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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

Phase 1
2 Years
18 Years
Not Enrolling
Brain and Central Nervous System Tumors, Childhood Germ Cell Tumor, Kidney Cancer, Liver Cancer, Neuroblastoma, Ovarian Cancer, Sarcoma, Unspecified Childhood Solid Tumor, Protocol Specific

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Trial Information

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



- 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.

- 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.

- Define the toxicity profile of talabostat when used in combination with temozolomide or

- Describe the pharmacokinetic profile of talabostat in pediatric patients.


- 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.

- Evaluate the antitumor effect of talabostat in combination with temozolomide or
carboplatin on pediatric solid tumors by direct assessment of tumor response.

- Study the effect of talabostat on neutrophil function.

- 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.

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. (Closed to accrual as of 5/25/2009)

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.

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

Inclusion Criteria


- Histologically confirmed solid tumors, including, but not limited to, any of the

- 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

- Surgery

- Radiotherapy

- Chemotherapy

- Combination of modalities

- No other potentially curative treatment options available


- ECOG performance status 0-2

- Absolute neutrophil count ≥ 1,500/mm^3

- Hemoglobin ≥ 8 mg/dL

- Platelet count ≥ 100,000/mm^3 (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

- 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


- 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

- 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

Type of Study:


Study Design:

Primary Purpose: Treatment

Principal Investigator

Holly Meany, MD

Investigator Role:

Study Chair

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Food and Drug Administration

Study ID:




Start Date:

December 2005

Completion Date:

February 2010

Related Keywords:

  • Brain and Central Nervous System Tumors
  • Childhood Germ Cell Tumor
  • Kidney Cancer
  • Liver Cancer
  • Neuroblastoma
  • Ovarian Cancer
  • Sarcoma
  • Unspecified Childhood Solid Tumor, Protocol Specific
  • unspecified childhood solid tumor, protocol specific
  • recurrent childhood rhabdomyosarcoma
  • recurrent childhood soft tissue sarcoma
  • recurrent Ewing sarcoma/peripheral primitive neuroectodermal tumor
  • recurrent osteosarcoma
  • recurrent neuroblastoma
  • recurrent Wilms tumor and other childhood kidney tumors
  • recurrent childhood malignant germ cell tumor
  • recurrent childhood liver cancer
  • recurrent childhood brain stem glioma
  • recurrent childhood cerebellar astrocytoma
  • recurrent childhood cerebral astrocytoma
  • recurrent childhood ependymoma
  • recurrent childhood medulloblastoma
  • recurrent childhood supratentorial primitive neuroectodermal tumor
  • childhood atypical teratoid/rhabdoid tumor
  • childhood low-grade cerebral astrocytoma
  • childhood high-grade cerebral astrocytoma
  • childhood choroid plexus tumor
  • childhood craniopharyngioma
  • childhood infratentorial ependymoma
  • childhood supratentorial ependymoma
  • childhood oligodendroglioma
  • recurrent childhood visual pathway and hypothalamic glioma
  • recurrent childhood brain tumor
  • childhood central nervous system germ cell tumor
  • childhood grade I meningioma
  • childhood grade II meningioma
  • childhood grade III meningioma
  • childhood malignant ovarian germ cell tumor
  • childhood malignant testicular germ cell tumor
  • childhood teratoma
  • Brain Neoplasms
  • Carcinoma, Renal Cell
  • Kidney Neoplasms
  • Liver Neoplasms
  • Nervous System Neoplasms
  • Neuroblastoma
  • Ovarian Neoplasms
  • Central Nervous System Neoplasms
  • Neoplasms, Germ Cell and Embryonal
  • Neoplasms
  • Sarcoma



Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office Bethesda, Maryland  20892-1182