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

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

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.

Study Overview

• Status: Terminated
• Conditions: Sarcoma; Unspecified Childhood Solid Tumor, Protocol Specific; Brain and Central Nervous System Tumors; Neuroblastoma
• Intervention / Treatment: Drug: Temsirolimus; Drug: Valproic Acid

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.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7295
      • Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
    • Charlotte, North Carolina, United States
      • Carolina Healthcare System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: 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	Drug: Temsirolimus; 60-230mg/m2 weekly during each 28 day course, for up to 12 courses; Other Names: Torisel; 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; Other Names: VPA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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

Collaborators and Investigators

• Sponsor: UNC Lineberger Comprehensive Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Julie Blatt, MD, UNC Lineberger Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (Actual): November 1, 2012
• Study Completion (Actual): March 1, 2013

Study Registration Dates

• First Submitted: September 16, 2010
• First Submitted That Met QC Criteria: September 16, 2010
• First Posted (Estimate): September 17, 2010

Study Record Updates

• Last Update Posted (Estimate): December 23, 2016
• Last Update Submitted That Met QC Criteria: December 22, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Keywords: unspecified childhood solid tumor, protocol specific; recurrent childhood rhabdomyosarcoma; recurrent neuroblastoma; recurrent Ewing sarcoma/peripheral primitive neuroectodermal tumor; recurrent osteosarcoma; recurrent childhood supratentorial primitive neuroectodermal tumor; recurrent childhood brain tumor; recurrent childhood soft tissue sarcoma
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Neoplasms; Sarcoma; Nervous System Neoplasms; Central Nervous System Neoplasms; Neuroblastoma; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Central Nervous System Depressants; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Tranquilizing Agents; Psychotropic Drugs; GABA Agents; Anticonvulsants; Antimanic Agents; Antibiotics, Antineoplastic; Antifungal Agents; Valproic Acid; Sirolimus
• Other Study ID Numbers: LCCC 0901; P30CA016086 (U.S. NIH Grant/Contract); CDR0000665319 (Other Identifier: PDQ)