GDC-0449 in Treating Young Patients With Medulloblastoma That is Recurrent or Did Not Respond to Previous Treatment - Full Text View

Sponsor:	Pediatric Brain Tumor Consortium
Collaborator:	National Cancer Institute (NCI)
Information provided by (Responsible Party):	Pediatric Brain Tumor Consortium
ClinicalTrials.gov Identifier:	NCT00822458

Purpose

RATIONALE: GDC-0449 may be effective in treating young patients with medulloblastoma.

PURPOSE: 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.

Condition	Intervention	Phase
Brain and Central Nervous System Tumors	Drug: Hedgehog antagonist GDC-0449	Phase 1

Study Type:	Interventional
Study Design:	Endpoint Classification: Safety Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: 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

Resource links provided by NLM:

MedlinePlus related topics: Cancer

Drug Information available for: Vismodegib

U.S. FDA Resources

Further study details as provided by Pediatric Brain Tumor Consortium:

Primary Outcome Measures:

Number of dose limiting toxicities observed with 150 mg/day formulations [ Time Frame: First 28 days of treatment ] [ Designated as safety issue: Yes ]
Stratum I will include 6 patients with BSAs ≤1.32 m2, and they will receive 150 mg/day. Stratum II will enroll 6 patients with BSAs ≥ 1.33 m2. Patients with BSAs between 1.33 and 2.20 inclusive will receive 300 mg/day and those with BSAs between 2.21 and 2.50 inclusive will recieve 450 mg/day.

Secondary Outcome Measures:

Toxicity [ Time Frame: From Day 1 of treatment until off study ] [ Designated as safety issue: Yes ]
Pharmacokinetics [ Time Frame: Days 1 and 4, Day 5 or 6 or 7, and Days 14 and 21 of course 1. Day 1 of courses 3, 5, 7, 9, 11, and 13. Day 7, 14, 21, 28, 42, and 56 after the last dose of the study drug. ] [ Designated as safety issue: No ]
Blood samples from all patients will be collected on the time points listed for GDC-0449 pharmacokinetic studies.
Tumor response [ Time Frame: Prior to courses 3, 5, 8, 11, 15, 19, and 23 and at the end of treatment ] [ Designated as safety issue: No ]
Agreement between tumors with Sonic Hedgehog (SHH) pathway activation identified by in situ hybridization and tumors with SHH pathway activation identified by realtime-polymerase chain reaction (RT-PCR) [ Time Frame: Pre-treatment ] [ Designated as safety issue: No ]
Progression-free survival [ Time Frame: From starting treatment until progression, death, or off study ] [ Designated as safety issue: No ]

Enrollment:	21
Study Start Date:	January 2009
Primary Completion Date:	June 2011 (Final data collection date for primary outcome measure)

Intervention Details:

150 mg, 300 mg, or 450 mg once daily for 28 days (1 course). Treatment may continue for 13 courses (approximately 1 year) in the absence of unacceptable toxicity or disease progression.

Detailed Description:

OBJECTIVES:

Primary

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

To document and describe toxicities associated with this drug in these patients.
To characterize the pharmacokinetics of this drug in these patients.
To document preliminary antitumor activity of this drug in these patients.
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

Ages Eligible for Study:	3 Years to 21 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

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

PATIENT CHARACTERISTICS:

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

PRIOR CONCURRENT THERAPY:

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00822458

Locations

United States, California
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California, United States, 94115
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010-2970
United States, Illinois
Children's Memorial Hospital - Chicago
Chicago, Illinois, United States, 60614
United States, North Carolina
Duke Comprehensive Cancer Center
Durham, North Carolina, United States, 27710
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104-4318
Children's Hospital of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15213
United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
United States, Texas
Dan L. Duncan Cancer Center at Baylor College of Medicine
Houston, Texas, United States, 77030

Sponsors and Collaborators

Pediatric Brain Tumor Consortium

National Cancer Institute (NCI)

Investigators

Study Chair:

Amar Gajjar, MD

St. Jude Children's Research Hospital

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Pediatric Brain Tumor Consortium
ClinicalTrials.gov Identifier:	NCT00822458 History of Changes
Other Study ID Numbers:	CDR0000631677, U01CA081457, PBTC-025
Study First Received:	January 13, 2009
Last Updated:	March 2, 2012
Health Authority:	United States: Food and Drug Administration

Keywords provided by Pediatric Brain Tumor Consortium:

recurrent childhood medulloblastoma

Additional relevant MeSH terms:

Medulloblastoma
Nervous System Neoplasms
Central Nervous System Neoplasms
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type
Neoplasms
Neuroectodermal Tumors, Primitive
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms by Site
Nervous System Diseases

ClinicalTrials.gov processed this record on May 23, 2012