Clinical trial NCT00822458: GDC-0449 in Treating Young Patients With Medulloblastoma That is Recurrent or Did Not Respond to Previous Treatment
Official title: A Phase I Pharmacokinetic and Safety Study in Children With Recurrent or Refractory Medulloblastoma to Identify a Pharmacokinetic Based Dose for GDC-0449
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Recurrent Childhood Medulloblastoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2009-01-14
Enrollment: 34
Sex: ALL
Minimum age (years): 3
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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:

  * ≤ 0.8 mg/dL (for patients ≤ 5 years of age)
  * ≤ 1.0 mg/dL (for patients 6 to 10 years of age)
  * ≤ 1.2 mg/dL (for patients 11 to 15 years of age)
  * ≤ 1.5 mg/dL (for patients \> 15 years of age)
* 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

  * NOTE: \* In the absence of bone marrow involvement
* 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

Primary outcomes:
measure: Mean steady-state total (protein bound and non-protein bound) GDC-0449 plasma concentrations (Css)
timeFrame: 21 days
measure: Pharmacokinetics of GDC-0449, including the elimination rate constant and terminal half life
timeFrame: Up to 3 months after completion of study treatment
Secondary outcomes:
measure: Tumor responses
timeFrame: Up to 30 days after completion of study treatment
measure: Progression-free survival
timeFrame: Up to 30 days after completion of study treatment
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF-Mount Zion
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Chicago
country: United States
facility: Lurie Children's Hospital-Chicago
state: Illinois
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Memphis
country: United States
facility: Pediatric Brain Tumor Consortium
state: Tennessee
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
Study officials:
affiliation: Pediatric Brain Tumor Consortium
name: Amar Gajjar
role: PRINCIPAL_INVESTIGATOR
References: