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:

1. Histologically confirmed, (surgically incurable or unresectable) stage III or IV
metastatic malignant melanoma.

2. Prior systemic therapy for metastatic disease is permitted but not required

3. A minimum of 1 measurable lesion according to irRC criteria.

4. ECOG performance status of 0-2.

5. Men and women, age ≥ 18 years.

6. 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

7. No active or chronic infection with HIV, Hepatitis B, or Hepatitis C

8. Patients must have recovered from effects of major surgery.

9. 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:

1. Brain metastases that are not treated and not stable for at least 1 month.

2. History of or known spinal cord compression, or carcinomatous meningitis, or evidence
of symptomatic brain or leptomeningeal disease on screening CT or MRI scan.

3. 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.

4. 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).

5. 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.

6. 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.

7. Any non-oncology vaccine therapy used for prevention of infectious diseases (for up
to one month prior to or after any dose of ipilimumab.

8. A history of prior treatment with ipilimumab, CD137 agonist, CTLA-4 inhibitor or
agonist; GM-CSF, or monoclonal antibody.

9. 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.

10. 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

11. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for
treatment of either a psychiatric or physical (e.g., infectious) illness

12. 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