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

A Phase I, Open Label, Study To Evaluate The Safety And Immune Function Effects Of CP-675,206 In Combination With MART-1 Peptide-Pulsed Dendritic Cells In Patients With Advanced Melanoma

RATIONALE: Biological therapies, such as CP-675,206, work in different ways to stimulate the immune system and stop tumor cells from growing. Vaccines may make the body build an immune response to kill tumor cells. Combining CP-675,206 with vaccine therapy may cause a stronger immune response and kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of CP-675,206 when given with 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