Sequential ATRA Then IL-2 for Modulation of Dendritic Cells and Treatment of Metastatic Renal Cell Cancer

Study Overview
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Brief Summary
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RATIONALE: Tretinoin may help cells that are involved in the body's immune response to work better. Interleukin-2 may stimulate the white blood cells to kill kidney cancer cells. Giving tretinoin together with interleukin-2 may kill more tumor cells. PURPOSE: This randomized phase II trial is studying how well giving three different doses of tretinoin together with interleukin-2 works in treating patients with stage IV kidney cancer.

Detailed Description
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OBJECTIVES: Primary Determine the ratio of dendritic cells (DC) to circulating immature cells (ImC) before and after treatment with 3 different doses of tretinoin in patients with stage IV renal cell cancer. Assess in vitro immune response assays to tetanus toxoid and influenza virus peptide before and after treatment with tretinoin and interleukin-2 in these patients. Secondary Determine the frequency of treatment-related side effects in these patients. Determine clinical objective response and progression-free survival of patients treated with this regimen. Correlate DC:ImC ratio with clinical objective response in patients treated with this regimen. Correlate the extent of change of the DC:ImC ratio with tretinoin dose and tretinoin blood levels in these patients. OUTLINE: This is a randomized, open-label study. Specimens are stratified according to patient prognostic factors, tumor bulk, and extent of dendritic cell to circulating immature cell ratio derangement. Patients are randomized to 1 of 3 tretinoin doses. Patients are followed for up to 2 years. PROJECTED ACCRUAL: A total of 27-36 patients (9-12 per treatment arm) will be accrued for this study within 2 years.

Official Title
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Randomized Phase II Trial Of Sequential ATRA Then IL-2 For Modulation Of Dendritic Cells And Treatment Of Metastatic Renal Cancer

Conditions
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Kidney Cancer

Intervention / Treatment
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* Drug: IL-2
* Drug: ATRA


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed renal cell cancer Stage IV disease Histology with clear cell component Metastatic OR incompletely resected disease Non-measurable disease allowed Underwent complete or partial nephrectomy more than 90 days ago No unresected primary cancer No more than 2 of the following adverse factors: Hemoglobin < 10.0 g/dL Corrected calcium > upper limit of normal (ULN) Lactic dehydrogenase > 1.5 times ULN Eastern Cooperative Oncology Group (ECOG) performance status 2 Brain metastasis allowed provided more than 90 days of clinical and radiologic stability after the end of its active treatment PATIENT CHARACTERISTICS: Age Over 18 Performance status See Disease Characteristics ECOG 0-2 Life expectancy Not specified Hematopoietic See Disease Characteristics Hepatic See Disease Characteristics Serum glutamic oxaloacetic transaminase (SGOT) < 3 times normal Bilirubin < 2 times normal Renal See Disease Characteristics Creatinine clearance > 40 mL/min Cardiovascular None of the following cardiovascular conditions within the past year: Uncontrolled hypertension Myocardial infarction Unstable angina New York Heart Association class II-IV congestive heart failure Serious cardiac arrhythmia requiring medication Class II-IV peripheral vascular disease within the past year Other clinically significant cardiovascular disease Immunologic No history of immunodeficiency disease No HIV infection No ongoing serious infection Other Not pregnant or nursing Negative pregnancy test Fertile patients must use two methods of effective contraception during and for 1 month (for women) or 6 months (for men) after study treatment Other prior malignancy allowed provided there is no evidence of active disease No other medical contraindication to tretinoin or interleukin-2 No serious non-healing wound, ulcer, or bone fracture PRIOR CONCURRENT THERAPY: Biologic therapy At least 60 days since prior immunotherapy Chemotherapy At least 60 days since prior cytotoxic chemotherapy Endocrine therapy See Radiotherapy No prior corticosteroids at > physiologic replacement doses for > 3 days within the past 90 days Concurrent tamoxifen, toremifene, megestrol, or gonadotropin-releasing hormone agonists allowed Concurrent inhaled steroids allowed Radiotherapy More than 7 days since prior external-beam radiotherapy No steroid requirement during radiotherapy Surgery See Disease Characteristics At least 30 days since other prior debulking surgery Other Prior adjuvant therapy for resected, synchronous stage IV disease allowed Prior adjuvant therapy allowed Study therapy is not to be used as adjuvant therapy for completely resected late (> 1 year until identification) solitary site of disease metastasis or non-metastatic disease No prior participation in this clinical study At least 60 days since other prior anticancer drugs Concurrent seizure medication allowed

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 |
| --- | --- |
| Active Comparator: ATRA Followed by IL-2 - Dose Level A<br>Patients were assigned to one of three ATRA dose levels, at a 1:1:1 ratio, using a randomly permuted list assignments, with the assignment generally being made on the initial day of treatment. Week 1: One dose daily of IL-2 for 5 days followed by 2 days off. Weeks 2-6: One dose daily of IL-2 for 5 days followed by 2 days off. After the IL-2: 2-3 weeks rest, with no treatment. During this time a repeat physical exam, history and X-ray scans will be performed. If there has not been progression (worsening) of the patient's tumor, they will continue to a second 8-week treatment schedule. This schedule will be the same as the first, unless the patients dose had to be reduced. If so, patient's will get that reduced dose. It consists of 1 week of ATRA, 1 week of rest, followed by 6 weeks of IL-2. The same blood tests are collected during that second cycle. | Drug: IL-2<br>* Immunotherapy with interleukin-2<br>* Other names: Recombinant Human Interleukin-2;Drug: ATRA<br> <br> * Other names: all-trans retinoic acid;|
| Active Comparator: ATRA Followed by IL-2 - Dose Level B<br>Patients were assigned to one of three ATRA dose levels, at a 1:1:1 ratio, using a randomly permuted list assignments, with the assignment generally being made on the initial day of treatment. Week 1: One dose daily of IL-2 for 5 days followed by 2 days off. Weeks 2-6: One dose daily of IL-2 for 5 days followed by 2 days off. After the IL-2: 2-3 weeks rest, with no treatment. During this time a repeat physical exam, history and X-ray scans will be performed. If there has not been progression (worsening) of the patient's tumor, they will continue to a second 8-week treatment schedule. This schedule will be the same as the first, unless the patients dose had to be reduced. If so, patient's will get that reduced dose. It consists of 1 week of ATRA, 1 week of rest, followed by 6 weeks of IL-2. The same blood tests are collected during that second cycle. | Drug: IL-2<br>* Immunotherapy with interleukin-2<br>* Other names: Recombinant Human Interleukin-2;Drug: ATRA<br> <br> * Other names: all-trans retinoic acid;|
| Active Comparator: ATRA Followed by IL-2 - Level C<br>Patients were assigned to one of three ATRA dose levels, at a 1:1:1 ratio, using a randomly permuted list assignments, with the assignment generally being made on the initial day of treatment. Week 1: One dose daily of IL-2 for 5 days followed by 2 days off. Weeks 2-6: One dose daily of IL-2 for 5 days followed by 2 days off. After the IL-2: 2-3 weeks rest, with no treatment. During this time a repeat physical exam, history and X-ray scans will be performed. If there has not been progression (worsening) of the patient's tumor, they will continue to a second 8-week treatment schedule. This schedule will be the same as the first, unless the patients dose had to be reduced. If so, patient's will get that reduced dose. It consists of 1 week of ATRA, 1 week of rest, followed by 6 weeks of IL-2. The same blood tests are collected during that second cycle. | Drug: IL-2<br>* Immunotherapy with interleukin-2<br>* Other names: Recombinant Human Interleukin-2;Drug: ATRA<br> <br> * Other names: all-trans retinoic acid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ratio of Dendritic Cells (DC) to Circulating Immature Cells (ImC) Before and After Treatment | Determine the ratio of dendritic cells (DC) to circulating immature cells (ImC) before and after treatment with 3 different doses of tretinoin in patients with stage IV renal cell cancer. | 1 year, 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Treatment-Related Side Effects | Review of adverse events utilizing Common Toxicity Criteria (CTC) V3. | 1 year, 3 months | 
| Overall Response Rate (ORR) | Objective Response Rate according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Evaluate per-patient observed best clinical responses, after 11-12 weeks of treatment. | 1 year, 3 months | 

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