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

Sponsor

National Institutes of Health Clinical Center (CC) (NIH)

Overall Status

Completed

CT.gov ID

NCT00303940

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Talabostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving talabostat together with temozolomide or carboplatin may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of talabostat when given together with temozolomide or carboplatin in treating young patients with relapsed or refractory brain tumors or other solid tumors.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors Childhood Germ Cell Tumor Kidney Cancer Liver Cancer Neuroblastoma Ovarian Cancer Sarcoma Unspecified Childhood Solid Tumor, Protocol Specific	Drug: carboplatin Drug: talabostat mesylate Drug: temozolomide Other: pharmacological study	Phase 1

Detailed Description

OBJECTIVES:

Primary

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 carboplatin.
Describe the pharmacokinetic profile of talabostat in pediatric patients.

Secondary

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

26 participants

Primary Purpose:

Treatment

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

Study Start Date :

Dec 1, 2005

Actual Study Completion Date :

Feb 1, 2010

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

PATIENT CHARACTERISTICS:

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 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

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