Comparison of MDX-010 Monotherapy, MDX-010 in Combination with a Melanoma Peptide Vaccine, and Melanoma Vaccine Monotherapy in HLA-A*0201 Positive Patients with a Previously Treated Unresectable Stage III or IV Melanoma

MDX-010 is a monoclonal antibody against CTLA-4 on the surface of activated T-cells. Interaction of the antibody with the CTLA-4 results in enhanced T cell responses and can lead to tumor rejection in animal models. Evaluation of animal models and early clinical findings also suggest that the efficacy of the antibody may be enhanced when it is combined with vaccine therapy.

Inclusion Criteria (conditions the patient must meet):

1. Diagnosis of malignant melanoma;
2. Measurable unresectable Stage III or IV melanoma;
3. At least 18 years of age;
4. Positive for HLA-A*0201;
5. Previous treatment with and failure/relapse/inability to IL-2, dacarbazine and/or temozolomide (in the judgment of the Investigator and documented in the patient’s chart);
6. At least 4 weeks since prior treatment (chemotherapy, biochemotherapy, surgery, radiation, hormone, immunotherapy, etc.) for melanoma;
7. Negative pregnancy;
8. Life expectancy greater than 4 months;
9. ECOG performance status of 0 or 1;
10. Laboratory values required to be in relatively normal range
11. HIV, Hepatitis B, and Hepatitis C negative.

Exclusion Criteria
Patients who exhibit any of the following conditions at screening will not be eligible for admission into the study:

1. Any other prior malignancy from which the patient has been disease-free for less than 5 years, except treated and cured basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix, or any other cancer;
2. Ocular melanoma;
3. Active, untreated CNS metastasis;
4. Prior treatment with an anti-CTLA4 antibody;
5. Prior treatment with any cancer therapeutic vaccine;
6. Active autoimmune disease or history of autoimmune disease;
7. Pregnant or nursing;
8. Hypersensitivity to Incomplete Freund’s Adjuvant (IFA);
9. Underlying medical conditions deemed hazardous if treated with study drug;
10. Concomitant therapy with anti-melanoma drugs, chemotherapies, other investigational therapies, chronic use of systemic corticosteroids;
11. Unable to provide informed consent.

Treatment Regimen
This is a randomized, double-blind, multicenter study in HLA-A*0201-positive patients with a diagnosis of unresectable Stage III or IV melanoma whose disease is not responding, or the patient could not tolerate, prior therapy.

Patients will be randomized in a double-blinded fashion in a 1:3:1 ratio (to achieve a total of 150:450:150 patients/group, respectively, to 1 of the following regimens: melanoma peptide vaccine monotherapy; MDX010 in combination with melanoma peptide vaccine; or MDX010 monotherapy.

The MDX010 or placebo will be administered intravenously every 3 weeks for 4 doses. The peptide vaccine or placebo will be administered subcutaneously every 3 weeks for 4 doses immediately following the MDX010 or placebo. The primary efficacy endpoint of the study is the objective response rate and secondary endpoints are overall survival, major durable response rate, duration of response, progression-free survival, evaluation of health-related Quality of Life, and time to progression.

The study also evaluates safety of the treatment, especially specific immune-mediated breakthrough events (IBEs).