doctor thinks it is needed, you will have an EKG and either an ECHO or MUGA
scan.

End-of-Treatment Visit:

About 30 days after your last dose of study drugs:

- You will have a physical exam.

- Blood (about 2 teaspoons) will be drawn for routine tests. If the disease got worse,
this sample will also be used for biomarker testing.

- If the disease got worse, you will have an image-guided core biopsy to check the status
of the disease.

Follow-Up:

About every 3 months after your end-of-treatment visit, you or your family/caregiver will be
called by the study staff and asked how you are doing. This call should last about 15
minutes. The study staff may also access your medical records or publically available records
to learn about your long-term health status.

Inclusion Criteria:

1. Signed Informed Consent Form

2. Age >/= 18 years

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

4. Measurable disease according to RECIST v1.1. 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 as specified in the appended
manuscript.

5. ECOG Performance Status of 0 or 1

6. Adequate hematologic and end-organ function, defined by the following laboratory test
results, obtained within 14 days prior to initiation of study treatment: ANC >/= 1.5 x
10(9)/L without granulocyte colony-stimulating factor support; Lymphocyte count >/=
0.5 x 10(9)/L; Platelet count >/= 100 x 10(9)/L without transfusion; WBC Count >/=
2500/ul; Hemoglobin >/= 90 g/L [Patients may be transfused to meet this criterion];
AST, ALT, and alkaline phosphatase (ALP) the following exceptions: Patients with documented liver metastases: AST and ALT x ULN Patients with documented liver or bone metastases: ALP bilirubin ≤ 1.5 x ULN - Serum creatinine /= 2.5 g/dL -
For patients not receiving therapeutic anticoagulation: INR or aPTT
7. For patients receiving therapeutic anticoagulation: stable anticoagulant regimen

8. 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.

9. (cont.) A woman is considered to be of childbearing potential if she is
postmenarcheal, 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.

10. Appendiceal adenocarcinoma basket

1. Metastatic appendiceal adenocarcinoma

2. Not considered candidate for curative surgery

11. Nasopharyngeal carcinoma basket a. Metastatic or locally recurrent disease not
amenable to curative intent treatment b. Any number of prior therapies, including 0

12. Human Papilloma Virus-associated cancers a. 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 or
carboplatin will be enrolled. HPV confirmation is not required. b. Patients must have
metastatic disease not amenable to surgical resection. c. If HIV+ positive, all
patients infected with Human Immunodeficiency Virus (HIV) and CD4+ T cell count > 400
cells/mm3 may be eligible for study. d. 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.

13. Merkel Cell Carcinoma basket a. Metastatic or locally recurrent disease not amenable
to curative intent treatment b. Any number of prior therapies, including 0

14. Neuroendocrine tumors, pancreatic basket a. Grade 1 or grade 2 (or described as low
grade, intermediate grade, well differentiated, or moderately differentiated)
according to reviewing pathologist b. Progressive disease over the preceding 12 months
c. Any number of prior therapies, including 0 d. Patients using a somatostatin
analogue for symptom control must be on stable doses for 56 days prior to enrollment.

15. Neuroendocrine tumors, extrapancreatic basket a. 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 b. Progressive disease over the preceding 12 months c. Any number of prior
therapies, including 0 d. Patients using a somatostatin analogue for symptom control
must be on stable doses for 56 days prior to enrollment.

16. Peritoneal mesothelioma basket a. Refractory or intolerant to platinum and pemetrexed
systemic therapy b. Any number of prior therapies

17. Pleural mesothelioma basket

1. Metastatic or locally recurrent disease not amenable to curative intent treatment

2. Refractory to platinum and pemetrexed systemic therapy

3. Any number of prior therapies

Exclusion Criteria:

1. Treatment for the studied cancer within 28 days prior to initiation of study treatment

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

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

4. Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovary
cells

5. Known allergy or hypersensitivity to any component of the atezolizumab formulation

6. Known allergy or hypersensitivity to any component of the bevacizumab formulation

7. 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, Sjögren's syndrome, Guillain-Barré
syndrome, or multiple sclerosis, with the following exceptions:

8. (cont.) 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

9. Prior allogeneic stem cell or solid organ transplantation

10. 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)

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

12. 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 DNA test at screening, are eligible for the study.

13. 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.

14. Active tuberculosis

15. 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

16. 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.

17. 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

18. 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

19. 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.

20. 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)

21. 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

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

23. 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

24. Treatment with systemic immunosuppressive medication (including, but not limited to,
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
anti－TNF-α 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.

25. 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.

26. 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.

27. Prior history of hypertensive crisis or hypertensive encephalopathy

28. History of stroke or transient ischemic attack within 6 months prior to Cycle 1, Day 1

29. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months prior to Cycle 1, Day 1

30. Patients with a baseline ECG demonstrating a QTc > 460 ms

31. Evidence of bleeding diathesis or clinically significant coagulopathy (in the absence
of therapeutic anticoagulation)

32. Current or recent (within 10 calendar days prior to Cycle 1, Day 1) use of
dipyramidole, ticlopidine, clopidogrel, or cilostazol

33. 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

34. History of abdominal or tracheoesophageal fistula or gastrointestinal perforation
within 6 months prior to Cycle 1, Day 1

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

36. Evidence of abdominal free air not explained by paracentesis or recent surgical
procedure

37. Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture

38. 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.

39. Appendiceal adenocarcinoma basket

1. Complete or partial bowel obstruction

40. Epstein-Barr Virus-associated nasopharyngeal carcinoma basket.

41. Human Papilloma Virus-associated cancers basket

a. None

42. Merkel Cell Carcinoma basket

a. none

43. Neuroendocrine tumors, pancreatic basket

1. Grade 3, poorly differentiated neuroendocrine carcinoma

2. Large cell or small cell histology

44. Neuroendocrine tumors, extrapancreatic basket

1. Grade 3, poorly differentiated neuroendocrine carcinoma

2. Large cell or small cell histology

45. Peritoneal mesothelioma basket

a. None

46. Pleural mesothelioma basket a. None