Trial Information

Studies on the Mechanism of Action of High-Dose IL-2 in Metastatic Melanoma and Renal Cell Cancer

Background:

- Although interleukin-2 (IL-2) was approved as standard therapy by the US Food and Drug
Administration for metastasis melanoma and renal cell carcinoma, the mechanism of
action in these patient populations is still not completely understood.

- Methods for studying regulatory T-cells and measuring recently discovered cytokines
were not available during earlier studies of IL-2 administration.

Objectives:

- Explore peripheral blood samples of patients with metastatic renal cell cancer or melanoma
receiving high-dose IL-2 to identify serum protein levels and lymphocyte phenotypes that may
be associated with or predictive of tumor regression.

Eligibility:

- Patients with metastatic renal cell cancer or melanoma who are greater than or equal to
18 years of age, with an ECOG of 0 or 1 who have an expected survival greater than
three months.

- Patients with systemic infections, coagulation disorders, or major medical illnesses of
the cardiovascular, respiratory or immune system will be excluded, including patients
with ejection fractions less than 45% or FEV1 or VC less than or equal to 60%
predicted.

- Patients must not have had prior therapy within 28 days, previous IL-2 therapy, be
pregnant, have untreated or clinically significant tumor involvement of the CNS or
major nerve compression, or have greater than 25% estimated hepatic replacement.

Design:

- Aldesleukin 720,000 IU/kg intravenous bolus over 15 minutes every eight hours for up to
12 doses will be administered as a cycle of treatment.

- Seven to 10 days after discharge, a second cycle of treatment will be administered.

- 20 mLs of blood for serum and 20 mLs of blood for peripheral blood cells will be
collected daily during the first cycle of aldesleukin administration and the day
following the last dose. 20 mLs of blood for serum and 50 mLs of blood for cell
separation will be obtained on days 2 through 4 following completion of IL-2
administration. On one of these days, an additional 50 mLs of blood for cell
separation or a 2 hour apheresis may be substituted.

- Approximately two months from the beginning of therapy, a response assessment will be
performed.

- Patients with stable or regressing disease will receive a second complete treatment
course. Subsequent courses may be administered if there is evidence of on-going tumor
regression without long-term or irreversible toxicity.

- In the first 5 patients of each diagnosis (metastatic renal cell cancer and melanoma)
the following cytokine levels will be assayed: VEGF, CD40L, FASL, TRAIL, GRO-alpha,
IP10, GM-CSF, IFN-gamma, IFN-alpha, IL-1, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15,
TNF-alpha, TNF-beta; and the following phenotypic markers will be studied: CD3, CD4,
CD8, CD16, CD25, CD27, CD28, CD56, CD80, CD95, CD107a, CD152, FoxP3, annexin V.

- After the first 10 patients have been analyzed, the scope of the tests will be narrowed
to those which show a response to IL-2.

- Initially, a total of 127 evaluable patients with melanoma will be enrolled, with a
presumed 15% response rate. With the approval of amendment F, a new accrual ceiling
of 200 patients with metastatic melanoma will be established to complete the proposed
analysis.

- A total of 100 evaluable patients with renal cell carcinoma will be enrolled with a
presumed 20% response rate.

- Allowing for a small number of inevaluable patients, a total of 200 patients with
melanoma and 110 patients with renal cell carcinoma may be enrolled.