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

NCT ID: NCT01204450

Last Updated: 2016-12-23

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 7 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-11-30
• Study Completion Date: 2013-03-31

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.

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: OTHER

Temsirolimus

Intervention Type: DRUG

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

Valproic Acid

Intervention Type: DRUG

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

Interventions

Temsirolimus

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

Intervention Type: 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

Intervention Type: DRUG

Other Intervention Names

Torisel; VPA

Eligibility Criteria

Inclusion 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

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

UNC Lineberger Comprehensive Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Julie Blatt, MD

Role: PRINCIPAL_INVESTIGATOR

UNC Lineberger Comprehensive Cancer Center

Locations

Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill

Chapel Hill, North Carolina, United States

Carolina Healthcare System

Charlotte, North Carolina, United States

Countries

United States

Other Identifiers

P30CA016086

Identifier Type: NIH

Identifier Source: secondary_id

View Link

CDR0000665319

Identifier Type: OTHER

Identifier Source: secondary_id

LCCC 0901

Identifier Type: -

Identifier Source: org_study_id