Comparison Study of Dendritic Cell Vaccine With and Without Cyclophosphamide to Treat Stage IV Melanoma Patients

Vaccination of patients with metastatic melanoma using ex vivo generated dendritic cells
(DCs) loaded with tumor-associated antigen(s) have been shown to induce tumor-specific
immunity against melanoma antigens measured by in vitro assays and, in some cases, tumor
regression. At the present time, the numbers of recorded patients with metastatic melanoma
who have been treated with DC vaccinations are too small to predict with certainty the future
of overall therapeutic value of DC vaccinations in the management of patients with metastatic
melanoma. The purpose of this study is to gather data on feasibility and efficacy of novel
combination therapy of CPA and a DC vaccine outlined in this protocol to treat metastatic
melanoma.

Inclusion Criteria:

1. Biopsy-proven metastatic melanoma, Stages M1a, M1b, M1c

2. HLA-A*0201 phenotype

3. Age: 21-75 years

4. ECOG performance status 0-1

5. Measurable metastatic melanoma lesions by physical examination or radiographs or
scans.

6. Adequate marrow function:

- White count ≥ 4,000/microliter: Subjects who have recently completed chemotherapy
will be allowed study entry with White count ≥ 3,500/microliter

- Hemoglobin ≥ 10.0 gm: Subjects who have recently completed chemotherapy will be
allowed study entry with Hemoglobin ≥ 9.0 gm.

- Platelets ≥ 100,000/microliter

7. Adequate hepatic function:

- Bilirubin ≤ 1.5/mg/dL

- Alkaline phosphatase ≤ 5 times the upper limit of normal

- SGOT ≤ 5 times the upper limit of normal

- SGPT ≤ 5 times the upper limit of normal

8. Adequate renal function:

- Serum creatinine ≤ 1.5/mg/dL

9. No active CNS metastatic disease at screening.

- Patients with a history of CNS melanoma lesions must have had lesions resected by
surgery and/or gamma knife irradiation at least 3 months prior to study entry.

- The total number of CNS lesions at diagnosis should not have exceeded 3.

10. Written informed consent

Exclusion Criteria:

1. Patients who have received > 8 cycles of cytotoxic chemotherapy or metastatic melanoma

2. Patients who have received any chemotherapy < 4 weeks before the beginning of the
trial

3. Patients who have received interferon alpha (IFNα-2b) or sargramostim (GM-CSF) < 4
weeks before the beginning of the trial

4. Patients who have received high-dose interleukin-2 (IL-2) < 4 weeks before the
beginning of the trial

5. Patients that have been diagnosed with more than 3 CNS melanoma lesions.

6. Patients that have been diagnosed with more than 5 hepatic metastases or any hepatic
metastasis > 5 cm.

7. Baseline serum LDH > 1.1 times the upper limit of normal

8. Patients who are HIV+ (HIV patients are often profoundly immunodeficient because of
the viral infection and this additional parameter will interfere with the evaluation
of DC induced immune responses in melanoma patients. Furthermore, the safety of
collecting DCs, loading them with antigen and re-infusing these cells to HIV+ patients
has not yet been determined.)

9. Pregnancy (Pregnancy is associated with considerable immunosuppression 70 and this
additional parameter will interfere with the evaluation of DC induced immune responses
in melanoma patients. In addition, the safety and tolerability of cell body-loaded DC
given subcutaneously is entirely unknown.)

10. Patients who have received corticosteroids or other immunosuppressive agents < 4 weeks
before beginning the trial

11. Patients with active asthma and/or on treatment for asthma

12. Patients with angina pectoris

13. Patients with congestive heart failure

14. Patients with a history of autoimmune disease including lupus erythematosus,
rheumatoid arthritis or thyroiditis

15. Patients with active infections including viral hepatitis

16. Patients with a history of neoplastic disease other than melanoma < 5 years prior to
entry on the trial except for patients with carcinomas in situ of the cervix and
basal/squamous cell carcinomas of the skin. Patients who have any of these two types
of cancer and melanoma can be included.