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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

Phase 1
18 Years
Open (Enrolling)
Cervical Adenocarcinoma, Cervical Adenosquamous Cell Carcinoma, Cervical Squamous Cell Carcinoma, Stage IB Cervical Cancer, Stage IIA Cervical Cancer, Stage IIB Cervical Cancer, Stage IIIB Cervical Cancer, Stage IVA Cervical Cancer

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Trial Information

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
ipilimumab treatment.

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 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 glutamic pyruvate transaminase [SGPT]) =< 2.5 x

- 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

Exclusion Criteria:

- 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-PD 1 antibody, CD137
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

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

DLTs occurring during adjuvant ipilimumab in the dose escalation phase

Outcome Time Frame:

During first 2 courses of treatment

Safety Issue:


Principal Investigator

Yvonne Lin-Liu

Investigator Role:

Principal Investigator

Investigator Affiliation:

Gynecologic Oncology Group


United States: Food and Drug Administration

Study ID:




Start Date:

October 2012

Completion Date:

Related Keywords:

  • Cervical Adenocarcinoma
  • Cervical Adenosquamous Cell Carcinoma
  • Cervical Squamous Cell Carcinoma
  • Stage IB Cervical Cancer
  • Stage IIA Cervical Cancer
  • Stage IIB Cervical Cancer
  • Stage IIIB Cervical Cancer
  • Stage IVA Cervical Cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Carcinoma
  • Carcinoma, Squamous Cell
  • Uterine Cervical Neoplasms
  • Carcinoma, Adenosquamous



Hartford HospitalHartford, Connecticut  06102-5037
University of Oklahoma Health Sciences CenterOklahoma City, Oklahoma  73104
UC Davis Comprehensive Cancer CenterSacramento, California  95817
Thomas Jefferson University HospitalPhiladelphia, Pennsylvania  19131
University of Southern CaliforniaLos Angeles, California  90033
The Hospital of Central ConnecticutNew Britain, Connecticut  06050
University of California Medical Center At Irvine-Orange CampusOrange, California  92868
Women and Infants HospitalProvidence, Rhode Island  02905