Pegylated Liposomal Doxorubicin Hydrochloride With Atezolizumab and/or Bevacizumab in Treating Patients With Recurrent Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

PRIMARY OBJECTIVES:

I. Estimate the probability of a dose limiting toxicity (DLT) following cycle 1 of
experimental regimens (pegylated liposomal doxorubicin hydrochloride [pegylated liposomal
doxorubicin] [PLD] and atezolizumab and PLD/bevacizumab and atezolizumab). (Safety lead-in)
II. Estimate and compare the hazard of first progression or death (progression free survival
[PFS]) of each experimental regimen relative to the reference regimen, PLD and bevacizumab.
(Phase II study) III. Estimate and compare the hazard of death and the hazard of first
progression or death (PFS) of each experimental regimen relative to the reference regimen.
(Phase III)

SECONDARY OBJECTIVES:

I. Estimate and compare the probabilities of response rate (objective response rate [ORR],
either partial or complete response) defined by Response Evaluation Criteria in Solid Tumors
(RECIST) version (v)1.1 criteria on each study regimen. (Phase II study) II. Estimate the
frequency and severity of adverse events as classified and graded with Common Terminology
Criteria for Adverse Events (CTCAE) in those patients who initiate their randomly assigned
study treatment. (Phase II study) III. Estimate and compare ORR in each treatment group.
(Phase III study) IV. Estimate the frequency and severity of adverse events in those patients
who initiate their randomly assigned study treatment. (Phase III study) V. Estimate and
compare mean patient reported outcome scores (PROs) as measured by National Comprehensive
Cancer Network (NCCN)-Functional Assessment of Cancer Therapy (FACT) ovarian symptom index
(NFOSI)-18 disease-related symptoms (DRS). (Phase III study) VI. Estimate and compare the
treatment groups on the basis of the PROs: treatment side effects (TSE), function/well-being
(FWB), fatigue (Functional Assessment of Chronic Illness Therapy [FACIT]-fatigue [F]
subscale) and abdominal discomfort (FACT/Gynecologic Oncology Group [GOG]-abdominal
discomfort [AD] subscale). (Phase III study)

TRANSLATIONAL SCIENCE OBJECTIVES:

I. To determine whether biomarker levels in pre-treatment tissue, and pre- or on-treatment
peripheral blood, and stool specimens are associated with ORR, PFS and/or overall survival
(OS).

II. To determine whether changes in quantitative biomarker parameters after the first 6 and
12 weeks of therapy predict ORR, PFS and/or OS.

OUTLINE: Patients will be randomized to 1 of 3 arms.

ARM I: Patients receive pegylated liposomal doxorubicin hydrochloride intravenously (IV) over
60 minutes on day 1 and atezolizumab IV over 30-60 minutes on days 1 and 15.

ARM II: Patients receive pegylated liposomal doxorubicin hydrochloride IV over 60 minutes on
day 1, bevacizumab IV over 30-90 minutes on days 1 and 15, and atezolizumab IV over 30-60
minutes on days 1 and 15.

ARM III: Patients receive pegylated liposomal doxorubicin hydrochloride IV over 60 minutes on
day 1 and bevacizumab IV over 30-90 minutes on days 1 and 15.

In all arms, courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 2
years, then every 6 months for up to 3 years.

Inclusion Criteria:

- Patients must have the psychological ability and general health that permits
completion of the study requirements and required follow up

- Women of child-bearing potential (WOCBP) must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry, for
the duration of study participation, and for 5 months (150 days) after the last dose
of study agent; should a woman become pregnant or suspect she is pregnant while she is
participating in this study, she should inform her treating physician immediately

- Submission of tumor tissue is required for all patients; investigators should check
with their site pathology department regarding release of biospecimens before
approaching patients about participation in the trial

- High grade ovarian cancer, including high grade serous; clear cell; endometrioid,
grade 3; and others (adenocarcinoma, nitric oxide synthase [NOS]; mixed epithelial
carcinoma; undifferentiated carcinoma); NOTE: low grade serous, mucinous and
carcinosarcoma histologies are excluded; ovarian cancer = ovarian, fallopian tube or
primary peritoneal cancer; required data element: submission of pathology report

- Recurrent, platinum resistant ovarian cancer (defined as progression within < 6 months
from completion of platinum based therapy; the date should be calculated from the last
administered dose of platinum therapy)

- 1-2 prior regimens (including primary therapy); hormonal therapies (e.g., tamoxifen,
aromatase inhibitors) will not count toward the prior regimen limit

- Measurable disease (defined by RECIST v. 1.1) or evaluable disease (defined as solid
and/or cystic abnormalities on radiographic imaging that do not meet RECIST 1.1
definitions for target lesions OR ascites and/or pleural effusion that has been
pathologically demonstrated to be disease related in the setting of cancer antigen
[CA]25 >= 2 x upper limit of normal [ULN])

- Performance status 0, 1 or 2

- Absolute neutrophil count (ANC) >= 1,500/mcl (within 14 days prior to registration)

- Platelets >= 100,000/mcl (within 14 days prior to registration)

- Hemoglobin (Hgb) >= 8 g/dl (within 14 days prior to registration)

- Creatinine =< 1.5 x institutional upper limit of normal (ULN) (within 14 days prior to
registration)

- Urine protein creatinine (UPC) ratio must be < 1.0 (within 14 days prior to
registration); if UPC ratio >= 1, collection of 24-hour urine measurement of urine
protein is recommended (24-hour urine protein level must be < 1000 mg for patient
enrollment); UPC ratio of spot urine is an estimation of the 24-hour urine protein
excretion - a UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm

- Total bilirubin =< 1.5 x ULN (patients with known Gilbert disease who have serum
bilirubin level =< 3 x ULN may be enrolled) (within 14 days prior to registration)

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN (AST and/or
ALT =< 5 x ULN for patients with liver involvement) (within 14 days prior to
registration)

- International normalized ratio (INR) and activated partial thromboplastin time (aPTT)
=< 1.5 x ULN (or on stable dose of therapeutic anticoagulation, such as
low-molecular-weight heparin, warfarin or rivaroxaban)

- Thyroid-stimulating hormone (TSH) within normal limits (TSH < ULN allowed in euthyroid
patients on thyroid replacement therapy)

- The patient or legally authorized representative must provide study-specific informed
consent prior to study entry and, for patients treated in the United States (U.S.),
authorization permitting release of personal health information

Exclusion Criteria:

- Patients with prior allogeneic bone marrow transplantation or prior solid organ
transplantation

- Patients who have had systemic anticancer therapy (e.g., chemotherapy, targeted
therapy) within 3 weeks prior to entering the study

- Patients who have had hormonal therapy (e.g., tamoxifen, aromatase inhibitor) within 1
week prior to entering the study

- Patients with prior treatment with anti-programmed cell death (PD)-1, anti- programmed
cell death ligand (PD-L)1 or anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4
therapeutic antibody or other similar agents

- Patients with prior treatment with bevacizumab (or any other anti vascular therapy,
e.g., cediranib) for platinum resistant recurrence; (Note: prior bevacizumab in
initial therapy and/or platinum sensitive recurrent setting is allowed)

- Patients with prior treatment with PLD

- Prior radiotherapy to the abdomen or pelvis

- Patients who have not recovered from adverse events to < grade 1 (other than alopecia)
due to agents administered more than 3 weeks earlier; however, the following therapies
are allowed:

- Hormone replacement therapy or oral contraceptives

- 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)

- Palliative radiotherapy for bone metastases > 2 weeks prior to cycle 1, day 1

- Treatment with any other investigational agent within 4 weeks prior to cycle 1, day 1

- Treatment with systemic immunostimulatory agents (including, but not limited to,
interferon [IFN]-alpha or interleukin [IL]-2) within 6 weeks prior to cycle 1, day 1

- 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

- Patients who have received acute, low dose, systemic immunosuppressant
medications (e.g., a one-time dose of dexamethasone for nausea or steroids as
computed tomography [CT] scan contrast premedication) may be enrolled

- The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone)
for patients with orthostatic hypotension or adrenocortical insufficiency is
allowed

- Patients taking bisphosphonate therapy for symptomatic hypercalcemia within the past
28 days; use of bisphosphonate therapy for other reasons (e.g., bone metastasis or
osteoporosis) is allowed

- Patients with known primary central nervous system (CNS) malignancy or symptomatic CNS
metastases are excluded, with the following exceptions:

- Patients with asymptomatic untreated CNS disease may be enrolled, provided all of
the following criteria are met:

- Evaluable or measurable disease outside the CNS

- No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within
10 mm of the optic apparatus (optic nerves and chiasm)

- No history of intracranial hemorrhage or spinal cord hemorrhage

- No ongoing requirement for dexamethasone for CNS disease; patients on a
stable dose of anticonvulsants are permitted

- No neurosurgical resection or brain biopsy within 28 days prior to cycle 1,
day 1

- Patients with asymptomatic treated CNS metastases may be enrolled, provided all
the criteria listed above are met as well as the following:

- Radiographic demonstration of improvement upon the completion of CNS
directed therapy and no evidence of interim progression between the
completion of CNS directed therapy and the screening radiographic study

- No stereotactic radiation or whole-brain radiation within 28 days prior to
cycle 1, day 1

- Screening CNS radiographic study >= 4 weeks from completion of radiotherapy
and >= 2 weeks from discontinuation of corticosteroids

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

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

- Patients requiring treatment with a receptor activator of nuclear factor kappa-B
ligand (RANKL) inhibitor (e.g. denosumab) who cannot discontinue it before treatment
with atezolizumab

- Known clinically significant liver disease, including active viral, alcoholic, or
other hepatitis; cirrhosis; fatty liver; and inherited liver disease

- 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

- Patients positive for hepatitis C virus (HCV) antibody are eligible only if
polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)

- History or risk 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, Sjogren's
syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune
thyroid disease, vasculitis, or glomerulonephritis

- Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid
replacement hormone are eligible

- Patients with controlled type 1 diabetes mellitus on a stable insulin regimen, or
type 2 diabetes mellitus are eligible

- Patients with eczema, psoriasis, lichen simplex chronicus or 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)

- 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)

- 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; history of radiation pneumonitis in the radiation field
(fibrosis) is permitted

- Patients with active tuberculosis (TB) are excluded

- 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

- Signs or symptoms of infection within 2 weeks prior to cycle 1, day 1

- Received oral or intravenous (IV) antibiotics within 2 weeks prior to cycle 1, day 1;
patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract
infection or chronic obstructive pulmonary disease) are eligible

- Major surgical procedure within 28 days prior to cycle 1, day 1 or anticipation of
need for a major surgical procedure during the course of the study

- 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
and up to 5 months after the last dose of atezolizumab

- Influenza vaccination should be given during influenza season only (approximately
October to March); patients must not receive live, attenuated influenza vaccine
within 4 weeks prior to cycle 1, day 1 or at any time during the study

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Patients positive for human immunodeficiency virus (HIV) are NOT excluded from this
study, but HIV-positive patients must have:

- A stable regimen of highly active anti-retroviral therapy (HAART)

- No requirement for concurrent antibiotics or antifungal agents for the prevention
of opportunistic infections

- A cluster of differentiation (CD)4 count above 250 cells/mcL and an undetectable
HIV viral load on standard PCR-based tests

- Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
for a minimum of 3 years, with the exception of those with a negligible risk of
metastases or death, such as carcinoma in situ of the breast or cervix

- Severe, active co-morbidity defined as follows:

- Current (within 28 days of cycle 1, day 1) signs and/or symptoms of bowel
obstruction

- Patients who require parental hydration and/or nutrition

- Patients who require drainage gastrostomy tube

- Evidence of bleeding diathesis or clinically significant coagulopathy

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

- History of hemoptysis (>= 1/2 teaspoon of bright red blood per episode) within 1
month of study enrollment

- Significant cardiovascular or cerebrovascular disease including:

- Uncontrolled hypertension (systolic blood pressure [SBP] >= 150; diastolic blood
pressure [DBP] >= 90)

- History of myocardial infarction within 6 months

- Unstable angina

- New York Heart Association functional classification II, III or IV

- Baseline ejection fraction =< 50% as assessed by echocardiogram or multi-gated
acquisition (MUGA)

- Cerebral vascular accident (CVA) or transient ischemic attack (TIA) within 6
months

- Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or
peripheral arterial thrombosis) within 6 months

- History of abdominal/pelvic or tracheoesophageal fistula or gastrointestinal
perforation and/or abscess within 6 months prior to initiation of treatment

- Pregnant or lactating patients