Phase II Study of Interleukin-21 (rIL-21) vs Dacarbazine (DTIC) in Patients With Metastatic or Recurrent Melanoma

• Histologically documented cutaneous malignant melanoma which is recurrent or metastatic and is not curable by surgical or other means.
• Patients must have tumour tissue from their primary and/or metastatic tumour available to assess putative molecular markers of response (paraffin block or 12 unstained slides).
• Presence of clinically and/or radiologically documented disease. At least one site of disease must be unidimensionally measurable as follows:

Chest X-ray > 20 mm, CT scan (with slice thickness of \< 5 mm) >10 mm (longest diameter), Physical exam (using calipers) > 10 mm, Lymph nodes by CT scan > 15 mm measured in short axis.

All radiology studies must be performed within 21 days prior to randomization (Exception: Within 28 days if negative).

• Patients must have either maximum tumour lesion size of ≤ 50 mm OR if tumour lesion is > 50 mm, LDH must be ≤ 2.5 x ULN.
• Patients must have a life expectancy of at least 12 weeks.
• Age > 18 years.
• ECOG performance status of 0-1.
• Previous Therapy:

Immunotherapy: Prior adjuvant immunotherapy for melanoma is permitted if completed ≥ 1 month prior to study entry. No immunotherapy for metastatic disease is permitted. rIL-21 or dacarbazine must be the first systemic therapy for metastatic disease.

Chemotherapy: Patients must not have received any prior chemotherapy (including regional therapy). rIL-21 or dacarbazine must be the first systemic therapy for metastatic disease (except for RAF and MEK-Inhibitors).

Surgery: Previous surgery is permissible. Patient must be > 4 weeks since any major surgery.

Radiation Therapy: Previous radiation therapy is permitted with exception of radiation therapy for brain metastases. Patients must be > 4 weeks since the last treatment with radiation. Exceptions may be made, however, for low dose, non-myelosuppressive radiotherapy. Patients must have recovered from the toxic effects of radiation.

• Laboratory Requirements: (must be done within 7 days prior to randomization) Hematology: Absolute granulocytes (AGC) ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L Chemistry: Serum creatinine ≤ 1.5 x UNL, Bilirubin ≤ UNL AST and ALT ≤ 2.5 x UNL, LDH ≤ 2.5 x UNL.
• Female patients of child-bearing potential must have a negative serum or urine pregnancy test within 7 days of enrollment.
• Sexually active patients must agree to use a medically accepted form of contraception while receiving study therapy.
• Patient consent must be obtained according to local Institutional and/or University Human Experimentation Committee requirements. It will be the responsibility of the local participating investigators to obtain the necessary local clearance, and to indicate in writing to the NCIC CTG Study Coordinator that such clearance has been obtained, before the trial can commence in that centre. Because of differing requirements, a standard consent form for the trial will not be provided but a sample form is given in Appendix VII. A copy of the initial REB approval and approved consent form must be sent to the central office. The patient must sign the consent form prior to randomization. Please note that the consent form for this study must contain a statement which gives permission for qualified representatives of the NCIC CTG, BMS, ZymoGenetics, the company collaborator, and regulatory authorities to review patient records (see section 16 for further details) and a statement which gives permission for NCIC CTG to access and study tissue for biomarker assessments.
• Patients must be accessible for treatment and follow-up. Patients randomized on this trial must be treated and followed at the participating centre. This implies there must be reasonable geographical limits (for example: 2 hour's driving distance) placed on patients being considered for this trial.
• In accordance with NCIC CTG policy, protocol treatment is to begin within 5 working days of patient randomization.

Exclusion Criteria:

• Patients with known HIV, Hepatitis B or Hepatitis C infection.
• History of other malignancies, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for > 5 years.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, myocardial infarction, other interventional cardiac procedure within the past 12 months, autoimmune conditions requiring chronic immunosuppressive therapy, or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients may not have received any other investigational agents within 28 days of study entry, and may not receive concurrent treatment with other anti-cancer therapy or investigational agents while on protocol therapy.
• Patients with known brain metastases or history of CNS metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. A head CT or MRI is required on all patients to rule out brain metastases.
• Pregnant or lactating women. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with rIL-21 or dacarbazine, breastfeeding should be discontinued if the mother is treated with protocol therapy.
• Prohibited Medications: Long Term (> 7 days) Systemic Corticosteroids (e.g. prednisone, dexamethasone, etc.) because these may counteract the stimulatory effects of rIL-21 on lymphocytes. (Note: Topical steroids are allowed).