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

Sarcoma Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01204450
• Other study ID #: LCCC 0901
• Secondary ID: P30CA016086CDR00
• Status: Terminated
• Phase: Phase 1
• First received: September 16, 2010
• Last updated: December 22, 2016
• Start date: November 2009
• Est. completion date: March 2013

Study information

• Verified date: December 2016
• Source: UNC Lineberger Comprehensive Cancer Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 7
• Est. completion date: March 2013
• Est. primary completion date: November 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 2 Years to 18 Years

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

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

Intervention

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

Locations

Country	Name	City	State
United States	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill	Chapel Hill	North Carolina
United States	Carolina Healthcare System	Charlotte	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
UNC Lineberger Comprehensive Cancer Center	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum tolerated dose (MTD) of temsirolimus in combination with valproic acid	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	4 weeks	Yes
Secondary	Objective response rate	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	every 12 weeks	No
Secondary	Progression-free survival	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 years	No
Secondary	Temsirolimus pharmakokinetic parameters (Maximum plasma concentration)	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	doses 1 and 5	No