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
- 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
- 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.
- 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.
- 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.
Masking: Open Label, Primary Purpose: Treatment
Charles M. Rudin, MD, PhD
Sidney Kimmel Comprehensive Cancer Center
United States: Food and Drug Administration