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A Phase I Trial of Sequential Ipilimumab After Chemoradiation for the Primary Treatment of Patients With Locally Advanced Cervical Cancer Stages IB2/IIA With Positive Para-Aortic Lymph Nodes Only and Stage IIB/IIIB/IVA With Positive Lymph Nodes
I. To estimate the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of
adjuvant ipilimumab following concurrent weekly cisplatin and extended field radiation in
women with newly diagnosed locally advanced cervical cancer stage IB2/ IIA with-positive
para-aortic lymph nodes only and stage IIB/IIIB/IVA with positive lymph nodes.
II. To determine the feasibility of the treatment regimen over the four cycles of adjuvant
ipilimumab once the MTD is estimated.
III. To assess the toxicities of the treatment regimen per the National Cancer Institute
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
I. To examine progression free survival for 1 year after study completion. II. To determine
site of recurrence, loco-regional versus distant, for one year after completion of therapy.
III. To estimate the frequency of chronic toxicities experienced within one year after
completion of therapy.
I. To enumerate the human papillomavirus (HPV)-subtype-specific T-cells and characterize the
kinetics of HPV-subtype-specific T-cell expansion associated with chemoradiation and
II. To characterize the association between differential expression of immune markers on
leukocytes from human leukocyte antigen (HLA)-A*0201 patients and response to chemoradiation
and ipilimumab treatment.
III. To assess qualitative changes in maximum standardized uptake value (SUVmax) from
positron emission tomography (PET)/computed tomography (CT) after treatment with
chemoradiation and ipilimumab.
IV. To bank residual plasma (obtained from leukocyte processing) for future research.
OUTLINE: This is a dose-escalation study of ipilimumab.
Patients receive cisplatin intravenously (IV) over 1 hour on days 1, 8, 15, 22, 29, and 36,
undergo external beam radiation therapy 5 days a week for 6 weeks, and then undergo
intracavitary brachytherapy for approximately 2 weeks. Within 2 weeks, patients receive
ipilimumab IV over 90 minutes once every 3 weeks for 12 weeks.
After completion of study treatment, patients are followed up every 3 months for 1 year and
then every 6 months for 1 year.
Inclusion and Exclusion Criteria
- Patients with histologically confirmed advanced cervical cancer (squamous cell carcinoma, adenocarcinoma, and adenosquamous cell carcinoma): International Federation of Gynecology and Obstetrics (FIGO) clinical stages IB2/IIA with positive para-aortic lymph nodes or FIGO clinical stages IIB/IIIB/IVA with positive pelvic and/or para-aortic lymph nodes; nodal status will be confirmed by PET/CT scan, fine needle biopsy, extra peritoneal biopsy, laparoscopic biopsy or lymphadenectomy
- Patients must have a Gynecologic Oncology Group (GOG) performance status of 0-1
- Absolute neutrophil count (ANC) >= 1,500/mcl
- Platelets >= 100,000/mcl
- Creatinine =< institutional upper limit normal (ULN); note: if creatinine > ULN, creatinine clearance must be > 50 mL/min
- Bilirubin =< 1.5 x ULN
- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN
- Alkaline phosphatase =< 2.5 x ULN
- Neuropathy (sensory and motor) =< grade 1
- Patients with ureteral obstruction (i.e., hydronephrosis identified on CT imaging) must undergo stent or nephrostomy tube placement prior to study entry
- Patients must meet the pre-entry requirements specified
- Patients must have signed an approved informed consent and authorization permitting the release of personal health information
- Patients of child-bearing potential must have a negative serum pregnancy test prior to study entry (within 72 hours prior to initiation of study treatment) and be practicing an effective form of contraception; women should not breast-feed while on this study
- Patients must not be receiving any other investigational agent
- Patients should have an audiogram at baseline, and patients with pre-existing hearing loss or hearing loss during treatment should be assessed frequently during cisplatin therapy
- Patients who have received previous pelvic or abdominal radiation, cytotoxic chemotherapy, or previous therapy of any kind for this malignancy or any pelvic or abdominal radiation for any prior malignancy
- Patients with active infection
- Patients who have circumstances that will not permit completion of this study or the required follow-up
- Patients with renal abnormalities, such as pelvic kidney, horseshoe kidney, or renal transplantation, that would require modification of radiation fields
- Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of other malignancy being present within the last five years; patients are also excluded if their previous cancer treatment prevents full delivery of this protocol therapy
- Patients who have undergone major surgery, excluding diagnostic biopsy, within 30 days (to allow for full recovery) prior to registration
- Patients who have a significant history of cardiac disease, i.e., uncontrolled hypertension, unstable angina, congestive heart failure, or uncontrolled arrhythmias within 6 months of registration
- Patients with a history of prior treatment with ipilimumab, anti-programmed cell death (PD) 1 antibody, cluster of differentiation (CD)137 agonist or other immune activating therapy such as anti-CD 40 antibody
- Patients who are receiving any other investigational agents
- Autoimmune disease: patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's disease, are excluded from this study, as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener's Granulomatosis]); central nervous system (CNS) or motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre syndrome and myasthenia gravis, multiple sclerosis)
- Patients with known immune impairment who may be unable to respond to anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA 4) antibody
- History of allergic reactions attributed to compounds of similar chemical or biologic composition ipilimumab or other agents used in study
- Patients with chronic human immunodeficiency virus (HIV), hepatitis B or hepatitis C infections should be excluded
- University of New Mexico, Albuquerque, New Mexico, 87106