CP-675,206 (CTLA4-Blocking Monoclonal Antibody) Combined With Dendritic Cell Vaccine Therapy in Treating Patients With Stage III or Stage IV Melanoma That Cannot Be Removed With Surgery

OBJECTIVES:

Primary

- Determine the safety and maximum tolerated dose of anti-cytotoxic
T-lymphocyte-associated antigen-4 monoclonal antibody (CTLA4-blocking monoclonal
antibody; CP-675,206) administered with autologous dendritic cells pulsed with MART-1
antigen in patients with unresectable stage III or stage IV melanoma.

- Determine the biological activity and immune effects of this regimen in these patients.

Secondary

- Correlate CTLA4 genotype with safety of this regimen and/or immune response in these
patients.

- Determine, preliminarily, the efficacy of this regimen, in terms of clinical benefit
rate, in these patients.

OUTLINE: This is an open-label, dose-escalation study of anti-cytotoxic
T-lymphocyte-associated antigen-4 monoclonal antibody (CTLA4-blocking monoclonal antibody;
CP-675,206).

Patients receive CP-675,206 IV on days 0, 28, 60, and 90 and autologous dendritic cells
pulsed with MART-1 antigen intradermally on days 0, 14, and 28. After day 120, patients with
stable or responding disease may receive additional doses of CP-675,206 monthly in the
absence of disease progression or unacceptable toxicity

Cohorts of 3-6 patients receive escalating doses of CP-675,206 until the maximum tolerated
dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2
of 6 patients experience dose-limiting toxicity.

Patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 3-21 patients will be accrued for this study within 3-10
months.

Inclusion Criteria:

- Histologically confirmed cutaneous or mucosal melanoma, meeting criteria for 1 of the
following:

- Unresectable stage III disease (locally relapsed unresectable, in-transit lesions, or
unresectable draining nodes)

- Stage IV disease, metastatic to 1 of the following sites:

- Skin, subcutaneous tissues, or distant lymph nodes

- Lung

- Other visceral sites with lactic dehydrogenase ≤ 2 times upper limit of normal
(unless due to liver stasis)

- De novo metastatic disease allowed provided patient refused any standard or approved
stage-appropriate therapy for melanoma

- Measurable disease

- HLA-A2.1 positive (HLA-A*0201 by molecular subtyping)

- MART-1-expressing tumor by reverse transcription polymerase chain reaction or
immunohistochemistry

- No symptomatic brain metastases and/or progression of CNS metastases within the past
4 weeks

- Age 18 and over

- Performance status ECOG 0-1 OR

- Karnofsky 70-100%

- HIV negative

- Negative pregnancy test

- Fertile patients must use effective barrier contraception during and for 3 months
after study participation

- More than 30 days since prior immunotherapy for metastatic, relapsed, or primary
melanoma

- More than 30 days since prior chemotherapy for metastatic, relapsed, or primary
melanoma

- More than 4 weeks since prior corticosteroids

- More than 30 days since prior radiotherapy for metastatic, relapsed, or primary
melanoma

- More than 30 days since prior surgery for metastatic, relapsed, or primary melanoma.

- More than 30 days since other prior therapy for metastatic, relapsed, or primary
melanoma

- More than 14 days since prior anti-infective therapy

- More than 4 weeks since prior immune suppressive therapy (e.g., cyclosporine)

Exclusion Criteria:

- chronic hepatitis B or C

- asthma

- inflammatory bowel disease

- celiac disease

- history of chronic colitis or other chronic gastrointestinal conditions associated
with diarrhea or bleeding

- active chronic inflammatory or autoimmune disease, including any of the following:

- Psoriasis

- Rheumatoid arthritis

- Multiple sclerosis

- Hashimoto's thyroiditis

- Addison's disease

- Graves' disease

- Systemic lupus erythematosus

- active infection OR fever over 100° F within the past 3 days

- allergy to study drugs

- pregnant

- symptomatic seizures

- other medical problem that would preclude study participation

- prior melanoma immunotherapy containing MART-1 antigen

- prior anti-T-cell therapy

- prior anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody
(CP-675,206)

- organ allografts requiring long-term immune suppressive therapy