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

UNC Lineberger Comprehensive Cancer Center

Status and phase: Terminated; Phase 1

Conditions: Sarcoma; Neuroblastoma; Brain and Central Nervous System Tumors; Unspecified Childhood Solid Tumor, Protocol Specific

Treatments: Drug: Valproic Acid; Drug: Temsirolimus

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT01204450

LCCC 0901

CDR0000665319 (Other Identifier)

P30CA016086 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 7 patients

Sex: All

Ages: 2 to 18 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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7 participants in 1 patient group

Single Arm Temsirolimus + Valproic Acid

Other group

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

Treatment:

Drug: Temsirolimus

Drug: Valproic Acid