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

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Brief Title

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

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

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.
    

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 Phase

Phase 1

Study Type

Interventional




Condition

Brain and Central Nervous System Tumors

Intervention

carboplatin


Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

26

Start Date

December 2005

Completion Date

February 2010


Eligibility 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

        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
      

Gender

All

Ages

2 Years - 18 Years

Accepts Healthy Volunteers

No

Contacts

Holly Meany, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00303940

Organization ID

050239

Secondary IDs

05-C-0239


Study Sponsor

National Institutes of Health Clinical Center (CC)

Collaborators

 National Cancer Institute (NCI)

Study Sponsor

Holly Meany, MD, Study Chair, National Cancer Institute (NCI)


Verification Date

March 2012