Clinical trial NCT01204450: Temsirolimus and Valproic Acid in Treating Young Patients With Relapsed Neuroblastoma, Bone Sarcoma, or Soft Tissue Sarcoma
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 type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Brain and Central Nervous System Tumors
Neuroblastoma
Sarcoma
Unspecified Childhood Solid Tumor, Protocol Specific
Keywords: 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
Lead sponsor: UNC Lineberger Comprehensive Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2010-09-17
Enrollment: 7
Sex: ALL
Minimum age (years): 2
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Maximum tolerated dose (MTD) of temsirolimus in combination with valproic acid
timeFrame: 4 weeks
Secondary outcomes:
measure: Objective response rate
timeFrame: every 12 weeks
measure: Progression-free survival
timeFrame: 3 years
measure: Temsirolimus pharmakokinetic parameters (Maximum plasma concentration)
timeFrame: doses 1 and 5
Other outcomes:
Locations:
city: Chapel Hill
country: United States
facility: Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
state: North Carolina
city: Charlotte
country: United States
facility: Carolina Healthcare System
state: North Carolina
Study officials:
affiliation: UNC Lineberger Comprehensive Cancer Center
name: Julie Blatt, MD
role: PRINCIPAL_INVESTIGATOR
References: