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

Sponsor:	UNC Lineberger Comprehensive Cancer Center
Collaborator:	National Cancer Institute (NCI)
Information provided by (Responsible Party):	UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier:	NCT01204450

Purpose

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	Intervention	Phase
Brain and Central Nervous System Tumors Neuroblastoma Sarcoma Unspecified Childhood Solid Tumor, Protocol Specific	Drug: temsirolimus Drug: valproic acid (VPA)	Phase 1

Study Type:	Interventional
Study Design:	Endpoint Classification: Safety Study Intervention Model: Single Group Assignment Masking: 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

Resource links provided by NLM:

MedlinePlus related topics: Cancer Neuroblastoma Soft Tissue Sarcoma

Drug Information available for: Valproic acid Valproate Sodium Sirolimus Divalproex sodium Everolimus Temsirolimus

U.S. FDA Resources

Further study details as provided by UNC Lineberger Comprehensive Cancer Center:

Primary Outcome Measures:

Maximum tolerated dose (MTD) of temsirolimus in combination with valproic acid [ Time Frame: 4 weeks ] [ Designated as safety issue: Yes ]
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 [ Time Frame: every 12 weeks ] [ Designated as safety issue: No ]
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 [ Time Frame: 3 years ] [ Designated as safety issue: No ]
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) [ Time Frame: doses 1 and 5 ] [ Designated as safety issue: No ]
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

Enrollment:	7
Study Start Date:	November 2009
Estimated Study Completion Date:	December 2014
Estimated Primary Completion Date:	November 2012 (Final data collection date for primary outcome measure)

Intervention Details:

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

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

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

Ages Eligible for Study:	2 Years to 18 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01204450

Locations

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)

Investigators

Principal Investigator:

Julie Blatt, MD

UNC Lineberger Comprehensive Cancer Center

More Information

No publications provided

Responsible Party:	UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier:	NCT01204450 History of Changes
Other Study ID Numbers:	LCCC 0901, P30CA016086, CDR0000665319
Study First Received:	September 16, 2010
Last Updated:	February 10, 2012
Health Authority:	United States: Food and Drug Administration United States: Institutional Review Board

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:

Nervous System Neoplasms
Neuroblastoma
Central Nervous System Neoplasms
Sarcoma
Neoplasms by Site
Neoplasms
Nervous System Diseases
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue

Neoplasms, Connective and Soft Tissue
Valproic Acid
Sirolimus
Everolimus
Anticonvulsants
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
GABA Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antimanic Agents
Tranquilizing Agents

ClinicalTrials.gov processed this record on May 23, 2012