Pilot Study of Denileukin Diftitox Plus High-Dose IL-2 for Patients With Metastatic Renal Cancer

OBJECTIVES:

Primary

• Determine the toxic effects of denileukin diftitox and high-dose interleukin-2 in patients with metastatic renal cell cancer.

Secondary

• Perform transforming growth factor (TGF)-beta promoter and TGF-beta receptor genotyping to search for variants that may be associated with tumor response to therapy.
• Determine the overall response rate (partial and complete) in patients treated with this regimen.
• Determine the time to progression in patients treated with this regimen.

OUTLINE: This is a randomized, pilot study.

The first 3 patients enrolled in the study receive high-dose interleukin-2 (IL-2) IV over 15 minutes, 3 times daily, on days 1-5 and 15-19 and denileukin diftitox IV over 15-60 minutes once daily on days 8-10. If no dose-limiting toxicity occurs after receiving denileukin diftitox, subsequent patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive denileukin diftitox (at a higher dose than for the first 3 patients enrolled in the study) IV over 15-60 minutes once daily on days -4 to -2 and high-dose IL-2 IV over 15 minutes, 3 times daily, on days 1-5 and 15-19.
• Arm II: Patients receive high-dose IL-2 as in arm I and denileukin diftitox (at a higher dose than for the first 3 patients enrolled in the study) IV over 15-60 minutes at a higher dose once daily on days 8-10.

All patients may receive additional treatment with IL-2 alone in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for at least 4 years.

PROJECTED ACCRUAL: A total of 13 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Documented histologically confirmed metastatic renal cell carcinoma

• Clear cell histology
• Disease must be measurable as defined by lesions that can be accurately measured in at least one dimension with longest diameter > 20 mm using conventional techniques or > 10 mm with spiral CT scan

• Must have at least one measurable lesion
• If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology
• Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes)
• The following are considered nonmeasurable lesions:

• Bone lesions
• Leptomeningeal disease
• Ascites
• Pleural/pericardial effusion
• Inflammatory breast disease
• Lymphangitis cutis/pulmonis
• Cystic lesions
• Abdominal masses not confirmed and followed by imaging techniques
• No CNS metastases

PATIENT CHARACTERISTICS:

• ECOG performance status < 2
• Life expectancy of at least 4 months
• Serum creatinine < 2.0 mg/dL OR creatinine clearance > 50 mL/min
• Total bilirubin normal
• Platelets > 100,000/mm³
• WBC > 3,500/mm³
• No evidence of congestive heart failure
• No symptoms of coronary artery disease
• No serious cardiac arrhythmias
• A pretreatment cardiac stress test must be performed within 42 days of IL-2 treatment if any cardiac symptoms are present (patients with documented ischemia on the pretreatment cardiac stress test will be excluded from the study)
• Adequate pulmonary reserve

• Pulmonary function tests (PFTs) must be performed within 42 days of IL-2 treatment

• FEV_1 > 2.0 liters of > 75% predicted for height and age
• Patients unable to perform PFTs will be excluded
• Women who are pregnant or lactating are not eligible
• Women of childbearing potential and sexually active males must commit to the use of effective contraception while on study
• Negative pregnancy test
• No known HIV-positive patients
• No evidence of active infection requiring antibiotic therapy
• Must not have a contraindication to treatment with pressor agents
• Must not have any significant medical disease that, in the opinion of the investigator, may interfere with completion of the study
• No history of another malignancy within the past 5 years other than basal cell skin cancer

PRIOR CONCURRENT THERAPY:

• Recovered from all toxic effects of prior therapy
• Must not currently receive chronic medication for asthma
• No prior interleukin-2 (IL-2) therapy
• No prior organ allografts
• No systemic corticosteroids in the 4 weeks prior to treatment
• No concurrent systemic steroids
• No radiotherapy, chemotherapy, or immunotherapy in the 4 weeks prior to the first dose of study treatment
• No concurrent radiotherapy, chemotherapy, or other immunotherapy
• No previous investigational agent within 4 weeks prior to the start of study treatment