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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01204450
Recruitment Status : Terminated (Funding has become unavailable)
First Posted : September 17, 2010
Last Update Posted : December 23, 2016
National Cancer Institute (NCI)
Information provided by (Responsible Party):
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.

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:



  • 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 7 participants
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 : November 2009
Actual Primary Completion Date : November 2012
Actual Study Completion Date : March 2013

Arm Intervention/treatment
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 Name: 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 Name: VPA

Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) of temsirolimus in combination with valproic acid [ Time Frame: 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 :
  1. Objective response rate [ Time Frame: 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

  2. Progression-free survival [ Time Frame: 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

  3. Temsirolimus pharmakokinetic parameters (Maximum plasma concentration) [ Time Frame: 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

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   2 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • 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


  • 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


  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01204450

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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
Sponsors and Collaborators
UNC Lineberger Comprehensive Cancer Center
National Cancer Institute (NCI)
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Principal Investigator: Julie Blatt, MD UNC Lineberger Comprehensive Cancer Center

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Responsible Party: UNC Lineberger Comprehensive Cancer Center Identifier: NCT01204450    
Other Study ID Numbers: LCCC 0901
P30CA016086 ( U.S. NIH Grant/Contract )
CDR0000665319 ( Other Identifier: PDQ )
First Posted: September 17, 2010    Key Record Dates
Last Update Posted: December 23, 2016
Last Verified: December 2016
Keywords provided by UNC Lineberger Comprehensive Cancer Center:
recurrent childhood brain tumor
recurrent childhood rhabdomyosarcoma
recurrent childhood soft tissue sarcoma
recurrent childhood supratentorial primitive neuroectodermal tumor
recurrent Ewing sarcoma/peripheral primitive neuroectodermal tumor
recurrent neuroblastoma
recurrent osteosarcoma
unspecified childhood solid tumor, protocol specific
Additional relevant MeSH terms:
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Nervous System Neoplasms
Central Nervous System Neoplasms
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms by Site
Nervous System Diseases
Valproic Acid
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action