Temsirolimus and Valproic Acid in Treating Young Patients With Relapsed Neuroblastoma, Bone Sarcoma, or Soft Tissue Sarcoma

Phase 1

Terminated

• Conditions: Brain and Central Nervous System Tumors; Neuroblastoma; Sarcoma; Unspecified Childhood Solid Tumor, Protocol Specific
• Interventions: Drug: Temsirolimus; Drug: Valproic Acid

• Registration Number: NCT01204450
• Lead Sponsor: UNC Lineberger Comprehensive Cancer Center

Brief Summary

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.

Detailed Description

OBJECTIVES:

Primary

* To identify the maximum-tolerated dose of temsirolimus in combination with valproic acid in highly pretreated pediatric patients with refractory solid tumors.

Secondary

* 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.

Study Timeline

• Study Start: 2009-11
• Study First Submitted: 2010-09-16
• Study First Submitted QC: 2010-09-16
• Study First Posted: 2010-09-17
• Primary Completion: 2012-11
• Study Completion: 2013-03
• Status Verified: 2016-12
• Last Update Submitted: 2016-12-22
• Last Update Posted: 2016-12-23

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 7

Inclusion Criteria

Not provided

Read More

Exclusion Criteria

Not provided

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Single Arm Temsirolimus + Valproic Acid	Temsirolimus	Drug: temsirolimus 60-230mg/m2 weekly during each 28 day course, for up to 12 courses Drug: 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
Single Arm Temsirolimus + Valproic Acid	Valproic Acid	Drug: temsirolimus 60-230mg/m2 weekly during each 28 day course, for up to 12 courses Drug: 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

Primary Outcome Measures

Name	Time	Method
Maximum tolerated dose (MTD) of temsirolimus in combination with valproic acid	4 weeks	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

Secondary Outcome Measures

Name	Time	Method
Progression-free survival	3 years	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
Objective response rate	every 12 weeks	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
Temsirolimus pharmakokinetic parameters (Maximum plasma concentration)	doses 1 and 5	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

Trial Locations

Locations (2)

Carolina Healthcare System; 🇺🇸 Charlotte, North Carolina, United States

Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill; 🇺🇸 Chapel Hill, North Carolina, United States