This phase I trial studies how well atezolizumab before and/or with standard of care chemoradiotherapy works in immune system activation in patients with stage IB2, II, IIIB, or IVA cervical cancer that has spread to the lymph nodes. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving atezolizumab before and/or with chemoradiotherapy may lower the chance of tumors growing or spreading.

PRIMARY OBJECTIVES:

I. To determine whether differences in sequencing of atezolizumab and chemoradiation result in differential immune activation, as determined by clonal expansion of T cell receptor beta (TCRB) repertoires in peripheral blood on day 21.

SECONDARY OBJECTIVES:

I. To investigate the feasibility of administration of the anti PD-L1 antibody (atezolizumab) as an immune primer and concurrent with chemoradiation (CRT) therapy in patients with locally advanced cervical cancer.

II. To determine the nature and degree of toxicity of the anti PD-L1 antibody (atezolizumab) administered as an immune primer and concurrent with chemoradiation (CRT) therapy in patients with locally advanced cervical cancer.

III. To examine the changes in T cell receptor (TCR) clonality, diversity, and frequency in peripheral blood and tissue and correlate this with clinical outcomes, such as the exploratory response assessment on the post-treatment positron emission tomography (PET)-computed tomography (CT) scan and 2-year disease-free survival (DFS).

IV. To assess the predictive value of baseline and on-treatment PD-L1 expression in the tissue in each treatment arm for clinical outcomes using post-treatment PET-CT scan and 2-year DFS as the outcome measures.

EXPLORATORY OBJECTIVES:

I. To explore baseline and on-treatment blood and tissue biomarkers that could predict response to the combination therapy, as correlated to the exploratory clinical endpoint of the week 12 (day 140) PET-CT scan and 2-year DFS.

II. To explore the response assessment on the exploratory and optional post-treatment week 12 (day 140) PET-CT scan and the clinical 2-year disease free survival (DFS).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on days -21, 0, and 21 in the absence of disease progression or unacceptable toxicity. Patients also receive standard of care cisplatin chemotherapy IV over 90 minutes on days 0, 7, 14, 21, 28, and 35. Beginning on day 0, patients also receive standard of care radiation therapy once daily (Monday-Friday) for a total of 25 fractions with image guided brachytherapy beginning in week 4, 5, or at the end of radiation therapy.

ARM B: Patients receive atezolizumab IV over 30-60 minutes on days 0, 21, and 42 in the absence of disease progression or unacceptable toxicity. Patients also receive standard of care cisplatin chemotherapy, radiation therapy, and image guided brachytherapy as in Arm A.

After completion of study treatment, patients are followed up at 1 and 3 months, and then every 3 months for 2 years.

Inclusion Criteria:

• Patients with histologically confirmed newly diagnosed advanced cervical cancer (squamous cell carcinoma, adenocarcinoma, and adenosquamous cell carcinoma): Federation of Gynecology and Obstetrics (FIGO) clinical stages IB2/IIA with positive para-aortic nodes, or FIGO clinical stages IIB/IIIB/IVA with positive pelvic or para-aortic lymph nodes (PALN). Pelvic or PALN nodal status confirmed by PET/CT scan or fine needle biopsy or extra peritoneal biopsy or laparoscopic biopsy. The PALN must be inferior to the T12/L1 interspace

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

• Leukocytes >= 2,500/mcL

• Absolute neutrophil count >= 1,500/mcL

• Platelets >= 100,000/mcL (> 50,000 for patients with hematologic malignancies)

• Hemoglobin >= 8 g/dL (can be transfused with red blood cells pre-study)

• 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 (AST and/or ALT =< 5 x ULN for patients with liver involvement)

• Alkaline phosphatase =< 2.5 x ULN (=< 5 x ULN for patients with documented liver involvement or bone metastases)

• Creatinine clearance =< 1.5 mg/dL to receive weekly cisplatin

  • Patients whose serum creatinine is between 1.5 and 1.9 mg/dL are eligible for cisplatin if there is no hydronephrosis and the estimated creatinine clearance (CCr) is >= 30 ml/min. For the purpose of estimating the CCr, the formula of Cockcroft and Gault for females should be used

• 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)

• Patient does not have a known allergy to cisplatin or compounds of similar biologic composition

• Patient is not actively breastfeeding (or has agreed to discontinue breastfeeding before the initiation or protocol therapy)

• Thyroid-stimulating hormone (TSH) within normal limits or normal free T4 in those with abnormal TSH

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

• Patients positive for human immunodeficiency virus (HIV) are allowed on 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 polymerase chain reaction (PCR)-based tests

Exclusion Criteria:

• Patients who have received prior radiation therapy to the pelvis or abdominal cavity, PALN radiation, or previous therapy of any kind for this malignancy or pelvic, PALN, or abdominal radiation for any prior malignancy

• Patients with PALN nodal metastasis above the T12/L1 interspace

• Patients who had a radical hysterectomy with positive PALNs are not eligible

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

• Patients previously treated with systemic anticancer therapy (e.g., chemotherapy, targeted therapy, immunotherapy) within 3 years prior to entering the study

• 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 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

• 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 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

• 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 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 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

• 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 multigated acquisition scan (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

• If patients are of child-bearing potential and do not agree to use two forms of birth control then they are ineligible

• Patients who have had a hysterectomy or are planning to have an adjuvant hysterectomy following radiation as part of their cervical cancer treatment are ineligible

• Patients scheduled to be treated with adjuvant consolidation chemotherapy at the conclusion of their standard chemoradiation

• Pregnant women are excluded from this study because radiation therapy has the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with atezolizumab, breastfeeding should be discontinued if the mother is treated with atezolizumab

• Women of child-bearing potential and men 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 the 5 months (150 days) after the last dose of the study agent. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

• Patients taking bisphosphonate therapy for symptomatic hypercalcemia. Use of bisphosphonate therapy for other reasons (e.g. osteoporosis) is allowed

• Patients with known primary central nervous system (CNS) malignancy or CNS metastases are excluded

• Patients with a prior known history of vesicovaginal, enterovaginal or colovaginal fistula