Granulocyte Macrophage-Colony Stimulating Factor and Ipilimumab as Therapy in Melanoma

The study is an open-label, single arm single Center Phase II study to evaluate the safety and efficacy of the combination of Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF, Leukine) and Ipilimumab (Yervoy) as therapy for patients with unresectable metastatic malignant melanoma. The patient sample will be approximately 43 evaluable individuals, males and females 18 years of age or older with measurable metastatic melanoma. Immunologic testing will be done to evaluate correlation with clinical outcome.

Patients will be treated with 4 courses of GM-CSF and ipilimumab administered every 3 weeks. GM-CSF will be administered subcutaneously daily for 14 days in a dose of 125 µg/m2 beginning on D1 of each 21-day cycle. Ipilimumab intravenously in a dose of 10 mg/kg, with appropriate stopping/de-escalation rules. After the initial 3 months (4 cycles) of treatment, GM-CSF administration will continue for 4 additional cycles on the same schedule and dose without ipilimumab for 14 days every 21 days until month 6. Maintenance therapy will begin at month 6 and will consist of ipilimumab in the same dose administered at the end of cycle 4 combined with 14 days of GM-CSF. Administration of this combination will be repeated every 3 months for up to 2 years or until disease progression, whichever occurs first. During the maintenance phase, GM-CSF will only be administered for 14 days in conjunction with ipilimumab and will not be administered in the intervening time period.

Inclusion criteria

• Histologically confirmed, (surgically incurable or unresectable) stage III or IV metastatic malignant melanoma.
• Prior systemic therapy for metastatic disease is permitted but not required
• A minimum of 1 measurable lesion according to irRC criteria.
• ECOG performance status of 0-2.
• Men and women, age ≥ 18 years.
• Adequate hematologic, renal and liver function as defined by laboratory values performed within 14 days prior to initiation of dosing.

• WBC ≥ 2000/uL
• Absolute neutrophil count (ANC) ≥ 1000/uL
• Platelet count ≥ 50,000/uL
• Hemoglobin ≥ 8.0 g/dL
• Serum creatinine ≤ 3.0 x upper limit of normal
• Total serum bilirubin ≤ 3.0 x upper limit of normal (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL
• LDH ≤ 4 times upper limit of laboratory normal
• Serum aspartate transaminase (ASAT/SGOT) or serum alanine transaminase (ALAT/SGPT) ≤ 2.5 times upper limit of laboratory normal for patients without liver metastases
• Alkaline phosphatase ≤ 2.5 times upper limit of normal, unless bone metastasis is present in the absence of liver metastases
• No active or chronic infection with HIV, Hepatitis B, or Hepatitis C
• Patients must have recovered from effects of major surgery.
• Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the study in such a manner that the risk of pregnancy is minimized.

WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal. Post-menopausal is defined as:

• Amenorrhea ≥ 12 consecutive months without another cause, or
• For women with irregular menstrual periods and taking hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level ≥ 35mIU/mL].

Exclusion criteria

• Brain metastases that are not treated and not stable for at least 1 month.
• History of or known spinal cord compression, or carcinomatous meningitis, or evidence of symptomatic brain or leptomeningeal disease on screening CT or MRI scan.
• Any other malignancy from which the patient has been disease-free for less than 5 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix.
• Autoimmune disease: Patients with a history of inflammatory bowel disease are excluded from this study as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis (e.g., Wegener's Granulomatosis), motor neuropathy considered of autoimmune origin (e.g. Guillain-Barré Syndrome).
• Any underlying medical condition, which in the opinion of the Investigator, will make the administration of study drug hazardous or obscure the interpretation of AEs, such as a condition associated with frequent diarrhea.
• Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before trial entry.
• Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to one month prior to or after any dose of ipilimumab.
• A history of prior treatment with ipilimumab, CD137 agonist, CTLA-4 inhibitor or agonist; GM-CSF, or monoclonal antibody.
• Concomitant therapy with any of the following: IL-2, interferon or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids.
• Women of child-bearing potential (WOCBP) who:

• are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 8 weeks after cessation of study drug, or
• have a positive pregnancy test at baseline, or
• are pregnant or breastfeeding
• Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness
• Persons of reproductive potential must agree to use and utilize an adequate method of contraception throughout treatment and for at least 8 weeks after study drug is stopped