GDC-0449 in Treating Adult Patients With Recurrent or Refractory Medulloblastoma - Full Text View

Sponsor:	Pediatric Brain Tumor Consortium
Collaborator:	National Cancer Institute (NCI)
Information provided by:	Pediatric Brain Tumor Consortium
ClinicalTrials.gov Identifier:	NCT00939484

Purpose

RATIONALE: GDC-0449 may slow the growth of tumor cells and may be an effective treatment for medulloblastoma.

PURPOSE: This phase II trial is studying how well GDC-0449 works in treating adult patients with recurrent or refractory medulloblastoma.

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

Study Type:	Interventional
Study Design:	Endpoint Classification: Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Phase II Clinical Trial Evaluating the Efficacy and Safety of GDC-0449 in Adults With Recurrent or Refractory Medulloblastoma

Resource links provided by NLM:

MedlinePlus related topics: Cancer

U.S. FDA Resources

Further study details as provided by Pediatric Brain Tumor Consortium:

Primary Outcome Measures:

Objective response rate for patients without evidence of having a tumor with the Sonic Hedgehog (SHH) signaling pathway activated [ Time Frame: From Day 1 of treatment until off therapy ] [ Designated as safety issue: No ]
Brain imaging to assess tumor response to the treatment is required prior to courses 3, 5, 8, 11, 14, 17, 20, 23, and 26. Objective response rate is defined as the number of study participants who have a tumor without the SHH pathway activated and have a complete response or a partial response to the therapy divided by the total number of study participants who have a tumor without the SHH pathway activated.
Objective response rate for patients with evidence of having a tumor with the Sonic Hedgehog (SHH) signaling pathway activated [ Time Frame: From Day 1 of treatment until off therapy ] [ Designated as safety issue: No ]
Brain imaging to assess tumor response to the treatment is required prior to courses 3, 5, 8, 11, 14, 17, 20, 23, and 26. Objective response rate is defined as the number of study participants who have a tumor with the SHH pathway activated and have a complete response or a partial response to the therapy divided by the total number of study participants who have a tumor with the SHH pathway activated.

Secondary Outcome Measures:

Number of patients with grade 3 and 4 toxicity [ Time Frame: From the first day of treatment until the end of study follow-up ] [ Designated as safety issue: Yes ]
Duration of objective response [ Time Frame: From the initial brain image documenting the objective response until progressive disease, death, or 30 days after the last dose of study drug ] [ Designated as safety issue: No ]
Maximum concentration [ Time Frame: Days 7, 14, 21, and 28 of course 1 ] [ Designated as safety issue: No ]
Blood specimens will be collected on the days listed for pharmacokinetic studies. These specimens will be analyzed to produce steady-state plasma GDC-0449 concentration-time data in study participants. The concentration-time data will be analyzed to provide an estimate of the maximum concentration.
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) or sequencing methods [ Time Frame: Pre-treatment ] [ Designated as safety issue: No ]
Minimum concentration [ Time Frame: Days 7, 14, 21, and 28 of course 1 ] [ Designated as safety issue: No ]
Blood specimens will be collected on the days listed for pharmacokinetic studies. These specimens will be analyzed to produce steady-state plasma GDC-0449 concentration-time data in study participants. The concentration-time data will be analyzed to provide an estimate of the minimum concentration.
Area under the concentration-time curve [ Time Frame: Days 7, 14, 21, and 28 of course 1 ] [ Designated as safety issue: No ]
Blood specimens will be collected on the days listed for pharmacokinetic studies. These specimens will be analyzed to produce steady-state plasma GDC-0449 concentration-time data in study participants. The concentration-time data will be analyzed to provide an estimate of the area under the concentration-time curve.
Oral clearance [ Time Frame: Days 7, 14, 21, and 28 of course 1 ] [ Designated as safety issue: No ]
Blood specimens will be collected on the days listed for pharmacokinetic studies. These specimens will be analyzed to produce steady-state plasma GDC-0449 concentration-time data in study participants. The concentration-time data will be analyzed to provide an estimate of the oral clearance.
Progression-free survival [ Time Frame: From Day 1 of treatment until the earliest of progression, death, or 30 days after the last dose of study treatment ] [ Designated as safety issue: No ]
Objective response rate for patients who have tumors with unknown Sonic Hedgehog (SHH) signaling pathway activation [ Time Frame: From Day 1 of treatment until off therapy ] [ Designated as safety issue: No ]
Brain imaging to assess tumor response to the treatment is required prior to courses 3, 5, 8, 11, 14, 17, 20, 23, and 26. Objective response rate is defined as the number of study participants who have tumors with unknown SHH signaling pathway activation and have a complete response or a partial response to the therapy divided by the total number of study participants who have tumors with unknown SHH signaling pathway activation.

Estimated Enrollment:	50
Study Start Date:	June 2009
Estimated Primary Completion Date:	August 2014 (Final data collection date for primary outcome measure)

Intervention Details:

150 mg per day taken once daily for 28 days (1 course). In the absence of unacceptable toxicity or disease progression, treatment may continue for 26 courses (approximately 2 years).

Detailed Description:

OBJECTIVES:

Primary

To estimate the efficacy of hedgehog antagonist GDC-0449 in adult patients with recurrent or refractory medulloblastoma, as measured by the objective response rates in patients with and without evidence of activation of Sonic Hedgehog (SHH) signaling pathway tumors.

Secondary

To assess the safety and tolerability of hedgehog antagonist GDC-0449 when administered on a once daily schedule.
To estimate the duration of objective response and progression-free survival.
To characterize the pharmacokinetics (plasma and cerebrospinal fluid) of hedgehog antagonist GDC-0449.
To document pathologic and genomic methods to identify CNS tumors with activation of the PTCH/SHH pathway.
To describe the objective responses observed in patients whose pathologic assessment of tumor results in unknown evidence of activation of SHH signaling pathway.

OUTLINE: This is a multicenter study. Patients are stratified according to PTCH/Sonic Hedgehog signaling pathway activation (inactivated vs activated vs unknown).

Patients receive oral hedgehog antagonist GDC-0449 once daily on days 1-28. Treatment repeats every 28 days for up to 26 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for up to 12 months.

Eligibility

Ages Eligible for Study:	22 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Histologically confirmed medulloblastoma (including posterior fossa primitive neuroectodermal tumor) for which no known curative therapy exists
- Recurrent or progressive disease, or refractory to standard therapy
Evidence of residual measurable disease or lesion in pre-study MRI
- Patients with measurable spinal disease are eligible
Tissue samples (either from the initial diagnosis and/or relapse) must be available for biological studies
Neurological deficits allowed provided they are stable for ≥ 1 week before study registration

PATIENT CHARACTERISTICS:

ECOG performance status 0-2
Life expectancy ≥ 12 weeks (as determined by treating physician)
ANC ≥ 1,000/mm^3
Platelet count ≥ 100,000/mm^3 (transfusion-independent)
Hemoglobin ≥ 8.0 g/dL (RBC transfusions allowed)
Creatine clearance or radioisotope GFR ≥ 70 mL/min OR serum creatinine ≤ 1.5 mg/dL
Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age
ALT and AST ≤ 2.5 times ULN
Serum albumin ≥ 2.5 g/dL
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use two effective methods of contraception (including one barrier method) during and for 12 months after completion of study treatment
Able to return for follow-up visits and complete follow-up studies required to assess toxicity to study treatment
Able to swallow capsules
No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, or hypokalemia, defined as less than the lower limit of normal despite adequate electrolyte supplementation
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 congenital long QT syndrome
No 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
No blood donation for ≥ 12 months after completion of study treatment

PRIOR CONCURRENT THERAPY:

Recovered from prior treatment-related toxicity
No prior hedgehog antagonist GDC-0449 or other antagonists of the hedgehog pathway
More than 4 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas) or immunotherapy
At least 3 months since prior craniospinal irradiation (≥ 23 Gy)
At least 8 weeks since prior local irradiation to primary tumor
At least 2 weeks since prior focal irradiation for symptomatic metastatic sites
At least 1 week since prior colony-stimulating factors (e.g., G-CSF, GM-CSF, or erythropoietin)
Concurrent decadron allowed provided the dose is stable or decreasing for ≥ 1 week before starting study treatment
No other concurrent anticancer or investigational agents or therapies

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00939484

Locations

United States, California
UCSF Helen Diller Family Comprehensive Cancer Center	Recruiting
San Francisco, California, United States, 94115
Contact: Clinical Trials Office - UCSF Helen Diller Family Comprehensi 877-827-3222
United States, District of Columbia
Children's National Medical Center	Recruiting
Washington, District of Columbia, United States, 20010-2970
Contact: Clinical Trials Office - Children's National Medical Center 202-884-2549
United States, Illinois
Children's Memorial Hospital - Chicago	Recruiting
Chicago, Illinois, United States, 60614
Contact: Stewart Goldman, MD 773-880-4562
United States, North Carolina
Duke University Medical Center	Recruiting
Durham, North Carolina, United States, 27710
Contact: Sri Gururangan, MD 919-668-6288 gurur002@mc.duke.edu
United States, Pennsylvania
Children's Hospital of Philadelphia	Not yet recruiting
Philadelphia, Pennsylvania, United States, 19104-4318
Contact: Peter C. Phillips, MD 215-590-2107
Children's Hospital of Pittsburgh	Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Clinical Trials Office - Children's Hospital of Pittsburgh 412-692-7056
United States, Tennessee
St. Jude Children's Research Hospital	Recruiting
Memphis, Tennessee, United States, 38105
Contact: Clinical Trials Office - St. Jude Children's Research Hospital 901-595-4644

Sponsors and Collaborators

Pediatric Brain Tumor Consortium

National Cancer Institute (NCI)

Investigators

Principal Investigator:

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:	James M. Boyett, Pediatric Brain Tumor Consortium
ClinicalTrials.gov Identifier:	NCT00939484 History of Changes
Other Study ID Numbers:	CDR0000648049, U01CA081457, PBTC-025B
Study First Received:	July 14, 2009
Last Updated:	June 22, 2011
Health Authority:	United States: Food and Drug Administration

Keywords provided by Pediatric Brain Tumor Consortium:

adult medulloblastoma
recurrent adult brain tumor
recurrent adult spinal cord neoplasm

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 February 02, 2012