GDC-0449 in Treating Young Patients With Medulloblastoma That is Recurrent or Did Not Respond to Previous Treatment
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| ClinicalTrials.gov Identifier: NCT00822458 |
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Recruitment Status :
Completed
First Posted : January 14, 2009
Last Update Posted : April 2, 2014
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Recurrent Childhood Medulloblastoma | Drug: vismodegib Other: laboratory biomarker analysis Other: pharmacological study | Phase 1 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 34 participants |
| Intervention Model: | Single Group Assignment |
| Masking: | None (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 |
| Study Start Date : | January 2009 |
| Actual Primary Completion Date : | September 2013 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Arm I
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. |
Drug: vismodegib
Given orally
Other Names:
Other: laboratory biomarker analysis Other: pharmacological study Other Name: pharmacological studies |
- Mean steady-state total (protein bound and non-protein bound) GDC-0449 plasma concentrations (Css) [ Time Frame: 21 days ]95% confidence interval estimates for 2 doses compared.
- Pharmacokinetics of GDC-0449, including the elimination rate constant and terminal half life [ Time Frame: Up to 3 months after completion of study treatment ]We will study two BSA defined strata.
- Tumor responses [ Time Frame: Up to 30 days after completion of study treatment ]Descriptive statistics will be provided describing tumor responses.
- Progression-free survival [ Time Frame: Up to 30 days after completion of study treatment ]Kaplan-Meier estimates of the distribution of progression-free survival (PFS) will be constructed.
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| Ages Eligible for Study: | 3 Years to 21 Years (Child, Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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)*
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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
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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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00822458
| United States, California | |
| UCSF-Mount Zion | |
| San Francisco, California, United States, 94115 | |
| United States, District of Columbia | |
| Children's National Medical Center | |
| Washington, District of Columbia, United States, 20010 | |
| United States, Illinois | |
| Lurie Children's Hospital-Chicago | |
| Chicago, Illinois, United States, 60614 | |
| United States, North Carolina | |
| Duke University Medical Center | |
| Durham, North Carolina, United States, 27710 | |
| United States, Pennsylvania | |
| Children's Hospital of Philadelphia | |
| Philadelphia, Pennsylvania, United States, 19104 | |
| Children's Hospital of Pittsburgh of UPMC | |
| Pittsburgh, Pennsylvania, United States, 15224 | |
| United States, Tennessee | |
| Pediatric Brain Tumor Consortium | |
| Memphis, Tennessee, United States, 38105 | |
| St. Jude Children's Research Hospital | |
| Memphis, Tennessee, United States, 38105 | |
| United States, Texas | |
| Texas Children's Hospital | |
| Houston, Texas, United States, 77030 | |
| Principal Investigator: | Amar Gajjar | Pediatric Brain Tumor Consortium |
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT00822458 History of Changes |
| Other Study ID Numbers: |
NCI-2009-01180 NCI-2009-01180 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) CDR0000631677 PBTC-025 ( Other Identifier: Pediatric Brain Tumor Consortium ) PBTC-025 ( Other Identifier: CTEP ) U01CA081457 ( U.S. NIH Grant/Contract ) |
| First Posted: | January 14, 2009 Key Record Dates |
| Last Update Posted: | April 2, 2014 |
| Last Verified: | June 2013 |
Additional relevant MeSH terms:
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Medulloblastoma 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 |