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

Sponsor

UNC Lineberger Comprehensive Cancer Center (Other)

Overall Status

Terminated

CT.gov ID

NCT01204450

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Locations

Arm

Duration (Months)

3.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors Neuroblastoma Sarcoma Unspecified Childhood Solid Tumor, Protocol Specific	Drug: Temsirolimus Drug: Valproic Acid	Phase 1

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 Design

Study Type:

Interventional

Actual Enrollment :

7 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (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

Study Start Date :

Nov 1, 2009

Actual Primary Completion Date :

Nov 1, 2012

Actual Study Completion Date :

Mar 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Other: Single Arm Temsirolimus + 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	Drug: Temsirolimus 60-230mg/m2 weekly during each 28 day course, for up to 12 courses Other Names: Torisel Drug: Valproic Acid All patients will be given oral VPA (5 mg/kg, 3 times a day for each 28 day course, up to 12 courses Other Names: VPA

Arm

Intervention/Treatment

Other: Single Arm Temsirolimus + 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

Drug: Temsirolimus

60-230mg/m2 weekly during each 28 day course, for up to 12 courses

Other Names:

Torisel

Drug: Valproic Acid

All patients will be given oral VPA (5 mg/kg, 3 times a day for each 28 day course, up to 12 courses

Other Names:

VPA

Outcome Measures

Primary Outcome Measures

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

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
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
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically confirmed malignant solid tumor at original diagnosis, including the following:
Neuroblastoma
Bone sarcomas (primary neuroectodermal tumors/ Ewing sarcoma (PNET/ES), osteosarcoma)
Soft tissue sarcomas (rhabdosarcoma and related tumors)
Histologically confirmed of relapsed disease is highly recommended but not mandatory
Measurable disease according to RECIST
Refractory or progressive disease after ≥ 1 and ≤ 4 prior chemotherapy regimens
Patients with neuroblastoma, PNET/ES, or rhabdosarcoma must have failed a cyclophosphamide/topotecan-containing regimen
Stem cell transplantation, including preparative regimen and post-transplant immunotherapy, is considered to be 1 regimen

PATIENT CHARACTERISTICS:

Karnofsky performance status (PS) 50-100% (or Lansky PS 50-100%)
Life expectancy ≥ 8 weeks
ANC ≥ 750/mm^3
Platelet count ≥ 75,000/mm^3 (transfusion independent)
Hemoglobin 8.0 g/dL (may receive RBC transfusions)
Patients with tumor metastatic to bone marrow are allowed to receive transfusions to maintain hemoglobin and platelet counts
Serum creatinine normal
Total bilirubin ≤ 1.5 times upper limit of normal (ULN) OR direct bilirubin < 1.0 mg/dL (if total bilirubin > 2.0 mg/dL)
ALT < 5 times ULN
Negative pregnancy test
Not pregnant or nursing
Fertile patients must use effective contraception
Families must be able to give consent in English or Spanish
No allergy to H1 antihistamines

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
More than 2 weeks since prior chemotherapy, immunotherapy, or radiotherapy and recovered
No concurrent anticonvulsants, including valproic acid
No concurrent strong inducers or inhibitors of CYP3A4, including grapefruit juice

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill	Chapel Hill	North Carolina	United States	27599-7295
2	Carolina Healthcare System	Charlotte	North Carolina	United States