Atezolizumab Before and/or With Chemoradiotherapy in Immune System Activation in Patients With Node Positive Stage IB2, II, IIIB, or IVA Cervical Cancer
Condition: Cervical Adenocarcinoma; Cervical Adenosquamous Carcinoma; Cervical Squamous Cell Carcinoma; Stage IB2 Cervical Cancer AJCC v8; Stage II Cervical Cancer AJCC v8; Stage IIA Cervical Cancer AJCC v8; Stage IIA1 Cervical Cancer AJCC v8; Stage IIA2 Cervical Cancer AJCC v8; Stage IIB Cervical Cancer AJCC v8; Stage IIIB Cervical Cancer AJCC v8; Stage IVA Cervical Cancer AJCC v8
MeSH terms: Carcinoma; Uterine Cervical Neoplasms; Carcinoma, Adenosquamous
Intervention: Atezolizumab; Brachytherapy; Cisplatin; Radiation Therapy
Intervention description: Given IV; Undergo standard of care image guided brachytherapy; Given IV; Undergo standard of care radiation therapy
Intervention MeSH terms: Cisplatin; Atezolizumab; Antibodies, Monoclonal
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 40.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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