GDC-0449 in Treating Patients With Recurrent Glioblastoma Multiforme That Can Be Removed by Surgery

NCT00980343 | Completed Phase 2 Results DMC

• 4 other identifiers: NCI-2012-02922CDR0000654829ABTC-0904U01CA137443
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 9

Brief Summary

This randomized phase II trial is studying how well GDC-0449 works in treating patients with recurrent glioblastoma multiforme that can be removed by surgery. GDC-0449 may be effective in treating patients with glioblastoma multiforme.

Conditions

Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Recurrent Adult Brain Tumor

Outcome Measures

Primary Outcomes (1)

• 6 Months Progression-free Survival (PFS)

  Estimated using Kaplan Meier curves. six months calculated from date of treatment onset post-operatively. MRI scan at 6 months must be free of progression Progressive disease Progressive neurological abnormalities not explained by other causes or greater than 25% increase in size of tumor or if new lesion.

  6 months

Secondary Outcomes (6)

• Overall Survival Time

  3 years

• Best Tumor Response Assessed by the Modified Macdonald Radiographic Response Criteria

  evaluated every 8 weeks - 1 year

• Toxicity Incidence Grade 3 or 4 According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0

  30 days from last dose of drug treatment - 1.5 years

• Incidence of CD133+ Neurospheres by Arm

  12 hours post-vismodegib administration

• Changes in Sonic Hedgehog Pathway Activation

  Pre-tumor resection and post tumor resection (12 hours)

Study Arms (2)

Arm I (pre-surgery vismodegib)

EXPERIMENTAL

Patients receive oral Hedgehog antagonist GDC-0449 (vismodegib) once daily for 7 days before therapeutic conventional surgery. Beginning within 28 days after surgical resection, all patients receive oral Hedgehog antagonist GDC-0449 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Other: pharmacological study; laboratory biomarker analysis

Drug: vismodegib; Procedure: therapeutic conventional surgery; Other: laboratory biomarker analysis; Other: pharmacological study

Arm II (no vismodegib pre-surgery)

EXPERIMENTAL

Patients do not receive treatment before therapeutic conventional surgery. Beginning within 28 days after surgical resection, all patients receive oral Hedgehog antagonist GDC-0449 (vismodegib) once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Other: laboratory biomarker analysis

Procedure: therapeutic conventional surgery; Other: laboratory biomarker analysis

Interventions

vismodegib DRUG

Given orally

Also known as: Erivedge, GDC-0449, Hedgehog antagonist GDC-0449

Arm I (pre-surgery vismodegib)

therapeutic conventional surgery PROCEDURE

undergo surgery

Arm I (pre-surgery vismodegib); Arm II (no vismodegib pre-surgery)

laboratory biomarker analysis OTHER

correlative studies

Arm I (pre-surgery vismodegib); Arm II (no vismodegib pre-surgery)

pharmacological study OTHER

correlative studies

Arm I (pre-surgery vismodegib)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically proven glioblastoma which is progressive or recurrent following radiation therapy +/- chemotherapy
• Patients must have measurable contrast-enhancing progressive or recurrent glioblastoma by MRI imaging prior to starting treatment; patient must be able to tolerate MRIs
• Patients must be eligible for surgical resection according to the following criteria:
• Patient competent to sign consent
• Expectation that the surgeon can resect \>= 50% of the Gd-enhancing tumor with low risk of inducing neurological injury
• Lack of hematologic, cardiac or other medical contraindications to surgery
• Surgery must take place Monday-Thursday, with the exception of patients being treated at Cleveland Clinic/University Hospitals: these patients may undergo surgery Monday-Friday
• Patients must have a tumor size ≥ 2.5 cm in diameter in two perpendicular planes in order to enable correlative studies
• Paraffin embedded tissue must be available from initial surgical resection at diagnosis (prior to any treatment)
• Patients may have an unlimited number of prior therapy regimens
• Patients must have recovered from severe toxicity of prior therapy; the following intervals from previous treatments are required to be eligible:
• months from the completion of radiation
• weeks from a nitrosourea chemotherapy
• weeks from a non-nitrosourea chemotherapy
• weeks from any investigational (not FDA-approved) agents

You may not qualify if:

• Patients with serious concurrent infection or medical illness, which would jeopardize the ability of the patient to receive the treatment outlined in this protocol with reasonable safety, are ineligible
• Patients may not be receiving any other investigational agents
• Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to GDC-0449 or other agents used in the study are ineligible
• Patients taking medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible
• GDC-0449 inhibits CYP2C8, CYP2C9, and CYP2C19 drug metabolism enzymes in vitro at concentrations that may be clinically relevant; therefore, caution should be exercised when dosing GDC-0449 concurrently with medications that are substrates of CYP2C8, CYP2C9, and CYP2C19 and have narrow therapeutic windows; in addition, GDC-0449 is a substrate of CYP3A4; however, the in vitro metabolic conversion of GDC-0449 is low; effects of CYP inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St. John's wort, and troglitazone) on clinical concentrations of GDC-0449 are unknown; likewise, the effects of strong inhibitors of CYP3A4 (e.g., clarithromycin, erythromycin, itraconazole, ketoconazole, nefazodone, and telithromycin) on GDC-0449 clinical concentrations are unknown, and caution should be exercised when dosing GDC-0449 concurrently with inhibitors of CYP3A4
• Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption are ineligible; patients must be able to swallow capsules
• Patients with clinically important history of liver disease, including viral or other hepatitis or cirrhosis are ineligible
• Patients with a history of uncontrolled hypocalcemia, hypomagnesemia, hyponatremia or hypokalemia defined as less than the lower limit of normal for the institution, despite adequate electrolyte supplementation are excluded from this study
• Patients with uncontrolled intercurrent illness including, but not limited to, hypertension, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, are ineligible
• Pregnant women are excluded from this study because GDC-0449 is an Hh pathway inhibiting agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with GDC-0449, breastfeeding should be discontinued if the mother is treated with GDC-0449
• HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with GDC-0449

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (9)

University of California at Los Angeles

Los Angeles, California, 90095, United States

Location

University of California San Francisco

San Francisco, California, 94115, United States

Location

Emory University/Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

Henry Ford Hospital

Detroit, Michigan, 48202, United States

Location

Wake Forest University Health Sciences

Winston-Salem, North Carolina, 27157, United States

Location

University Hospitals Case Medical Center

Cleveland, Ohio, 44106, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

University of Pennsylvania/Abramson Cancer Center

Philadelphia, Pennsylvania, 19104, United States

Location

MeSH Terms

Conditions

Glioblastoma; Gliosarcoma; Brain Neoplasms

Interventions

HhAntag691

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Results Point of Contact

• Title: Charles J Nock, MD
• Organization: Adult Brain Tumor Consortium (ABTC)

jfisher@jhmi.edu

410-955-8837

Study Officials

• Charles Nock, MD

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 18, 2009
• First Posted: September 21, 2009
• Study Start: February 1, 2010
• Primary Completion: May 1, 2012
• Study Completion: June 1, 2012
• Last Updated: August 16, 2017
• Results First Posted: August 16, 2017

Record last verified: 2017-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (9)