Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Trial Contact Information
Related Information
Registry Information

Alternate Title

Talabostat Combined With Temozolomide or Carboplatin in Treating Young Patients With Relapsed or Refractory Brain Tumors or Other Solid Tumors

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase I Biomarker/Laboratory analysis, Treatment Temporarily closed 2 to 18 NCI NCI-05-C-0239 NCI-P6672, NCT00303940

Special Category: NCI Web site featured trial

Objectives

Primary

1. Determine the dose of talabostat, when used in combination with either temozolomide or carboplatin, at which maximum plasma dipeptidyl peptidase IV enzyme inhibition is achieved (in the absence of talabostat-related dose-limiting toxicity) in pediatric patients with refractory or relapsed solid tumors, including brain tumors.
2. Determine the maximum tolerated dose of talabostat, when used in combination with temozolomide or carboplatin in pediatric patients, if dose-limiting toxicity attributed to talabostat is observed.
3. Define the toxicity profile of talabostat when used in combination with temozolomide or carboplatin.
4. Describe the pharmacokinetic profile of talabostat in pediatric patients.

Secondary

1. Study levels, at baseline and after drug administration, of serum cytokines (interleukin [IL]-2, IL-6, IL-10, filgrastim [G-CSF], tumor necrosis factor-α, IL-1β, IL-8, IP10, and thrombospondin) that may be important in the immune-mediated antitumor effect of talabostat.
2. Evaluate the antitumor effect of talabostat in combination with temozolomide or carboplatin on pediatric solid tumors by direct assessment of tumor response.
3. Study the effect of talabostat on neutrophil function.
4. Evaluate the expression of fibroblast activation protein (FAP) in pediatric tumors using immunohistochemistry to detect FAP in paraffin-embedded tissue sections from existing tumor specimens, when available.

Entry Criteria

Disease Characteristics:

• Histologically confirmed solid tumors, including, but not limited to, any of the following:
  • Rhabdomyosarcoma and other soft tissue sarcomas
  • Ewing's sarcoma family of tumors
  • Osteosarcoma
  • Neuroblastoma
  • Wilms' tumor
  • Hepatic tumors
  • Germ cell tumors
  • Primary brain tumors
    • In patients with brainstem or optic gliomas, requirement for histological confirmation can be waived if biopsy was not performed
      • Patients with brainstem gliomas that did not respond to therapy but that are without radiographic evidence of disease progression must have clinical evidence of progression
    • Patients with brain tumors must be on stable or tapering dose of corticosteroids for 7 days prior to study entry



• Measurable or evaluable disease



• Relapsed or failed to respond to frontline curative therapy, including any of the following:
  • Surgery
  • Radiotherapy
  • Chemotherapy
  • Combination of modalities



• No other potentially curative treatment options available

Prior/Concurrent Therapy:

• See Disease Characteristics
• Recovered to ≤ grade 1 from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to study entry
• Any number of prior chemotherapy regimens allowed
• Prior temozolomide or carboplatin as frontline therapy or in the adjuvant setting allowed provided patient did not experience severe toxicities related to the drug and tumor progressed during this therapy
• At least 3 weeks since last dose of all myelosuppressive chemotherapy
• At least 7 days since last dose of anticancer biologic agents (e.g., retinoids)
• At least 30 days since prior investigational agents
• At least 4 weeks since prior radiotherapy to > 25% of marrow-containing bones (pelvis, spine, or skull) (2 weeks for palliative [limited-port] radiotherapy)
• At least 2 months since prior autologous stem cell transplantation and recovered
• At least 1 week since prior filgrastim (G-CSF), sargramostim (GM-CSF), or epoetin alfa
• At least 2 weeks since prior pegfilgrastim
• No history of allogeneic stem cell transplantation
• No other concurrent anticancer chemotherapy, radiation therapy, or immunotherapy
• No other concurrent investigational agents

Patient Characteristics:

• ECOG performance status 0-2
• Absolute neutrophil count ≥ 1,500/mm³
• Hemoglobin ≥ 8 mg/dL
• Platelet count ≥ 100,000/mm³ (platelet transfusion independent)
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• SGPT ≤ 2.5 times ULN
• Creatinine clearance ≥ 60 mL/min OR age-adjusted creatinine* as follows:
  • No more than 0.8 mg/dL (for patients ≤ 5 years of age)
  • No more than 1.0 mg/dL (for patients 6 to 10 years of age)
  • No more than 1.2 mg/dL (for patients 11 to 15 years of age)
  • No more than 1.5 mg/dL (for patients > 15 years of age)

   [Note: *For patients receiving carboplatin a nuclear glomerular filtration rate study, 24-hour urine collection, and serum creatinine for estimation of creatinine clearance is required if under 15 years of age OR serum creatinine and weight for estimation of creatinine clearance is required if 15-18 years of age]

• Patients with history of seizures eligible if seizures controlled by anticonvulsants
• No clinically significant, unrelated systemic illness, including either of the following:
  • Serious infections
  • Hepatic, renal, or other organ dysfunction that would preclude study treatment
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No generalized pitting peripheral edema
• No sensitivity to valine-proline boronic acid

Expected Enrollment

A total of 26 patients will be accrued for this study.

Outline

This is a dose-escalation study of talabostat. Patients are stratified according to tumor histology and prior therapy.

Based on stratification, patients receive either oral temozolomide on days 1-5 or carboplatin IV over 30 minutes on days 1-2. Patients also receive oral talabostat on days 7-20. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 2-6 patients receive escalating doses of talabostat until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 or < 4 of 12 patients experience dose-limiting toxicity during the first course of therapy.

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research

Holly Meany, MD, Protocol chair		Ph: 301-451-7020
Frank Balis, MD, Principal investigator		Ph: 301-496-0085 Email: balisf@nih.gov

Related Information

Featured trial article

Registry Information
Official Title		A Phase I Trial and Pharmacokinetic Study of Talabostat (PT-100, Val-Boro-Pro) in Combination with Temozolomide or Carboplatin in Pediatric Patients with Relapsed or Refractory Solid Tumors Including Brain Tumors
Trial Start Date		2005-12-28
Registered in ClinicalTrials.gov		NCT00303940
Date Submitted to PDQ		2005-12-05
Information Last Verified		2008-12-21