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

This study has been completed.
National Cancer Institute (NCI)
Sidney Kimmel Comprehensive Cancer Center
Information provided by:
Genentech, Inc. Identifier:
First received: January 31, 2008
Last updated: May 4, 2010
Last verified: May 2010

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.

Condition Intervention Phase
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
Phase 1

Study Type: Interventional
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

Resource links provided by NLM:

Further study details as provided by Genentech, Inc.:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Enrollment: 68
Study Start Date: April 2007
Study Completion Date: November 2009
Detailed Description:



  • 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.


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No


  • 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 malignancy
  • 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 absorption
  • 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 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


  • 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:

    • 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., ketoconazole)
  • No concurrent grapefruit juice
  Contacts and Locations
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Please refer to this study by its identifier: NCT00607724

Sponsors and Collaborators
Genentech, Inc.
National Cancer Institute (NCI)
Sidney Kimmel Comprehensive Cancer Center
Study Chair: Charles M. Rudin, MD, PhD Sidney Kimmel Comprehensive Cancer Center
  More Information

Additional Information:
No publications provided by Genentech, Inc.

Additional publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: Clinical Trials Posting Group, Genentech, Inc. Identifier: NCT00607724     History of Changes
Obsolete Identifiers: NCT00862771
Other Study ID Numbers: CDR0000585468, JHOC-J06131, GENETECH-SHH3925g
Study First Received: January 31, 2008
Last Updated: May 4, 2010
Health Authority: United States: Food and Drug Administration

Keywords provided by Genentech, Inc.:
unspecified adult solid tumor, protocol specific processed this record on October 06, 2015