Ipilimumab in Treating Patients With Metastatic or Recurrent Human Papilloma Virus-Related Cervical Cancer

PRIMARY OBJECTIVES:

I. To assess the safety of ipilimumab in eligible patients with recurrent or metastatic
cervical cancer.

II. To assess the antitumor activity of ipilimumab in eligible patients with recurrent or
metastatic cervical cancer via assessment of objective response rates (ORR).

SECONDARY OBJECTIVES:

I. To assess the antitumor activity of ipilimumab through secondary endpoints including of
disease stabilization and progression free survival (PFS).

II. Assessment of antitumor activity of ipilimumab using immune-related response criteria
(irRC) III. Assessment of the predictive value of baseline C-reactive protein. IV. Assess the
biologic responses of exposure to ipilimumab via correlative studies involving analysis of
lymphocyte subsets and assessment of cervical cancer-antigen specific T cells anti-tumor
response.

V. Evaluation of archival tissue with regard to markers of immune population in correlation
with clinical stage and response to treatment.

OUTLINE:

Patients receive ipilimumab intravenously (IV) over 90 minutes. Treatment repeats every 21
days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients
achieving objective response or stable disease continue to receive maintenance therapy
comprising ipilimumab IV over 90 minutes once every 12 weeks for 4 courses in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed metastatic or recurrent
cervical cancer of squamous, adenocarcinoma or mixed histology type not suited to
definitive localized therapy; HPV status will be confirmed for all patients following
enrollment

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as > 10 mm with computed
tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam

- Previous therapy:

- Patients may have undergone surgery and/or received definitive radiation or
chemo-radiation for localized disease in the past

- Radiation treatment with curative intent (radical chemoradiotherapy or adjuvant
chemoradiotherapy) must have been completed >= 3 months prior to enrollment

- Note: patients who completed palliative radiation therapy 2 weeks before
start of ipilimumab are allowed as long as this does not affect measurable
disease

- Patients must have been exposed to platinum chemotherapy either as part of
definitive chemo-radiation OR as first line systemic treatment for metastatic
disease

- Patients MAY have received up to two prior lines of systemic chemotherapy for
metastatic or recurrent disease; patients with metastatic disease at first
presentation MUST have received one platinum based line of chemotherapy

- All chemotherapy must have been completed >= 4 weeks prior to enrollment with
radiologic evidence of radiological disease progression

- Eastern Cooperative Oncology Group (ECOG) performance status 0-1

- Life expectancy of greater than 3 months

- Leukocytes >= 3.0 x 10^9/L

- Absolute neutrophil count >= 1.5 x 10^9/L

- Platelets >= 100 x 10^9/L

- Total bilirubin within normal institutional limits (except in Gilbert's syndrome)

- Thyroid stimulating hormone (TSH) =< upper limit of normal (ULN)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal

- Creatinine < 1.25 ULN OR creatinine clearance >= 50 mL/min/1.73 m^2 as calculated by
the Cockcroft and Gault formula

- All radiology studies must be performed =< 3 weeks prior to the start of therapy

- Subjects with treated and asymptomatic brain metastases are eligible; patients that
received palliative radiation (for brain metastases) are eligible if they have been
asymptomatic for at least 2 weeks with use of maintenance steroid therapy, and last
received radiation at least 4 weeks prior to start of therapy

- Ability to understand and willing to sign a written informed consent document

- Ongoing prior toxicities related to previous treatments must be recovered to =< grade
1 at the time of registration (with the exception of alopecia or skin depigmentation)

- Patients are willing to undergo tumor biopsy pre-treatment (within 14 days prior to
registration) and post-treatment (within the first week of cycle 2 onset); patients
who consent but have tumor that is not amenable to safe biopsy will be allowed to
enter the trial/continue therapy as per protocol if this has been addressed and
permission is granted from the lead consortium principal investigator (PI) prior to
registration continuation of treatment

Exclusion Criteria:

- Patients who have had chemotherapy < 4 weeks prior to enrollment (< 6 weeks for
nitrosoureas or mitomycin C) or who had radiation therapy with curative intent < 3
months prior to enrollment (< 2 weeks for palliative radiation therapy) or those who
have not recovered (=< grade 1) from adverse events related to previous treatments are
excluded

- Patients with a history of prior treatment with ipilimumab or other cytotoxic
T-lymphocyte antigen 4 (CTLA4) agonists or antagonists, anti-programmed death 1 (PD 1)
antibody, cluster of differentiation (CD)137 agonist or other immune activating
therapy such as anti-CD 40 antibody are excluded

- 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 requiring immunosuppressive agents, unless required for treating potential
immune related adverse effects; steroids at their lowest effective dose in patients
with radiated brain metastases is permitted

- Patients with known immune impairment who may be unable to respond to anti-CTLA 4
antibody

- Any other prior malignancy from which the patient has been disease free for less than
3 years, with the exception of adequately treated and cured basal or squamous cell
skin cancer, superficial bladder cancer, carcinoma in situ of any site or any other
cancer

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ipilimumab

- Patients requiring systemic steroids are excluded; narcotics should be used with
caution

- 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; patients with chronic hepatitis B or hepatitis C infections should
be excluded

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with ipilimumab

- Patients with active or chronic infection with human immunodeficiency virus (HIV) who
have raised viral loads or uncontrolled disease are ineligible; those patients however
who exhibit minimal viral loads with good control whilst on stable anti-viral regimen
may be considered if they meet all other eligibility criteria