• Efficacy
  
• Phase II: assess the anti-neoplastic activity, as determined by overall response rate (complete plus partial responses) according to the RECIST criteria
  
• Phase III: evaluate and compare the survival time of the two treatment groups, as selected in Phase II, to DTIC alone
  
• Safety- drug exposure, adverse events, laboratory tests, vital signs, ECG, and physical examinations
  

• Secondary Efficacy
  
• -overall response rate (complete plus partial responses) according to the RECIST criteria (in Phase III)
  
• -degree of clinical benefit defined as the proportion of patients experiencing complete response,partial responses, stable disease
  
• -duration of response
  
• -time to progression
  
• -pharmacokinetic profile and immunopharmacodynamic response
  

In phase II, 160 eligible patients will be randomized in a balanced allocation to CPG 7909 Injection current dose (10 mg given in two 5 mg injections); CPG 7909 Injection intensified dose (40 mg given in four 10 mg injections); CPG 7909 Injection 40 mg plus DTIC; or DTIC alone. An interim analysis will be performed after 160 patients have completed the cycle 5 tumor burden assessment to determine the optimal two arms, based on overall response rate, to continue to Phase III. Subsequent to the interim analysis, three-hundred-seventy patients will be enrolled into Phase III of the trial in a balanced randomization to two arms; either 1:1 DTIC alone or CPG 7909 monotherapy or 1:1 DTIC alone or CPG 7909 in combination with DTIC.

In the monotherapy arms, CPG 7909 Injection will be administered subcutaneously every week. In the combination arm, CPG 7909 Injection will be administered subcutaneously weekly, and chemotherapy will be administered on Week 1 (Day 1) of a three-week cycle. In the DTIC monotherapy arm, patients will receive DTIC on week 1 (Day 1) of a three-week cycle. All patients will undergo complete disease evaluation at the end of the third treatment cycle and then at the end of every other treatment cycle (after cycles 3, 5, 7 etc.) until confirmation of disease progression.

Patients will remain on study until the development of objective tumor progression, as defined by RECIST criteria, is confirmed; intolerance to any study medication; or until any other protocol conditions for withdrawal are met.

Inclusion criteria:

• Histologically or cytologically confirmed melanoma that is metastatic (unresectable Stage III b/c or Stage IV according to AJCC 2002, Appendix D).
• Patients must have measurable disease according to the RECIST criteria (Appendix F). A cutaneous or subcutaneous lesion identified as a target lesion must be at least 10 mm in diameter in one dimension.
• Age > 18 years
• Karnofsky Performance Status of > 70
• Adequate bone marrow reserve as evidenced by WBC > 3,000/mL, ANC > 1,500/mL, and PLT > 100,000/mL
• Adequate renal function as evidenced by serum creatinine < 2.0 mg/dL
• Adequate hepatic function as evidenced by serum total bilirubin < 2.0 mg/dL, AST < 5 X ULN for the reference lab
• LDH ≤ 3 times upper limit of normal
• Patients must be recovered from the effects of any prior surgery or radiotherapy
• Patients or their legal representatives must be able to understand and provide informed consent to participate in the trial

Exclusion Criteria:

• Patients with active infection or with a fever >38.50 C within three days prior to the first scheduled day of dosing
• Prior treatment with anti-neoplastic biologic or chemotherapy for recurrent or metastatic disease (except one course of adjuvant immunotherapy and/or adjuvant chemotherapy which completed at least four weeks prior to Day 1)
• Patients with suspected or known CNS metastases
• Pre-existing autoimmune or antibody-mediated diseases including but not limited to: systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sjogren's syndrome, autoimmune thrombocytopenia
• Significant cardiovascular disease (e.g., NYHA class 3 congestive heart failure; myocardial infarction within the past 6 months; unstable angina; coronary angioplasty within the past 6 months; uncontrolled atrial or ventricular cardiac arrhythmias)
• Chloroquine and related compounds within 12 weeks of study entry (1st dose of protocol therapy)
• Current treatment with phenytoin or phenobarbital
• The need for pharmacologic doses of systemic steroids will be excluded; but replacement doses, topical or inhalation glucocorticoids are permitted.
• Patients who have received an investigational therapy within 30 days of study entry (1st dose of protocol therapy)
• History of other prior malignancy within the past 5 years other than basal cell carcinoma of the skin or cervical intra-epithelial neoplasia, or cured, early prostate cancer in a patient with PSA < 10 ng/mL
• Patients with known hypersensitivity to any of the components of CPG 7909 Injection or to dacarbazine
• Serious medical or psychiatric condition, which would hinder the patient's ability to fully comply with the protocol
• Patients who are pregnant or lactating. Adults of reproductive potential and their partners must agree to use effective contraceptive measures
• Known HIV