A Phase I Pharmacokinetic and Safety Study in Children With Recurrent or Refractory Medulloblastoma to Identify a Pharmacokinetic Based Dose for GDC-0449
A Phase I Pharmacokinetic and Safety Study in Children With Recurrent or Refractory Medulloblastoma to Identify a Pharmacokinetic Based Dose for GDC-0449
This phase I trial is studying the side effects and best dose of GDC-0449 in treating young patients with medulloblastoma that is recurrent or did not respond to previous treatment. GDC-0449 may be effective in treating young patients with medulloblastoma.
PRIMARY OBJECTIVE:
I. To investigate the safety and pharmacokinetics of a daily dose of hedgehog antagonist GDC-0449 using the available formulation in pediatric patients with recurrent or refractory medulloblastoma.
SECONDARY OBJECTIVES:
I. To document and describe toxicities associated with this drug in these patients.
II. To characterize the pharmacokinetics of this drug in these patients. III. To document preliminary antitumor activity of this drug in these patients. IV. To document pathologic and genomic methods to identify CNS tumors with activation of the PTCH/SHH pathway.
OUTLINE: This is a multicenter study.
Patients receive oral hedgehog antagonist GDC-0449 once daily on days 1 and 4-28 in course 1 and on days 1-28 in all subsequent courses. Treatment repeats every 28 days for up to 26 courses in the absence of disease progression or unacceptable toxicity.
Blood samples are collected periodically for pharmacokinetic studies. Archival tumor tissue samples are collected and analyzed for the expression of genes that activate the SHH (e.g., Gli1, Gli2, SFRP1, ATOH1, and PTCH2) or WNT (e.g., DKK2 and DKK4) cell signal pathways by in situ hybridization and reverse transcriptase real time-PCR.
After completion of study therapy, patients are followed for 90 days.
Inclusion Criteria:
Histologically confirmed medulloblastoma, including posterior fossa primitive neuroectodermal tumor (PNET)
Recurrent, progressive, or refractory to standard therapy
No known curative therapy exists
Neurological deficits allowed provided they are stable for ≥ 1 week prior to study entry
No atypical teratoid/rhabdoid tumor or supratentorial PNET
Karnofsky performance status (PS) 60-100% (for patients > 16 years of age) OR Lansky PS 60-100% (for patients ≤ 16 years of age)
ANC ≥ 1,000/μL*
Platelet count ≥ 100,000/μL (transfusion independent)*
Hemoglobin ≥ 8.0 g/dL (RBC transfusion allowed)*
Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR serum creatinine based on age as follows:
Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age
ALT/AST ≤ 2.5 times ULN for age
Serum albumin ≥ 2.5 g/dL
Not pregnant or nursing
Negative pregnancy test
Fertile female patients must use 2 effective methods of contraception during and for 12 months following study treatment
Fertile male patients must use effective barrier contraception during and for 12 months following study treatment
Body surface area > 0.67 m^2 and ≤ 2.5 m^2
Able to swallow capsules
No malabsorption syndrome or other condition that would interfere with enteral absorption
No history of congestive heart failure
No history of ventricular arrhythmia requiring medication
No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, or hypokalemia, defined as less than the lower limit of normal despite adequate electrolyte supplementation
No clinically important history of liver disease, including viral hepatitis or cirrhosis
No concurrent clinically significant unrelated 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 treatment or would likely interfere with study procedures or results
Recovered from prior treatment-related toxicity
At least 3 months since prior craniospinal radiotherapy (at doses ≥ 23 Gy)
At least 8 weeks since prior local radiotherapy to primary tumor
At least 2 weeks since prior focal radiotherapy to symptomatic metastatic sites
More than 4 weeks since prior myelosuppressive chemotherapy or immunotherapy (6 weeks for nitrosoureas)
More than 1 week since prior colony-stimulating factors (e.g., filgrastim [G-CSF], sargramostim [GM-CSF], or erythropoietin)
No other concurrent anticancer or investigational drug therapy
Concurrent dexamethasone allowed provided dosage is stable or decreasing for ≥ 1 week prior to study entry