Atezolizumab and Bevacizumab in Treating Patients With Recurrent, Persistent, or Metastatic Cervical Cancer

PRIMARY OBJECTIVES:

I. To assess the anti-tumor activity (proportion of patients with objective response by
Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1] criteria) of
atezolizumab and bevacizumab in patients with recurrent, persistent or metastatic cervical
cancer.

SECONDARY OBJECTIVES:

I. To estimate the duration of progression free survival (PFS) and overall survival (OS).

II. To assess safety by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE
v.5.0).

III. To describe the efficacy of the combination of atezolizumab and bevacizumab as measured
by objective response, by PD-L1 expression on tumor and immune cells measured by
semi-quantitative immunohistochemistry (IHC).

IV. To describe the efficacy of the combination of atezolizumab and bevacizumab as measured
by objective response, by intratumoral and peripheral T-cell receptor (TCR) clonality and
tumor infiltrating lymphocyte proportion.

OUTLINE:

Patients receive atezolizumab intravenously (IV) over 30-60 minutes and bevacizumab IV over
30-90 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 for 2 years.

Inclusion Criteria:

- Patients must have measurable disease per RECIST 1.1; measurable lesions are defined
as those that can be accurately measured in at least one dimension (longest diameter
to be recorded as >= 10 mm (>= 1 cm) with computed tomography (CT) scan, magnetic
resonance imaging (MRI), or calipers by clinical exam; to be considered pathologically
enlarged and measurable, a lymph node must be >= 15 mm (>= 1.5 cm) in short axis

- Patients must have had one prior systemic chemotherapeutic regimen for management of
recurrent, persistent or metastatic carcinoma of the cervix (e.g.;
paclitaxel/cisplatin, paclitaxel/cisplatin/bevacizumab), at least one which must have
contained bevacizumab

- NOTE: Patients are allowed to receive 1-2 prior regimens for management of
recurrent, persistent or metastatic carcinoma of the cervix; patients who have
received more than two prior systemic regimens for management of recurrent,
persistent or metastatic carcinoma of the cervix are NOT eligible

- NOTE: Prior adjuvant therapy is NOT counted as a systemic chemotherapeutic
regimen for management of recurrent, persistent or metastatic carcinoma of the
cervix; adjuvant therapy includes cisplatin given concurrent with primary
radiation therapy (CCRT) and adjuvant chemotherapy given following the completion
of concurrent chemotherapy and radiation therapy (e.g., paclitaxel and
carboplatin for up to 4 cycles)

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 9 g/dL

- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (however, patients
with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled)

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3 x ULN

- Alkaline phosphatase =< 2.5 x ULN

- Creatinine =< 1.5 x ULN

- International normalized ratio (INR) and activated partial thromboplastin time aPTT =<
1.5 x ULN (This applies only to patients who do not receive therapeutic
anticoagulation; patients receiving therapeutic anticoagulation, such as
low-molecular-weight heparin or warfarin, should be on a stable dose)

- Urine protein must be screened by urinalysis; if protein is 2+ or higher, 24-hour
urine protein should be obtained and the level should be < 1000 mg for patient
enrollment

- Patient must have recurrent, persistent or metastatic cervical cancer including
squamous cell, adenocarcinoma and adenosquamous histologies; mesonephric carcinoma,
minimal deviation/adenoma malignum, clear cell carcinoma and gastric type are excluded

- Women of child-bearing potential 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 atezolizumab;
fertile women must agree to use adequate contraceptive measures during study therapy
and for at least 6 months after the completion of bevacizumab therapy; should a woman
become pregnant or suspect she is pregnant while she is participating in this study,
she should inform her treating physician immediately

- Ability to understand and the willingness to sign a written informed consent document

- Tumors within previous radiated field will be designated "non-target" lesions unless
progression is documented or a biopsy is obtained to confirm persistence at least 90
days following completion of radiation therapy

- Willingness to undergo a tumor biopsy

Exclusion Criteria:

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

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events (other than alopecia) due to agents administered more
than 4 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)

- Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or
pathway-targeting agents

- Prior treatment with anti-CTLA-4 therapeutic antibody or pathway-targeting agents

- 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) 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; use of
bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is
allowed

- Patients with known brain metastases should be excluded from this clinical trial

- 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

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to bevacizumab or 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 may be eligible

- Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may
be eligible

- 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)

- 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 CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard
PCR-based tests

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with atezolizumab and/or bevacizumab

- Malignancies other than the cervical cancer within 5 years prior to cycle 1, day 1,
with the exception of those with a negligible risk of metastasis or death, such as
adequately controlled basal cell carcinoma or squamous cell carcinoma of the skin or
carcinoma in situ of the breast

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

- Patients with clinically significant cardiovascular disease are excluded

- Inadequately controlled hypertension (HTN) (systolic blood pressure [SBP] >= 160
mmHg and/or diastolic blood pressure [DBP] >= 90 mmHg despite antihypertensive
medication)

- History of cerebrovascular accident (CVA) within 6 months

- Myocardial infarction or unstable angina within 6 months

- New York Heart Association class II or greater congestive heart failure

- Serious and inadequately controlled cardiac arrhythmia

- Significant vascular disease (e.g. aortic aneurysm, history of aortic dissection)

- Clinically significant peripheral vascular disease

- History of abdominal/pelvic fistula, gastrointestinal perforation and/or
intraabdominal abscess within 6 months prior to day 1

- Evidence of bleeding diathesis or clinically significant coagulopathy

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

- Patients requiring treatment with a RANKL inhibitor (e.g. denosumab) who cannot
discontinue it before treatment with atezolizumab