Temsirolimus and Valproic Acid in Treating Young Patients With Relapsed Neuroblastoma, Bone Sarcoma, or Soft Tissue Sarcoma
RATIONALE: Drugs such as temsirolimus and valproic acid may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Valproic acid may also stop the growth of solid tumors by blocking blood flow to the tumor.
PURPOSE: This phase I trial is studying the side effects and the best dose of temsirolimus when given together with valproic acid in treating young patients with relapsed neuroblastoma, bone sarcoma, or soft tissue sarcoma.
Brain and Central Nervous System Tumors
Unspecified Childhood Solid Tumor, Protocol Specific
Drug: valproic acid (VPA)
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Multi-center Phase I Trial of Temsirolimus in Combination With Valproic Acid in Children and Adolescents With Multiply Relapsed Pediatric Solid Tumors|
- Maximum tolerated dose (MTD) of temsirolimus in combination with valproic acid [ Time Frame: 4 weeks ] [ Designated as safety issue: Yes ]The planned starting dose of Temsirolimus is 60mg/M2. The traditional 3+3 design will be used, where the MTD is defined as the dose with the probability of a DLT of 0.20
- Objective response rate [ Time Frame: every 12 weeks ] [ Designated as safety issue: No ]Each patient will be classified according to their "best response". Best response is determined from the sequence of the objective statuses as described in RECIST 1.1
- Progression-free survival [ Time Frame: 3 years ] [ Designated as safety issue: No ]If the patient's disease has not progressed at the time protocol-directed therapy is complete, any tumor assessments available during the follow-up period (up to 3 years) will be evaluated using RECSIT 1.1
- Temsirolimus pharmakokinetic parameters (Maximum plasma concentration) [ Time Frame: doses 1 and 5 ] [ Designated as safety issue: No ]Blood will be drawn prior to, 30 minutes, 1hr, 2hr, 5hr, 24hr after completion of doses 1 and 5. Levels of Temsirolimus will be measured using validated liquid chromatography and tandem mass spectroscopic methods
|Study Start Date:||November 2009|
|Study Completion Date:||March 2013|
|Primary Completion Date:||November 2012 (Final data collection date for primary outcome measure)|
|Single Arm Study||
60-230mg/m2 weekly during each 28 day course, for up to 12 coursesDrug: valproic acid (VPA)
All patients will be given oral VPA (5 mg/kg, 3 times a day for each 28 day course, up to 12 courses
- To identify the maximum-tolerated dose of temsirolimus in combination with valproic acid in highly pretreated pediatric patients with refractory solid tumors.
- To estimate the objective response rate in patients treated with this regimen.
- To estimate the progression-free survival of patients treated with this regimen.
- To explore the association between tumor IGF-IR, mTOR expression, HDAC, autophagy biomarkers, and sera levels of temsirolimus, valproate, and VEGF-A with toxicity and disease response.
- To evaluate the ability of selected member divisions of a newly developed North Carolina-based pediatric oncology consortium to cooperate in clinical trials.
OUTLINE: This a multicenter, dose-escalation study of temsirolimus.
Patients receive temsirolimus IV over 30-60 minutes on days 1, 8, 15, and 22 and oral valproic acid* 3 times daily on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Blood samples are collected at baseline and periodically during study for pharmacokinetic and VEGF-A studies. Tumor tissue samples from archived biopsy are also analyzed for IGF-IR, mTOR expression, HDAC, and autophagy biomarkers.
After completion of study therapy, patients are followed every 3 months for 1 year, every 4 months for 2 years, and then every 6 months for 2 years.
NOTE: * Doses of valproic acid are titrated beginning 3-7 days prior to starting temsirolimus to achieve plasma levels of 75-100 µg/mL.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01204450
|United States, North Carolina|
|Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill|
|Chapel Hill, North Carolina, United States, 27599-7295|
|Carolina Healthcare System|
|Charlotte, North Carolina, United States|
|Principal Investigator:||Julie Blatt, MD||UNC Lineberger Comprehensive Cancer Center|