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A Multi-center Phase I Trial of Temsirolimus in Combination With Valproic Acid in Children and Adolescents With Multiply Relapsed Pediatric Solid Tumors

Phase 1
2 Years
18 Years
Not Enrolling
Brain and Central Nervous System Tumors, Neuroblastoma, Sarcoma, Unspecified Childhood Solid Tumor, Protocol Specific

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Trial Information

A Multi-center Phase I Trial of Temsirolimus in Combination With Valproic Acid in Children and Adolescents With Multiply Relapsed Pediatric Solid Tumors



- 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.

Inclusion Criteria


- Histologically confirmed malignant solid tumor at original diagnosis, including the

- Neuroblastoma

- Bone sarcomas (primary neuroectodermal tumors/ Ewing sarcoma (PNET/ES),

- 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

- No concurrent anticonvulsants, including valproic acid

- No concurrent strong inducers or inhibitors of CYP3A4, including grapefruit juice

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose (MTD) of temsirolimus in combination with valproic acid

Outcome Description:

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

Outcome Time Frame:

4 weeks

Safety Issue:


Principal Investigator

Julie Blatt, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

UNC Lineberger Comprehensive Cancer Center


United States: Food and Drug Administration

Study ID:

LCCC 0901



Start Date:

November 2009

Completion Date:

December 2014

Related Keywords:

  • Brain and Central Nervous System Tumors
  • Neuroblastoma
  • Sarcoma
  • Unspecified Childhood Solid Tumor, Protocol Specific
  • 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
  • Nervous System Neoplasms
  • Neuroblastoma
  • Central Nervous System Neoplasms
  • Sarcoma



Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill Chapel Hill, North Carolina  27599-7570
Carolina Healthcare System Charlotte, North Carolina