Temsirolimus and Bevacizumab in Treating Patients With Stage III or Stage IV Malignant Melanoma (Mel47)
|Recurrent Melanoma Stage IIIB Skin Melanoma Stage IIIC Skin Melanoma Stage IV Skin Melanoma||Biological: Bevacizumab Other: Laboratory Biomarker Analysis Drug: Temsirolimus Procedure: Therapeutic Conventional Surgery||Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||A Phase II Study of CCI-779 in Combination With Bevacizumab in Stage III or IV Melanoma|
- Objective Tumor Response (Complete Response and Partial Response) and Progression in Participants With Stage III or IV Melanoma Following Treatment With Temsirolimus and Bevacizumab [ Time Frame: Up to 18 weeks after registration. ]Evaluated using Response Evaluation Criteria In Solid Tumor (RECIST) criteria. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI and/or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progression of Disease (POD); POD, 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Complete Response (CR), Disappearance of all target lesions.
- Adverse Events in Participants With Stage III or IV Melanoma Treated With Temsirolimus and Bevacizumab [ Time Frame: On days 1 and 8 of each cycle, and up to 2 years after registration. ]Defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome, or disease which either occurs during the study (having been absent at baseline) or if present at baseline, appears to worsen. Graded using scales found in the revised National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Tabulated by type and severity: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE.
- Association Between Expression or Activation of One Biomarker With Another, With Biochemical and Clinical Responses, With Alterations in Cell Proliferation and Apoptotic Markers, and With Time to Progression [ Time Frame: Day 1 of course 1 and day 8 of course 2 ]Changes in the ratio of phospho-S6Kinase (pS6K) S240/244 to total S6, in the tumor, from day 1 to day 23. These were assessed by reverse-phase protein array. A linear model was fit with PROC MIXED in SAS 9.3 using the log base 10 of expression as the outcome measure. This measure type is not listed in the data table form; so the number of patients who had decreases in that ratio is listed.
- Comparison of Biomarkers to Antitumor Activity/Patient Outcomes [ Time Frame: Day 1 of course 1 and day 8 of course 2 ]Assessed in both tumor tissue pretreatment. Mutations in BRAF were assessed in all 16 of the patients and were assessed for any association with clinical response
- Comparison of Pre- vs Post-treatment Measurements of Biomarkers and Vascular System/Immune System Parameters [ Time Frame: Day 1 of course 1 and day 8 of course 2 ]Biomarker expression in tumor and normal skin will be assessed by immunohistochemistry (IHC) or Western blotting, using marker-specific antibodies.
- Progression-free Survival [ Time Frame: Day 11 of courses 4, 8, 12, 16, 20, and 24, and then annually for up to 5 years ]Defined as the duration of time from start of treatment to time of progression, death or date of last follow-up.
|Actual Study Start Date:||January 2008|
|Study Completion Date:||July 2013|
|Primary Completion Date:||July 2013 (Final data collection date for primary outcome measure)|
Experimental: Treatment (enzyme inhibitor, monoclonal antibody)
Patients receive temsirolimus IV over 30 minutes on days 1 and 8 and bevacizumab IV over 30-90 minutes on day 8. Treatment repeats every 14 days for a maximum of 26 courses in the absence of disease progression or unacceptable toxicity. Patients undergo tumor resection on day 9 of course 2.
Other Names:Other: Laboratory Biomarker Analysis
Correlative studiesDrug: Temsirolimus
Other Names:Procedure: Therapeutic Conventional Surgery
Undergo tumor resection
I. Determine the objective tumor response rate (complete response and partial response) in patients with stage III or IV melanoma treated with temsirolimus and bevacizumab.
I. Describe the adverse event profile of this regimen in these patients. II. Determine the efficacy of this regimen, in terms of progression-free survival, in these patients.
III. Compare pre- vs post-treatment measurements of biomarkers and vascular system/immune system parameters in patients treated with this regimen.
IV. Correlate tumor and blood biomarkers with clinical response in these patients.
OUTLINE: This is a multicenter study.
Patients receive temsirolimus intravenously (IV) over 30 minutes on days 1 and 8 and bevacizumab IV over 30-90 minutes on day 8. Treatment repeats every 14 days for a maximum of 26 courses in the absence of disease progression or unacceptable toxicity. Patients undergo tumor resection on day 9 of course 2.Blood samples are collected during courses 1 and 2. Samples are examined by flow cytometry to evaluate peripheral blood mononuclear cells for molecular effects of study agents. Patients also undergo normal and tumor tissue biopsy (by core needle biopsy, incisional biopsy, or surgical resection) during courses 1 and 2. Samples are examined by immunohistochemistry, western blotting, protein array technology, gene expression analyses, DNA mutation analyses, and genomic analyses for pre-and post-treatment measurements of target molecules (epidermal growth factor receptor, B-Raf, MEK, MAPK), downstream pathway components (PI-3 kinase, AKT, mTOR), markers of angiogenesis, proliferation and apoptosis, markers that may modulate cell signaling or the response to investigational agents, and vascular and immune system parameters.
After completion of study treatment, patients are followed at 1 month, every 3 months for up to 2 years, and then periodically for up to 5 years.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00397982
|United States, Pennsylvania|
|Fox Chase Cancer Center|
|Philadelphia, Pennsylvania, United States, 19111|
|United States, Virginia|
|University of Virginia Cancer Center|
|Charlottesville, Virginia, United States, 22908|
|Principal Investigator:||Craig Slingluff||University of Virginia|