GDC-0449 in Treating Patients With Locally Advanced or Metastatic Solid Tumors
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.
Unspecified Adult Solid Tumor, Protocol Specific
Drug: Hedgehog antagonist GDC-0449
Genetic: gene expression analysis
Genetic: protein analysis
Genetic: reverse transcriptase-polymerase chain reaction
Other: liquid chromatography
Other: mass spectrometry
Other: pharmacological study
|Study Design:||Masking: Open Label
Primary Purpose: Treatment
|Official Title:||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|
- Safety [ Designated as safety issue: Yes ]
- Occurrence of dose-limiting toxicities and the associated NCI CTCAE grade [ Designated as safety issue: Yes ]
- Occurrence of adverse events and the associated NCI CTCAE grade [ Designated as safety issue: Yes ]
- Occurrence of grade 3 or 4 abnormalities in safety-related laboratory parameters [ Designated as safety issue: Yes ]
- Occurrence of grade 3 or 4 changes in vital signs [ Designated as safety issue: Yes ]
- Single- and multiple-dose pharmacokinetic parameters [ Designated as safety issue: No ]
- Reduction of GLI1 from baseline in hair follicle cells from pulled hair and skin punch biopsies as measured by quantitative reverse transcriptase-polymerase chain reaction [ Designated as safety issue: No ]
- Tumor response (objective response, duration of response, and progression-free survival) [ Designated as safety issue: No ]
|Study Start Date:||April 2007|
|Study Completion Date:||November 2009|
- 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.
- 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.
|Study Chair:||Charles M. Rudin, MD, PhD||Sidney Kimmel Comprehensive Cancer Center|