Study of BEvacizumab in Combination With ATezolizumab in Patients With Untreated Melanoma Brain Metastases

Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive atezolizumab by
vein over 30-60 minutes (+/-10-15 minutes). Bevacizumab will then be given by vein over 30,
60, or 90 minutes (+/-10-15 minutes).

You may be given standard drugs to help decrease the risk of side effects. You may ask the
study staff for information about how the drugs are given and their risks.

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.

Study Visits:

On Day 1 of each cycle:

- You will have a physical exam.

- Blood (about 2 tablespoons) and urine will be collected for routine tests.

- If you can become pregnant, urine will be collected for a pregnancy test.

On Day 1 of Cycle 2, 3, and every 2 cycles after that (Cycles 5, 7, and so on), you will have
a CT scan, PET-CT scan, and/or MRI to check the status of the disease. In Cycles 2, 3, and 5
only, you will have an additional MRI to look for biomarkers that may be related to an immune
response.

On Day 1 of Cycle 3, if you have extracranial disease that can have a biopsy, you will have a
tumor biopsy for biomarker and PD testing.

On Day 1 of Cycles 3, 5, and every 2 cycles after that, blood (about 3 tablespoons) will be
drawn for biomarker testing.

On Day 1 of Cycles 5, 9, and every 4 cycles after that (Cycles 13, 17, and so on), if your
main language is English, you will have a neurocognitive exam. You will also complete the
symptom and quality-of-life questionnaires.

End of Treatment Visit:

After you stop the study drugs:

- You will have a physical exam.

- Blood (about 5 tablespoons) will be drawn for routine and biomarker testing.

- Urine will be collected for routine tests.

- You will have an EKG.

- If you can become pregnant, urine will be collected for a pregnancy test.

Follow-Up:

Ninety (90) days after your last study drug dose, or sooner if you start another anti-cancer
therapy:

- You will have a physical exam.

- Blood (about 2 tablespoons) and urine will be collected for routine tests.

- You will have an EKG.

- If you can become pregnant, urine will be collected for a pregnancy test.

Long-Term Follow-Up:

Every 3 months, the study staff will call and ask you about any symptoms and health problems
you have and any new drugs or changes in existing drugs that you are taking. The calls should
last up to 15 minutes.

Inclusion Criteria:

1. Signed Informed Consent Form (ICF)

2. Ability and willingness to comply with the requirements of the study protocol

3. Age >/= 18 years

4. Life expectancy > 12 weeks

5. Asymptomatic off steroids for at least 10 days Except patients: a) who have mild
symptoms from intracranial disease that do not affect their performance status; or b)
who are asymptomatic, but require steroids for control of symptoms on a maximum dose
of dexamethasone 4mg/day PO or equivalent

6. Prior therapies for extracranial metastatic melanoma including chemotherapy,
BRAFi/MEKi, cytokine or vaccine therapy as long as it did not include PD-1/PD-L1

7. At least one measurable intracranial target lesion for which all of the following
criteria are met: a) Previously untreated or progressive after previous local therapy
b) Immediate local therapy clinically not indicated or patient is not a suitable
candidate to receive immediate local therapy c) Largest diameter of >/= 0.5cm, but 3cm as determined by contrast-enhanced MRI

8. Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin
blocks (blocks are preferred) or at least 4 unstained slides, with an associated
pathology report, for central testing of tumor PD-L1 expression a) Tumor tissue should
be of good quality based on total and viable tumor content. Fine needle aspiration,
brushing, cell pellet from pleural effusion, bone metastases, and lavage samples are
not acceptable. For core-needle biopsy specimens, at least three cores should be
submitted for evaluation. b) Patients who do not have tissue specimens meeting
eligibility requirements may undergo a biopsy during the screening period. Acceptable
samples include core needle biopsies for deep tumor tissue (minimum of three cores) or
excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or
mucosal lesions. c) Tumor tissue from bone metastases is not evaluable for PD-L1
expression and is therefore not acceptable.

9. Adequate hematologic and end organ function, defined by the following laboratory
results obtained within 14 days prior to the first study treatment (Cycle 1, Day 1):
a) Absolute neutrophil count (ANC) >/= 1500 cells/µ b) White blood cell (WBC) counts >
2500/µL c) Lymphocyte count >/= 500/µL d) Platelet count >/= 100,000/µL; e) Hemoglobin
>/= 9.0 g/dL f) Total bilirubin following exception: 1) Patients with known Gilbert disease who have serum bilirubin
level exception: 1) Patients with documented liver metastases: AST and/or ALT Alkaline phosphatase patients with documented liver metastases metastases

10. (#9 CONTINUED) i) Serum creatinine /= 50 mL/min
on the basis of the Cockcroft-Gault glomerular filtration rate estimation: 1) (140 -
age) x (weight in kg) x (0.85 if female)/ 72 x (serum creatinine in mg/dL) j) Urine
dipstick for proteinuria < 2+ unless a 24-hour urine protein >/= 1g of protein is
demonstrated

11. For female patients of childbearing potential and male patients with partners of
childbearing potential, agreement (by patient and/or partner) to use highly effective
form(s) of contraception (i.e., one that results in a low failure rate [< 1% per year]
when used consistently and correctly) and to continue its use for at least 12 months
after the last dose of atezolizumab

12. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2

13. INR and aPTT
Exclusion Criteria:

1. Symptomatic brain metastases requiring immediate local interventions such as
craniotomy or SRS

2. Patients who require immediate surgical or radiotherapy interventions

3. Increasing corticosteroid dose in 7 days prior to administration of first dose of
study drug. a) Symptomatic patients who have stable or decreasing corticosteroid use
in the past 7 days may be included

4. Patients with Leptomeningeal disease

5. Any approved anticancer therapy, including chemotherapy and hormonal therapy within 3
weeks prior to initiation of study treatment; however, the following are allowed: a)
Hormone-replacement therapy or oral contraceptives b) Herbal therapy > 1 week prior to
Cycle 1, Day 1 (herbal therapy intended as anticancer therapy must be discontinued at
least 1 week prior to Cycle 1, Day 1)

6. Current, recent (within 3 weeks of the first infusion of this study), or planned
participation in an experimental drug study other than a Genentech-sponsored
bevacizumab cancer study

7. AEs from prior anticancer therapy that have not resolved to Grade alopecia

8. Bisphosphonate therapy for symptomatic hypercalcemia a) Use of bisphosphonate therapy
for other reasons (e.g., bone metastasis or osteoporosis) is allowed.

9. Known clinically significant liver disease, including active viral, alcoholic, or
other hepatitis; cirrhosis; fatty liver; and inherited liver disease. Patients with
acute leukemias, accelerated/blast phase chronic myelogenous leukemia, chronic
lymphocytic leukemia, Burkitt lymphoma, plasma cell leukemia, or non-secretory myeloma

10. Patients who are pregnant, lactating, or breastfeeding

11. Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
human antibodies

12. Inability to undergo MRI secondary to: a) Metal b) Claustrophobia c) Gadolinium
Contrast allergy

13. Prior radiation therapy within the last 14 days

14. Inability to comply with study and follow-up procedures

15. History of autoimmune disease, including but not limited to systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's
syndrome, Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune
thyroid disease, vasculitis, or glomerulonephritis a) Patients with a history of
autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be
eligible. b) Patients with controlled Type 1 diabetes mellitus on a stable insulin
regimen may be eligible. c) Patients with eczema, psoriasis, lichen simplex chronicus
of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic
arthritis would be excluded) are permitted provided that they meet the following
conditions: Patients with psoriasis must have a baseline ophthalmologic exam to rule
out ocular manifestations Rash must cover less than 10% of body surface area (BSA)

16. (# 16 CONTINUED) Disease is well controlled at baseline and only requiring low potency
topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%,
fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%) No acute
exacerbations of underlying condition within the last 12 months (not requiring
psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic
agents, oral calcineurin inhibitors; high potency or oral steroids)

17. History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
pneumonia, etc.), or evidence of active pneumonitis on screening chest computed
tomography (CT) scan a) History of radiation pneumonitis in the radiation field
(fibrosis) is permitted.

18. Any other diseases, metabolic dysfunction, physical examination finding, or clinical
laboratory finding giving reasonable suspicion of a disease or condition that
contraindicates the use of an investigational drug or that may affect the
interpretation of the results or render the patient at high risk from treatment
complications

19. History of HIV infection or active hepatitis B (chronic or acute) or hepatitis C
infection a) Patients with past or resolved hepatitis B infection (defined as having a
negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to
hepatitis B core antigen] antibody test) are eligible. b) Patients positive for
hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR)
is negative for HCV RNA.

20. Active tuberculosis

21. Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to
hospitalization for complications of infection, bacteremia, or severe pneumonia

22. Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1

23. Received oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1 a) Patients
receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection
or chronic obstructive pulmonary disease) are eligible.

24. 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 a)
Influenza vaccination should be given during influenza season only (approximately
October to March). Patients must not receive live, attenuated influenza vaccine (e.g.,
FluMist®) within 4 weeks prior to Cycle 1, Day 1 or at any time during the study.

25. 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, localized prostate cancer treated surgically with
curative intent, 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, prostate cancer with Gleason score prostate-specific antigen [PSA]
26. Life expectancy of less than 12 weeks

27. (Atezolizumab-Related Exclusion) Prior treatment with anti-PD-1, or anti-PD-L1
therapeutic antibody or pathway targeting agents a) Patients who have received prior
treatment with anti-CTLA-4 may be enrolled, provided the following requirements are
met: Minimum of 12 weeks from the first dose of anti-CTLA-4 and >6 weeks from the last
dose No history of severe immune-related adverse effects from anti-CTLA 4 (NCI CTCAE
Grade 3 and 4)

28. (Atezolizumab-Related Exclusion) Treatment with systemic immunostimulatory agents
(including but not limited to interferon [IFN]-(alpha) or interleukin [IL]-2) within 6
weeks or five half-lives of the drug (whichever is shorter) prior to Cycle 1, Day 1

29. (Atezolizumab-Related Exclusion) Treatment with investigational agent within 4 weeks
prior to Cycle 1, Day 1 (or within five half lives of the investigational product,
whichever is longer)

30. (Atezolizumab-Related Exclusion) Treatment with systemic immunosuppressive medications
(including but not limited to prednisone, cyclophosphamide, azathioprine,
methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2
weeks prior to Cycle 1, Day 1 a) Patients who have received acute, low dose, systemic
immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may
be enrolled. b) The use of inhaled corticosteroids and mineralocorticoids (e.g.,
fludrocortisone) for patients with orthostatic hypotension or adrenocortical
insufficiency is allowed.

31. (Atezolizumab-Related Exclusion) History of severe allergic, anaphylactic, or other
hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

32. (Atezolizumab-Related Exclusion) Patients with prior allogeneic bone marrow
transplantation or prior solid organ transplantation

33. (Bevacizumab-Related Exclusion) Inadequately controlled hypertension (defined as
systolic blood pressure >150 mmHg and/or diastolic blood pressure > 100 mmHg)

34. (Bevacizumab-Related Exclusion) Prior history of hypertensive crisis or hypertensive
encephalopathy

35. (Bevacizumab-Related Exclusion) Clinically significant (i.e. active) cardiovascular
disease, for example cerebrovascular accidents myocardial infarction II or greater congestive heart failure, or serious cardiac arrhythmia uncontrolled by
medication or potentially interfering with protocol treatment.

36. (Bevacizumab-Related Exclusion) History or evidence upon physical/neurological
examination of central nervous system (CNS) disease (e.g. seizures) unrelated to
cancer unless adequately treated with standard medical therapy

37. (Bevacizumab-Related Exclusion) Significant vascular disease (e.g., aortic aneurysm,
requiring surgical repair or recent peripheral arterial thrombosis) within 6 months
prior of study enrollment

38. (Bevacizumab-Related Exclusion) Any previous venous thromboembolism > NCI CTCAE Grade
3

39. (Bevacizumab-Related Exclusion) History of hemoptysis (>/= 1/2 teaspoon of bright red
blood per episode) within 1 month of study enrollment for any tumor type.

40. (Bevacizumab-Related Exclusion) Evidence of bleeding diathesis or significant
coagulopathy (in the absence of therapeutic anticoagulation)

41. (Bevacizumab-Related Exclusion) Current or recent (within 10 days of study enrolment)
use of aspirin (> 325 mg/day), clopidogrel (> 75 mg/day), or current or recent (within
10 days prior to first dose of bevacizumab) use of therapeutic oral or parenteral
anticoagulants or thrombolytic agents for therapeutic purposes Note: The use of
full-dose oral or parenteral anticoagulants is NOT permitted for at least two weeks at
the time of study enrollment. Prophylactic use of anticoagulants is NOT allowed.

42. (Bevacizumab-Related Exclusion) Surgical procedure (including open biopsy, surgical
resection, wound revision, or any other major surgery involving entry into a body
cavity) or significant traumatic injury within 28 days prior to study enrollment, or
anticipation of need for major surgical procedure during the course of the study. For
patients with brain tumors, craniotomy or intracranial biopsy sites must be adequately
healed; free of drainage or cellulitis, and the underlying cranioplasty must appear
intact at the time of study enrollment.

43. (Bevacizumab-Related Exclusion) History of abdominal fistula or gastrointestinal
perforation within 6 months prior to the first study treatment Serious, non-healing
wound, active ulcer, or untreated bone fracture (Adjuvant trials: bone fractures must
be healed)

44. (Bevacizumab-Related Exclusion) Proteinuria as demonstrated by a UPC ratio >/= 1.0 at
screening

45. (Bevacizumab-Related Exclusion) Known hypersensitivity to any component of bevacizumab