Combination of Decitabine and Temozolomide in the Treatment of Patients With Metastatic Melanoma

Phase I/II Trial of the Combination of Decitabine and Temozolomide in the Treatment of Patients With Metastatic Melanoma

The combination of TMZ and DAC may effect dual modulation of DNA repair genes resulting in improved clinical response.

Primary Objectives:

• Phase I: To determine the safety, tolerability, and Phase II recommended dose of the combination of extended schedule TMZ and DAC.
• Phase II: To determine the efficacy, as measured by overall response rate, of the combination of extended schedule TMZ and DAC given at the Phase II recommended dose to patients with metastatic melanoma.

Secondary Objectives:

• To determine pharmacokinetics of the combination of TMZ and DAC in patients with metastatic melanoma.
• To determine, in peripheral blood mononuclear cells (PBMC) and tumor tissue, the pharmacodynamic effects of the combination of TMZ and DAC on promoter methylation and expression of selected genes and correlate these with response.
• To determine the progression-free survival of patients treated with the combination of TMZ and DAC.

Inclusion Criteria:

• Patients who have non-resectable Stage IIIB or stage IV metastatic melanoma that have progressed despite prior therapies.
• Life expectancy of at least 12 weeks.
• ECOG performance status of 0, 1 and 2.
• ≥18 years of age.
• Patients who have not received any other chemotherapeutic, biological or investigational agent within 28 days of study drug administration.
• First line and active brain metastases (metastatic lesions to the brain that have been adequately treated with surgery and/or appropriate radiation therapy and that have documented stability for >4 weeks or >2 weeks if treated with stereotactic radiosurgery, remain eligible)

Exclusion Criteria:

• Any evidence of renal dysfunction (proteinuria, estimated creatinine clearance from serum creatinine test of <60 ml/min).
• Impaired hepatic function (liver enzymes greater than twice the upper limit of normal or bilirubin > 2.0 except in patients with Gilbert's syndrome).
• Prior treatment with alkylating agents (including TMZ and DTIC).
• Active brain metastases (metastatic lesions to the brain that have been adequately treated with surgery and/or appropriate radiation therapy and that have documented stability for >4 weeks remain eligible).
• Active infections or serious general medical conditions.
• Female patients of child-bearing age who are not on adequate contraception, or are pregnant or breast-feeding.