RFT-5-dgA in Patients With Metastatic Melanoma

Background:

• RFT5-dgA is an immunotoxin comprised of the IL-2Ra-specific murine IgG1 antibody RFT5 linked to deglycosylated ricin A chain (dgA) via the sterically hindered heterobifunctional disulfide linker SMPT (4-succinimidyl-oxycarbonyl-a-methyl-a-(2-pyridyldithio)-toluene).
• RFT5-dgA is a recombinant immunotoxin that selectively targets CD25 expressing cells in vivo. Further, treatment of human PBMC with RFT5-dgA in vitro results in the preferential depletion of CD25+ Treg cells.
• Depletion of Treg cells can enhance tumor protection to tumor-associated antigens expressed as self antigens and the RFT5-dgA immunotoxin had potent antitumor effects in SCID mice xenografted with L540 cells which express CD25.
• The MTD established in the phase I trial of RFT5-dgA was 15mg/m(2)/course IV.

Objectives:

• The primary objective is to determine whether objective clinical responses can be obtained in patients with metastatic melanoma following administration of RFT5-dgA.
• Secondary objectives will determine whether changes occur in levels of CD4+CD25+ regulatory T cells (Treg cells) in peripheral blood from before to after treatment and evaluate the toxicity profile of patients treated on this trial.

Eligibility:

• Patients greater than 18 years of age with measurable metastatic melanoma, an expected survival greater than three months, who have progressed after receiving standard therapy will be included.
• Standard clinical laboratory values must be normal for study inclusion and patients may not be pregnant, breast-feeding or require anticoagulation.
• Patients must be willing to undergo leukapheresis.
• Patients with active infections, other major medical disorders, HAMA levels greater than 1 ug/mL, or who have had prior radiotherapy or who have extensive lung disease will be excluded.

Design:

• Patients will receive 3 mg/m(2) RFT5-dgA intravenously every other day for a total of 3 doses (one course).
• Four to five weeks after the last dose, patients will undergo tumor evaluation, evaluation of changes in T-regulatory cells (CD4+CD25+cells and Foxp3 expression), and toxicity assessment.
• One additional course may be administered to patients with stable disease or partial or complete response.
• Up to 41 evaluable patients may be accrued to determine whether theRFT5-dgA can produce a modest response rate targeted to be 20 percent (p1=0.20)
• Enrollment reflects the anticipated enrollment. Actual enrollment is unknown due to no longer having access to the data as records were destroyed

• INCLUSION CRITERIA:

• Patients age greater than 18 with measurable metastatic melanoma that have an expected survival of greater than three months will be considered. Patients with resectable local/regional disease would undergo standard treatment with surgical resection and will not be eligible.
• Patients must be able to understand and give informed consent.
• Patients must have progressed while receiving standard therapy which may include IL-2; however, prior IL-2 therapy is not a requirement for enrollment.
• Serum creatinine of 1.6 mg/dl or less.
• Total bilirubin 2.0 mg/dl or less, except for patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl.
• WBC 3000/mm(3) or greater.
• Platelet count 90,000 mm(3) or greater
• Serum albumin greater than 2.5 g/dl,
• Serum AST/ALT less then 2.5 times normal,
• ECOG performance status of 0 or 1 or 2.
• For patients greater than 50 years of age or who have a history of cardiovascular disease a thallium stress test is required with EF greater than or equal to 45%.
• Patients of both genders must be willing to practice effective birth control during this trial.
• Patients must be willing to undergo leukapheresis.

Exclusion criteria

Patients will be excluded:

• who are undergoing or have undergone in the past 3 weeks any other systemic form of therapy for their cancer.
• who received RFT5-dgA on another trial.
• who have uncontrolled concurrent illness including, but not limited to: ongoing or active infection; ongoing or active cardiac disease, such as symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia; or psychiatric illness/social situations that would limit compliance with study requirements.
• who require systemic steroid therapy upon entry into the trial.
• who are pregnant or breast-feeding.
• who are known to be positive for hepatitis B(s)AG, hepatitis C or HIV antibody (because of possible immune effects of these conditions).
• who require chronic anticoagulation.
• who are 50 years old or greater who do not have a normal stress cardiac test (stress thallium, stress MUGA, dobutamine echocardiogram, or other stress test) with a LVEF less than 45%.
• who have history of EKG abnormalities, symptoms of cardiac ischemia or arrhythmias who do not have a normal stress cardiac test (stress thallium, stress MUGA, dobutamine echocardiogram, or other stress test) with a LVEF lea than 45%.
• who have any autoimmune diseases or immunodeficiency (including HIV),or other concurrent malignancies.
• Who have HAMA levels greater than 1 ug/mL.
• Who have had prior radiotherapy including radiotherapy to the lung, except for patients who have undergone localized soft tissue radiotherapy.
• Who have extensive lung disease where greater than 15% of the lung is involved based on CT evaluation.