Study of the Drug Ipilimumab for Metastatic Merkel Cell Carcinoma

Background:

Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine cancer of the skin with a
mortality of approximately 33%. Approximately one-third of patients present with metastatic
disease, for which there is no effective treatment. Merkel cell polyomavirus (MCV), a DNA
virus that expresses T antigen oncoproteins, was found to be clonally integrated into the
genome of the majority of MCC tumors. MCC tumor progression is believed to be associated
with the development of immune evasion, and multiple lines of evidence (higher incidence in
immunocompromised populations, reports of spontaneous regression, responses to immune
modulators, and improved prognosis associated with CD8+ intratumoral lymphocytes) suggest
that immunotherapy may improve outcomes in patients with advanced MCC. Ipilimumab is a
recombinant, human monoclonal antibody that binds to cytotoxic Tlymphocyte- associated
antigen 4 and has shown efficacy in metastatic melanoma.

Objectives:

Primary:

-Determine overall survival at 12 months.

Secondary:

- Determine the best overall response rate, as assessed by modified RECIST immunerelated
response criteria, at week 12.

- Determine median survival.

- Determine disease-specific survival (DSS) and progression-free survival (PFS).

- Evaluate the safety and tolerability of ipilimumab in patients with metastatic MCC.

- Assess biomarkers of immune activation and MCV-specific immune response.

Eligibility:

- Patients (age greater than or equal to 18 years) with metastatic MCC (AJCC stage 3b or
4).

- Immunocompromised individuals and patients with autoimmune disease are excluded.

Design:

- Patients will enroll at the NIH Clinical Center, Bethesda, MD (primary site) or at a
study sub-sites Memorial Sloan-Kettering Cancer Center, New York, NY; University of
Michigan, Ann Arbor, MI; or University of Pennsylvania, Philadelphia, PA.

- Ipilimumab will be given at a dose of 10 mg/kg as a 90-minute intravenous infusion on
day 1 of each 21-day cycle for 4 cycles. After 4 doses, patients may receive a
maintenance dose every 12 weeks until disease progression or unacceptable toxicity, for
up to an additional 4 doses.

- Imaging scans will be done at week 12, and every 12 weeks on study starting week 21.

- Patients will remain on-study for follow-up for 96 weeks after the last of the initial
4 doses.

- Response and progression will be evaluated using modified RECIST immune-related
response criteria.

- INCLUSION CRITERIA:

- Diagnosis of Merkel cell carcinoma confirmed by the Laboratory of Pathology, NCI, or
the participating institute s Department of Pathology.

- Unresectable or metastatic Merkel cell carcinoma

- Measurable disease as defined by lesions that are measured in at least one dimension
> 20mm by CXR, as > 10mm with CT scans, or > 10mm with calibers by clinical exam.

- Life expectancy greater than or equal to 6 months.

- ECOG performance status of 0-2

- Willing to travel to the NIH or study sub-sites (MSKCC, UMich, or Penn) for follow-up
visits.

- Patients must have recovered from acute toxicities related to prior therapy or
surgery.

- Patients must receive at least one line of chemotherapy and achieve partial
response(30% reduction in tumor burden) or better prior to enrollment. EXCEPTION:
Patients with asymptomatic tumors showing no or minimal progression (< 20% tumor
burden) within the last 2 months can be enrolled without prior chemotherapy.

- Age greater than equal 18 years. Because no dosing or adverse event data are
currently available on the use of ipilimumab in patients < 18 years of age, children
are excluded from this study, but may be eligible for future pediatric trials.

- Patients must have adequate hematological, hepatic, and renal laboratory values, as
defined below:

- leukocytes > 3,000/mcL

- absolute neutrophil count > 1,500/mcL

- platelets > 100,000/mcL

-----total bilirubin within normal institutional limits (except subjects with
Gilbert s Syndrome, who must have a total bilirubin less than 3.0 mg/dL)

- AST(SGOT)/ALT(SGPT) < 2.5 times institutional upper limit of normal

- creatinine < 2.0 times institutional upper limit of normal.

- The effects of ipilimumab on the developing human fetus are unknown. For this reason
and because ipilimumab was found to have teratogenic and abortifacient effects in
animal studies, 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 4 months after the last
injection of ipilimumab. 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.

- Ability of subject to understand and the willingness to sign a written informed
consent document.

EXCLUSION CRITERIA:

Prior treatment with ipilimumab.

-Patients who are immunocompromised as listed:

- Human immunodeficiency virus infection, or Hepatitis B or C infection, due to the
unknown effects of ipilimumab on viral replication and immune function and the
potential for severe side effects.

- Chronic administration (defined as daily or every other day for continued use > 14
days) of systemic corticosteroids (including steroid eye drops) or other immune
suppressive drugs, within 14 days of the first planned dose of ipilimumab. Nasal, or
inhaled steroid, and topical steroid creams for small body areas are not excluded.

- Patients who have undergone allogeneic peripheral stem cell transplantation, or solid
organ transplantation requiring immunosuppression

Prior Splenectomy

-Patients with history of, or active autoimmune disease that has required treatment, such
as Addison's disease, autoimmune thyroiditis, Grave s disease, systemic lupus
erythematous, rheumatoid arthritis, autoimmune hepatitis, systemic sclerosis (scleroderma
and variants), autoimmune vasculitis, autoimmune neuropathies (such as
Guillain-Barr(SqrRoot)(Copyright) syndrome), Goodpasture syndrome, ulcerative or
hemorrhagic colitis, autoimmune hypophysitis/hypopituitarism, and autoimmune hemolytic
anemia.

EXCEPTIONS: Patients with a history of autoimmunity that has not required systemic
immunosuppressive therapy or does not threaten vital organ function including CNS, heart,
lungs, kidneys, skin, and GI tract will not be excluded. Patients with type 1 diabetes
mellitus, or vitiligo, or endocrine deficiencies such as hypothyroidism will not be
excluded if the condition is well controlled.

- Other active malignancies within the past 12 months. EXCEPTIONS: Patients with
adequately treated basal or squamous cell carcinoma of the skin or in situ carcinoma
of the cervix or bladder will not be excluded. Patients with low or intermediate-risk
CLL (Rai stage 0-II, Binet stage A or B) without progressive or symptomatic disease,
who are being monitored without therapy will not be excluded.

- Clinically significant (i.e., active) cardiovascular disease: cerebral vascular
accident/stroke < 6 months prior to enrollment, myocardial infarction < 6 months
prior to enrollment, unstable angina, or congestive heart failure ( (Bullet) NYHA
III).

- Pulmonary disease which, in the opinion of the investigator, may impair the patient's
respiratory tolerance to the study drug (e.g., interstitial lung disease, severe
chronic obstructive pulmonary disease).

- Presence of serious or life-threatening intercurrent medical illness.

- Patients with symptomatic or progressive (progression within the last 3 months) brain
metastases are excluded from this clinical trial because of their poor prognosis and
because they often develop progressive neurologic dysfunction that would confound the
evaluation of neurologic and other adverse events.

- Patients who have had a history of acute diverticulitis, intra-abdominal abscess, GI
obstruction and abdominal carcinomatosis which are known risk factors for bowel
perforation.

- Pregnant women are excluded from this study because, based on animal studies,
ipilimumab 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 ipilimumab, breastfeeding should be discontinued if the
mother is treated with ipilimumab.

- Any condition which, in the opinion of the investigator, would prevent full
participation in this trial (including the long-term follow-up), or would interfere
with the evaluation of the trial endpoints.

- Receipt of chemotherapy or an investigational agent within 21 days (or 60 days for an
antibody-based therapy) of the first planned dose of study drugs.