Medical Summary
This is an open-label multi-center, randomized study to evaluate the efficacy and safety of maxamine[TM], in combination with interferon-µ2b and interleukin-2 as compared to Dacarbazine in patients with stage IV metastatic melanoma.
Maxamine[TM] is histamine dihydrochloride, a 2-(1-H-imidazol-4-yl) ethylamine dihydrochloride. Maxamine[TM]is proposed for use as an adjunct to immunotherapy with interferon-µ2b plus interleukin -2 to prolong survival and improve quality of life in patients with malignant melanoma. The major acute toxicities experienced with maxamine[TM]may include transient hypotension, tachycardia and tachypnea, mucosal congestion, coughing, urticaria, rash, facial flushing, metallic taste, headaches and possible aggravation of asthma. Maxamine is contraindicated in patients with a history of hypersensitivity to histamine or histamine products.

Dacarbazine(DTIC) is an alkylating agent. Dacarbazine is commercially available and indicated for the treatment of metastatic malignant melanoma. The major toxicities seen are hemopoietic depression, primarily affecting the leukocytes and platelets, although anemia may sometimes occur. Hepatic toxicity accompanied by hepatic vein thrombosis and hepatocellular necrosis resulting in death has been reported although such incidences have been low (approximately 0.01% of patients treated). Anaphylaxis can occur following the administration of DTIC.

The objectives of the study include; to evaluate clinical efficacy measured as survival. Secondary measures of clinical efficacy are survival of patients with liver metastases, objective tumor response rate, and duration of response; to further characterize the safety and toxicities (adverse events) including dose limiting toxicities, should any occur; to evaluate health-related quality of life between treatment groups before and during the study; to evaluate the resource utilization and corresponding costs incurred for economically significant health care services outside the clinical protocol and; to adjust survival time for quality of life using the EuroQol EQ-5D scores to calculate the incremental cost of quality-adjusted survival time gained associated with Maxamine[TM] therapy combined with IL-2 and IFN-µ2b versus DTIC.

Treatment will be administered on an outpatient basis at the Jewish General Hospital in the Clinical Research Unit. Patients will be randomized to Arm A or B. Treatment on Arm A consists of Interferon-µ2b 3.0 million IU fixed dose s.c. daily for each week of study, Interleukin-2 2.4 million IU/m2 s.c. bid days 1-5, weeks 1 and 2 and Maxamine[TM] 1.0 mg s.c. bid 5 days per week, days 1-5 throughout treatment cycle. Treatment on Arm B consists of Dacarbazine 850mg/m2 IV on day one and every three weeks thereafter. Patients will be first prestratified on the basis of liver metastasis (present or absent) and then randomized to one of two treatment groups. Randomization will be done in consecutive sequence within each center.

Lay Summary
This is a study for patients with metastatic melanoma. Metastatic melanoma is non-responsive to many forms of therapy. Most chemotherapy drugs provide only a minor tumor response. This study is designed to evaluate the effectiveness of experimental immune therapy compared to standard chemotherapy.

Maxamine (Histamine), which is a new drug, has been reported to improve the effectiveness of immune therapy in patients who have melanoma which has spread to the liver. In this study, three drugs will be used namely: Interlukin-2, Interferon-a2b and Maximine. This will be compared to chemotherapy called Dacarbazine.

Patients will be selected by chance to receive either the experimental treatment or the standard chemotherapy. If you are chosen to receive the experimental (immune) therapy, the Interferon-a2b will be given by an injection under the skin (subcutaneous) every day for four weeks and the Interlukin-2 and Maxamine will be given by subcutaneous injections twice a day for four weeks. You will be shown how to self-administer these medications. You will be required to return to the clinic once a month for blood tests and evaluations. If on the other hand, you are selected for chemotherapy , you will be receiving Dacarbazine intervenously over 1 to 4 hours, which will be repeated every three weeks following a clinic evaluation . Study treatment will continue for at least 12 weeks and may continue longer if you and your physician agree to do so. Eligible patients may have received previous chemotherapy (except Dacarbazine), surgery, radiation therapy, immunotherapy (except Interlukin-2) or be untreated. Patients should have normal bone marrow, heart, kidney and liver function.

1. Males and females 18 years of age and older with progression of histologically (cytologically) proven Stage IV malignant melanoma.
2. Patients may be untreated, surgically treated, or may have received previous regiments of chemotherapy (except with DTIC), radiation therapy, or immunotherapy (except with IL-2).
3. There must be one or more bidimensionally measurable masses (in some cases, unidimensional lesions will be acceptable), taken within 3 weeks of the randomisation date. Measurements may be made by x-ray, CT or MRI scans, photograph or palpable masses. Initial brain scans should be, if possible, with MRI. Lesions such as skin nodules or superficial lymph nodes that can be evaluated by clinical examination, or tumors with clear circamferences on x-rays, CT or MRI scans, are considered measurable .
4. Have a life expectantcy of 3 months or more and be able to undergo routine outpatient evaluations for efficacy, safety, and/or compliance.
5. Have clinically adequate bone marrow, kidney, cardiac and liver function: Hemoglubin greater than 10.0 g/dL, white blood cell count greater than 2.5 x 10⁹ cells/L, absolute neutrophil count greater than 1.5 x 109 cells/L, platelet count greater than 100 x 10⁹/L and Partial Thromboplastin Time (PTT or APTT) within normal limits at time of pre-study evaluation; Creatinine clearance of at least 60 mL/min.; Serum bilirubin less than 1.5 times the upper limits of normal and AST (ASAT or ALAT) less than 3 times the upper limits of normal; Serum glucose less than 160 mg/dL, Normal cardiac function.
6. Have recoverred from the toxicity of and receive no other systemic antimalignancy therapy during the study including corticosteroid medication (except as per Section 7) or any investigational drugs within 14 days before initiation of therapy.
7. Have a Karnofsky status of 70 or greater.
8. The patient must be informed of the investigational nature of this study and Informed Consent obtained
9. Patients must not have any concurrent systemic antimalignancy therapy or radiation therapy to measurble malignant masses, and n o other ongoing active malignancies except in situ carcinoma of the cervix, localized squamous or basal cell carcinomas of the skin.
10. Patients cannot have primary or metastatic central nervous system malignancy at randomisation. However, patients with metastasis to the brain that have been completely resected or resolved may be included in the study.
11. Patients cannot have previous documented history of asthma treated within the last 5 years, respiratory insufficiency defined as FEV, and FVC < 70% of predicted by pulmonary function test or SaO2 < 90% by pulse oximetry. or a history of seizures, central nervous system disorders, or psychiatric disability thought to be clinically significant in the opinion of the investigator and adversely affecting compliance to protocol.
12. Serum HIV negative. Patients who become positive during the course of the study must be terminated.