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Brain & Spinal Tumors

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PBTC-024: Phase I Study of MK-0752 in Pediatric Patients With Recurrent or Refractory CNS Malignancies

Type Status Age Range Sponsor Protocol ID

Interventional

Active

Under 12 years old

Pediatric Brain
Tumor Consortium/
National Cancer
Institute (NCI)

PBTC-024

Outline    


This is a multicenter study.

Patients receive oral MK-0752 once daily on days 1-3, 8-10, 15-17, and 22-24. Treatment repeats every 28 days for up to 19 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed for 30 days.

Objectives

Primary

  1. To estimate the maximum tolerated dose (MTD) and recommended phase II dose of MK-0752 in young patients with recurrent or refractory CNS malignancies.

Secondary

  1. To characterize the pharmacokinetics of MK-0752.
  2. To document and describe toxicities associated with MK-0752.
  3. To preliminarily define the antitumor activity of MK-0752 within the confines of a phase I setting.

Mechanism of Action

NOTCH and APP are direct substrates for gamma secretase. Gamma-secratase action on NOTCH and APP yields a C-terminal fragment (NICD—the NOTCH intracellular domain) that is quantifiable by western blotting and leads to formation of Aβ peptides,respectively. MK-0752 dose-dependently reduces Aβ40 peptide formation in vitro, with IC50 values in the low nanomolar range. Mass spectrometry analysis has shown that MK-0752 reduces the formation of all species of Aβ peptide that are truncated at the Cterminus (e.g., Aβ42, Aβ40, Aβ39, etc.) with a similar IC50 value.

Projected Accrual

About 7 to 10 people will participate in this study at Cincinnati Children’s Hospital.

Entry Criteria

Disease Characteristics:

  • Histologically confirmed primary CNS tumor.
    • Patients with intrinsic brain stem tumors do not require histologic verification, but must have radiographic evidence of progression.
  • Recurrent disease or refractory to standard therapy.
  • No histologically benign brain tumors (e.g., low-grade glioma).

Patient Characteristics:

Age

  • < 12 years of age.

Performance Status

  • Karnofsky performance status (PS) or Lansky PS 60-100%.

Life Expectancy

  • Not specified.

Hematopoietic

  • Absolute neutrophil count ≥ 1,000/μL.
  • Platelet count ≥ 100,000/μL (unsupported).
  • Hemoglobin ≥ 8 g/dL (RBC transfusions allowed).

Hepatic

  • Bilirubin ≤ 1.5 times upper limit of normal (ULN) for age.
  • ALT ≤ 2.5 times ULN for age.
  • Albumin ≥ 2.5 g/dL.

Renal

  • Serum creatinine normal for age OR glomerular filtration rate ≥ 70 mL/min/1.73m2.

Other

  • Not pregnant or nursing.
  • Negative pregnancy test.
  • Fertile patients must use effective contraception.
  • Sodium, potassium, magnesium, and calcium normal.
  • Patients with neurological deficits are eligible provided these deficits are stable for ≥ 2 weeks prior to study registration.
  • No clinically significant systemic illness (e.g., serious infection or significant cardiac, pulmonary, hepatic, or other organ dysfunction) that would compromise the patient's ability to tolerate study therapy or would likely interfere with the study procedures or results.
  • No known hypersensitivity to MK-0752.

Prior Concurrent Therapy:

Biologic Therapy

  • At least 7 days since prior investigational or biologic agents.
  • At least 3 weeks since prior investigational or biologic agents that have a prolonged half-life or for which the patient has experienced ≥ grade 2 myelosuppression in the treatment course preceding discontinuation of therapy.
  • At least 4 weeks since prior monoclonal antibody therapy.

Chemotherapy

  • At least 3 weeks since prior myelosuppressive anticancer chemotherapy (6 weeks for nitrosoureas).

Radiotherapy

  • At least 6 months since prior total body irradiation or craniospinal radiotherapy.
  • At least 6 weeks since other prior substantial bone marrow irradiation.
  • At least 2 weeks since prior local palliative radiotherapy (small volume).

Surgery

  • Recovered from the acute toxic effects of all prior therapy.

Other

  • No prior MK-0752
  • No concurrent enzyme-inducing anticonvulsant drugs (EIACDs).
  • No other concurrent anticancer or investigational drug therapy.
  • Concurrent dexamethasone allowed provided patient is on a stable or decreasing dose for ≥ 2 weeks prior to study registration.
  • At least 6 months since prior allogeneic bone marrow transplantation (BMT).
  • No evidence of active graft versus host disease.
  • At least 3 months since prior autologous BMT or stem cell transplantation.
  • At least 7 days since prior hematopoietic growth factors (filgrastim [G-CSF], sargramostim [GM-CSF], or erythropoietin) (14 days for long-acting formulations).

Trial Contact Information

For more information, contact:
Cincinnati Children’s Hospital Medical Center
Division of Hematology/Oncology
3333 Burnet Ave., Cincinnati, OH 45229-3039
Phone: 513-636-2799
cancer@cchmc.org