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
