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

Study Overview
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Brief Summary
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RATIONALE: Combinations of biological substances in denileukin diftitox may be able to carry tumor-killing substances directly to kidney cancer cells. Interleukin-2 may stimulate the white blood cells to kill kidney cancer cells. Giving denileukin diftitox together with interleukin-2 may kill more tumor cells. PURPOSE: This randomized phase I trial is studying the side effects of denileukin diftitox and interleukin-2 in treating patients with metastatic kidney cancer.

Detailed Description
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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.

Official Title
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A Pilot Study of Denileukin Diftitox in Combination With High-Dose IL-2 for Patients With Metastatic Renal Cell Carcinoma

Conditions
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Kidney Cancer

Intervention / Treatment
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* Biological: aldesleukin
* Biological: denileukin diftitox


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>6 mcg/kg Denileukin Diftitox administered IV/daily on days 8-10 of standard interleukin 2 dose course | Biological: aldesleukin<br>* The IL-2 is given as a 15-minute infusion through an intravenous catheter (I.V.), a small plastic tube that is put into your vein for the time you are receiving the study treatment. IL-2 is given through the I.V. once every 8 hours for 5 days (days 1-5). A second 5 day cycle of IL-2 will begin on the 15th day (days 15-19). This is one complete cycle (days 1-19) of IL-2 treatment<br>* Other names: Proleukin;Biological: denileukin diftitox<br>* Denileukin diftitox will be administered once daily as a 15 to 60 minute infusion for 3 consecutive days.<br>* Other names: DAB 389 IL-2;|
| Experimental: B<br>9 mcg/kg Denileukin Diftitox administered IV/daily on days -4 to -2 of standard interleukin 2 dose course | Biological: aldesleukin<br>* The IL-2 is given as a 15-minute infusion through an intravenous catheter (I.V.), a small plastic tube that is put into your vein for the time you are receiving the study treatment. IL-2 is given through the I.V. once every 8 hours for 5 days (days 1-5). A second 5 day cycle of IL-2 will begin on the 15th day (days 15-19). This is one complete cycle (days 1-19) of IL-2 treatment<br>* Other names: Proleukin;Biological: denileukin diftitox<br>* Denileukin diftitox will be administered once daily as a 15 to 60 minute infusion for 3 consecutive days.<br>* Other names: DAB 389 IL-2;|
| Experimental: C<br>9 mcg/kg Denileukin Diftitox administered IV/daily on days 8-10 of standard interleukin 2 dose course | Biological: aldesleukin<br>* The IL-2 is given as a 15-minute infusion through an intravenous catheter (I.V.), a small plastic tube that is put into your vein for the time you are receiving the study treatment. IL-2 is given through the I.V. once every 8 hours for 5 days (days 1-5). A second 5 day cycle of IL-2 will begin on the 15th day (days 15-19). This is one complete cycle (days 1-19) of IL-2 treatment<br>* Other names: Proleukin;Biological: denileukin diftitox<br>* Denileukin diftitox will be administered once daily as a 15 to 60 minute infusion for 3 consecutive days.<br>* Other names: DAB 389 IL-2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary objective is to assess for toxicity | To assess the toxicity | After each cycle of therapy and 30 days after the last treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The secondary objectives are to investigate differences in peak and duration of the expansion of CD4+, CD8+, CD4+CD 25+ and CD56+(dim and bright)CD25+ cells | To investigate differences in peak and duration. | Follow-up measurements must have met the SD criteria at least once after study entry at a minimum interval of 8 weeks. | 
| To investigate the effects of denileukin diftitox in combination with IL-2 on plasma TGF-beta levels | To investigate the effects of denileukin diftitox | Cohort 1: Denileukin diftitox dose of 6μg/kg/ Days 1, 2, 3, 4, and 5. Cohort 2 Denileukin diftitox dose of 9μg/kg given 4, 3, 2, and 1 days prior to 1st day of each cycle. Cohort 3: Denileukin diftitox dose of 9μg/kg given days 8 and 9. | 
| To perform TGF-beta promoter and TGF-beta receptor genotyping prior to the start of treatment to search for variants that may be associated with tumor response to therapy. | To perform TGF-beta promoter and TGF-beta receptor genotyping | Cohort 1: Plasma TGF-beta levels to be given on day. Cohort 2: plasma TGF-beta levels to be given at day 1. Cohort 3: plasma TGF-beta levels given on days 1 through 5. | 
| Overall response rate and time to progression | Overall response rate will be assessed. | CT scans and other pertinent studies will be performed at week 10 to assess response. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent renal cell cancer, stage IV renal cell cancer, clear cell renal cell carcinoma