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

Primary Purpose

Kidney Cancer

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
IL-2
ATRA
Sponsored by
H. Lee Moffitt Cancer Center and Research Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Kidney Cancer focused on measuring stage IV renal cell cancer, recurrent renal cell cancer, clear cell renal cell carcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • H. Lee Moffitt Cancer Center and Research Institute

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Active Comparator

Arm Label

ATRA Followed by IL-2 - Dose Level A

ATRA Followed by IL-2 - Dose Level B

ATRA Followed by IL-2 - Level C

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Frequency of Treatment-Related Side Effects
Review of adverse events utilizing Common Toxicity Criteria (CTC) V3.
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.

Full Information

First Posted
January 6, 2005
Last Updated
August 15, 2013
Sponsor
H. Lee Moffitt Cancer Center and Research Institute
Collaborators
National Cancer Institute (NCI), National Institutes of Health (NIH), Chiron Corporation
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1. Study Identification

Unique Protocol Identification Number
NCT00100906
Brief Title
Sequential ATRA Then IL-2 for Modulation of Dendritic Cells and Treatment of Metastatic Renal Cell Cancer
Official Title
Randomized Phase II Trial Of Sequential ATRA Then IL-2 For Modulation Of Dendritic Cells And Treatment Of Metastatic Renal Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
July 2013
Overall Recruitment Status
Completed
Study Start Date
August 2004 (undefined)
Primary Completion Date
June 2006 (Actual)
Study Completion Date
July 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
H. Lee Moffitt Cancer Center and Research Institute
Collaborators
National Cancer Institute (NCI), National Institutes of Health (NIH), Chiron Corporation

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Kidney Cancer
Keywords
stage IV renal cell cancer, recurrent renal cell cancer, clear cell renal cell carcinoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
18 (Actual)

8. Arms, Groups, and Interventions

Arm Title
ATRA Followed by IL-2 - Dose Level A
Arm Type
Active Comparator
Arm Description
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.
Arm Title
ATRA Followed by IL-2 - Dose Level B
Arm Type
Active Comparator
Arm Description
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.
Arm Title
ATRA Followed by IL-2 - Level C
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
IL-2
Other Intervention Name(s)
interleukin-2, aldesleukin, Proleukin™, Recombinant Human Interleukin-2
Intervention Description
Immunotherapy with interleukin-2
Intervention Type
Drug
Intervention Name(s)
ATRA
Other Intervention Name(s)
tretinoin, Vesanoid™, all-trans retinoic acid
Primary Outcome Measure Information:
Title
Ratio of Dendritic Cells (DC) to Circulating Immature Cells (ImC) Before and After Treatment
Description
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.
Time Frame
1 year, 3 months
Secondary Outcome Measure Information:
Title
Frequency of Treatment-Related Side Effects
Description
Review of adverse events utilizing Common Toxicity Criteria (CTC) V3.
Time Frame
1 year, 3 months
Title
Overall Response Rate (ORR)
Description
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.
Time Frame
1 year, 3 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mayer Fishman, M.D., Ph.D.
Organizational Affiliation
H. Lee Moffitt Cancer Center and Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
H. Lee Moffitt Cancer Center and Research Institute
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612-9497
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
16982775
Citation
Mirza N, Fishman M, Fricke I, Dunn M, Neuger AM, Frost TJ, Lush RM, Antonia S, Gabrilovich DI. All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Res. 2006 Sep 15;66(18):9299-307. doi: 10.1158/0008-5472.CAN-06-1690.
Results Reference
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Sequential ATRA Then IL-2 for Modulation of Dendritic Cells and Treatment of Metastatic Renal Cell Cancer

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