NCT00607724

GDC-0449 in Treating Patients With Locally Advanced or Metastatic Solid Tumors

An Open-Label, Phase I Study of Systemic Hedgehog Pathway Antagonist, GDC-0449, in Patients With Locally Advanced or Metastatic Solid Tumors That Are Refractory to Standard Therapy or For Whom No Standard Therapy Exists

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 68 (actual)
• Sponsor: Genentech, Inc. · Industry
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

RATIONALE: Drugs used in chemotherapy, such as GDC-0449, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. PURPOSE: This phase I trial is studying the side effects and best dose of GDC-0449 in treating patients with locally advanced or metastatic solid tumors.

Detailed description

OBJECTIVES: Primary * To evaluate the safety and tolerability of escalating doses of systemic Hedgehog antagonist GDC-0449 in patients with locally advanced or metastatic solid tumors. * To estimate the maximum tolerated dose of GDC-0449 in these patients. * To define the dose-limiting toxicities of GDC-0449 in these patients. * To characterize the pharmacokinetic properties of GDC-0449 following a single dose and multiple doses. * To determine the recommended phase II dose and schedule of GDC-0449 for efficacy testing based on achievement of the target exposure with an acceptable safety profile. Secondary * To determine whether inhibition of Hedgehog (Hh) signaling by GDC-0449 can be reliably measured in human hair follicles and to define the relationship between this pharmacodynamic (PD) effect in surrogate tissue and GDC-0449 dose and exposure. * To make a preliminary assessment of tumor response in patients treated with this drug. Tertiary * To examine modulation of Hh target genes (other than GLI1) by GDC-0449 in hair follicles and/or tumor tissue. OUTLINE: This is a multicenter study. Patients receive oral systemic Hedgehog antagonist GDC-0449 once on day 1 and then once or twice daily beginning on day 8 and continuing for up to 49 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo plasma, urine, and hair sample collection and skin punch biopsies periodically for pharmacokinetic and pharmacodynamic analyses. The plasma and urine samples are analyzed separately using liquid chromatography/tandem mass spectrometry-based methods. Ex vivo plasma protein binding of GDC-0449 is assayed using an equilibrium dialysis approach. Expression levels of Gli1 and other Hedgehog target genes in hair follicle samples and/or tumor tissue are measured at the RNA level using qRT-PCR. After completion of study therapy, patients are followed at 21 days.

Conditions

• Unspecified Adult Solid Tumor, Protocol Specific

Interventions

Type	Name	Description
DRUG	GDC-0449

Timeline

• Start date: 2007-04-01
• Primary completion: 2009-11-01
• Completion: 2009-11-01
• First posted: 2008-02-06
• Last updated: 2015-10-08
• Results posted: 2015-10-08