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
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
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.
OBJECTIVES:
Primary
Secondary
Tertiary
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.
DISEASE CHARACTERISTICS:
Histologically confirmed locally advanced or metastatic solid tumor that is refractory to standard therapy or for which no standard therapy exists
Progressed after first-line and second-line therapy (if there is a second-line therapy that has been shown to provide clinical benefit)
Evaluable disease by physical examination, imaging, and/or one of the following:
No CNS cancer, either primary lesions or metastatic disease, as the current malignancy
No pleural effusions, ascites, or leptomeningeal disease as the only manifestation of the current malignancy
PATIENT CHARACTERISTICS:
ECOG performance status 0-2
Granulocyte count ≥ 1,500/μL
Platelet count ≥ 100,000/μL
Hemoglobin ≥ 9 g/dL
Serum bilirubin normal
Alkaline phosphatase ≤ 1.5 times upper limit of normal (ULN) (≤ 4 times ULN for patients with liver or bone metastases)
AST and ALT ≤ 1.5 times ULN (≤ 5 times the ULN for patients with liver metastases)
Serum creatinine ≤ 1.5 mg/dL
INR < 1.3
aPTT ≤ 1.5 times ULN
Fasting total serum cholesterol ≤ 220 mg/dL (without cholesterol-lowering drugs)
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
Able and willing to swallow pills
No malabsorption syndrome or other condition that would interfere with enteral absorption
No history of significant atherosclerotic disease, including the following:
No history of congestive heart failure or ventricular arrhythmia requiring medication
No congenital long QT syndrome
No baseline QTc intervals > 0.47 seconds on two of three baseline 12-lead ECGs recorded during the screening period
No active infection requiring intravenous antibiotics
No known HIV infection
No uncontrolled hypocalcemia, hypomagnesemia, or hypokalemia, defined as less than the lower limit of normal for the institution despite adequate electrolyte supplementation
No history of clinically important liver disease, including cirrhosis or viral or other hepatitis
No current alcohol abuse
No significant traumatic injury within the past 3 weeks
No other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the study results or renders the patient at high risk from treatment complications
PRIOR CONCURRENT THERAPY:
At least 4 weeks since prior chemotherapy, investigational therapy, radiotherapy, or major surgical procedure and recovered
No concurrent medications with narrow therapeutic indices that are cytochrome P450 substrates (warfarin sodium [Coumadin®])
No concurrent medications known to prolong the QT interval, including any of the following:
No concurrent medications that may interfere with the metabolism of GDC-0449 (e.g., ketoconazole)
No concurrent grapefruit juice