The combination of TMZ and DAC may effect dual modulation of DNA repair genes resulting in
improved clinical response.
- 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.
- To determine pharmacokinetics of the combination of TMZ and DAC in patients with
- 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.
- 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)
- 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.