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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

Phase 1
18 Years
Not Enrolling
Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

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
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.

Inclusion Criteria


- 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)

- Must receive standard second-line therapy if second-line therapy has been
shown to provide clinical benefit

- Evaluable disease by physical examination, imaging, and/or one of the following:

- Two rising prostate-specific antigen (PSA) levels ≥ 2 weeks apart, with one
obtained during screening (for patients with prostate cancer)

- Two rising CA-125 levels ≥ 2 weeks apart, with one obtained during screening
(for patients with ovarian cancer)

- No CNS cancer, either primary lesions or metastatic disease, as the current

- No pleural effusions, ascites, or leptomeningeal disease as the only manifestation of
the current malignancy


- 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

- No history of significant atherosclerotic disease, including the following:

- Coronary artery disease (i.e., myocardial infarction within the past year or
unstable angina)

- Documented carotid atheromas

- 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

- 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


- 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

- Quinidine or other anti-arrhythmic agents

- Haloperidol, fluoxetine, paroxetine, or sertraline

- Pentamidine, fluoroquinolone, or macrolide antibiotics

- No concurrent medications that may interfere with the metabolism of GDC-0449 (e.g.,

- No concurrent grapefruit juice

Type of Study:


Study Design:

Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:


Safety Issue:


Principal Investigator

Charles M. Rudin, MD, PhD

Investigator Role:

Study Chair

Investigator Affiliation:

Sidney Kimmel Comprehensive Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

April 2007

Completion Date:

November 2009

Related Keywords:

  • Unspecified Adult Solid Tumor, Protocol Specific
  • unspecified adult solid tumor, protocol specific
  • Neoplasms