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

This study has been terminated.
(Funding has become unavailable)
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT01204450
First received: September 16, 2010
Last updated: October 8, 2015
Last verified: October 2015
  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:


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
Study Completion Date: March 2013
Primary Completion Date: November 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Single Arm Study 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

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   (Child, Adult)
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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

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: October 8, 2015
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:
Neoplasms
Sarcoma
Neuroblastoma
Nervous System Neoplasms
Central Nervous System Neoplasms
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms by Site
Nervous System Diseases
Everolimus
Sirolimus
Valproic Acid
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Anticonvulsants
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 25, 2016