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

Primary Purpose

Brain and Central Nervous System Tumors, Neuroblastoma, Sarcoma

Status

Terminated

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Temsirolimus

Valproic Acid

About this trial

This is an interventional treatment trial for Brain and Central Nervous System Tumors focused on measuring 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

Eligibility Criteria

2 Years - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

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

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

Single Arm Temsirolimus + Valproic Acid

Arm Description

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

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

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

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

Full Information

NCT ID

NCT01204450

First Posted

September 16, 2010

Last Updated

December 22, 2016

Sponsor

UNC Lineberger Comprehensive Cancer Center

Collaborators

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT01204450

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

December 2016

Overall Recruitment Status

Terminated

Why Stopped

Funding has become unavailable

Study Start Date

November 2009 (undefined)

Primary Completion Date

November 2012 (Actual)

Study Completion Date

March 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

UNC Lineberger Comprehensive Cancer Center

Collaborators

National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

7 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Single Arm Temsirolimus + Valproic Acid

Arm Type

Other

Arm Description

Intervention Type

Drug

Intervention Name(s)

Temsirolimus

Other Intervention Name(s)

Torisel

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Valproic Acid

Other Intervention Name(s)

VPA

Intervention Description

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

Primary Outcome Measure Information:

Title

Maximum tolerated dose (MTD) of temsirolimus in combination with valproic acid

Description

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

Time Frame

4 weeks

Secondary Outcome Measure Information:

Title

Objective response rate

Description

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

Time Frame

every 12 weeks

Title

Progression-free survival

Description

Time Frame

3 years

Title

Temsirolimus pharmakokinetic parameters (Maximum plasma concentration)

Description

Time Frame

doses 1 and 5

10. Eligibility

Sex

All

Minimum Age & Unit of Time

2 Years

Maximum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Julie Blatt, MD

Organizational Affiliation

UNC Lineberger Comprehensive Cancer Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

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

City

Chapel Hill

State/Province

North Carolina

ZIP/Postal Code

27599-7295

Country

United States

Facility Name

Carolina Healthcare System

City

Charlotte

State/Province

North Carolina

Country

United States

12. IPD Sharing Statement

Learn more about this trial

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

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