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Evaluation of Food Effect on Pharmacokinetics of GDC-0449, an Inhibitor of Hedgehog Signaling

19 Years
Open (Enrolling)
Hematopoietic/Lymphoid Cancer, Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

Evaluation of Food Effect on Pharmacokinetics of GDC-0449, an Inhibitor of Hedgehog Signaling


I. To evaluate the effect of prandial states on the pharmacokinetic parameters of GDC-0449

II. To evaluate the effect of fat content of meals on the pharmacokinetic parameters of


I. To evaluate the effect of prandial states and fat content of meals on the safety profile
of GDC-0449.

II. To describe any anticancer activities of GDC-0449.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM I: Patients receive a single dose of vismodegib orally (PO) on an empty stomach.
Beginning 7 days later, patients receive vismodegib PO on an empty stomach daily on days

ARM II: Patients receive a single dose of vismodegib PO after eating a high fat meal.
Beginning 7 days later, patients receive vismodegib PO on an empty stomach daily on days

ARM III: Patients receive a single dose of vismodegib PO after eating a low fat meal.
Beginning 7 days later, patients receive vismodegib PO after eating a meal daily on days

In all arms, treatment repeats every 28 days for 2 courses in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Inclusion Criteria:

- Histologically confirmed advanced malignancies (except for leukemias) refractory to
standard of care therapy, or for whom no standard of care therapy is available

- Measurable or non-measurable disease

- An anticipated life expectancy > 3 months

- Karnofsky performance status of > 70%

- Leukocytes ≥ 3,000/mcL

- Absolute neutrophil count ≥ 1,500/mcL

- Platelets ≥ 100,000/mcL

- Total bilirubin within normal institutional limits

- AST(SGOT)/ALT(SGPT) ≤ 2.5 X institutional upper limit of normal

- Creatinine ≤ 1.5 X institutional upper limit of normal

- The effects of GDC-0449 on the developing human fetus at the recommended therapeutic
dose are unknown; for this reason and because Hh signal pathway inhibitors are known
to be teratogenic, women of child-bearing potential and men must use two forms of
contraception (i.e., barrier contraception and one other method of contraception) at
least 4 weeks prior to study entry, for the duration of study participation, and for
at least 12 months post-treatment; should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her treating physician

- Women of childbearing potential are required to have a negative serum pregnancy test
(with a sensitivity of at least 25 mIU/mL) within 48 hours prior to the first dose of
GDC-0449 (serum or urine); a pregnancy test (serum or urine) will be administered
every 4 weeks if their menstrual cycles are regular or every 2 weeks if their cycles
are irregular while on study within the 24-hour period prior to the administration of
GDC-0449; a positive urine test must be confirmed by a serum pregnancy test; prior to
dispensing GDC-0449, the investigator must confirm and document the patient's use of
two contraceptive methods, dates of negative pregnancy test, and confirm the
patient's understanding of the teratogenic potential of GDC-0449

- Female subjects of childbearing potential are defined as follows:

- Patients with regular menses

- Patients, after menarche with amenorrhea, irregular cycles, or using a
contraceptive method that precludes withdrawal bleeding

- Women who have had tubal ligation

- Female subjects may be considered to NOT be of childbearing potential for the
following reasons:

- The patient has undergone total abdominal hysterectomy with bilateral
salpingo-oophorectomy or bilateral oophorectomy

- The patient is medically confirmed to menopausal (no menstrual period) for
24 consecutive months

- Pre-pubertal females; the parent or guardian of young female patients who
have not yet started menstruation should verify that menstruation has not
begun; if a young female patient reaches menarche during the study, then
she is to be considered as a woman of childbearing potential from that time

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier

- Patients may not be receiving any other investigational agents

- Patients with known brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to GDC-0449 or other agents used in study

- Patients with malabsorption syndrome or other condition that would interfere with
intestinal absorption; patients must be able to swallow capsules

- Patients with clinically important history of liver disease, including viral or other
hepatitis or cirrhosis are ineligible

- Patients with uncontrolled hypocalcemia, hypomagnesemia, hyponatremia or hypokalemia
defined as less than the lower limit of normal for the institution, despite adequate
electrolyte supplementation are excluded from this study

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study because GDC-0449 is a Hh pathway
inhibiting agent with the potential for teratogenic or abortifacient effects; because
there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with GDC-0449, breastfeeding should be
discontinued if the mother is treated with GDC-0449; these potential risks may also
apply to other agents used in this study

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with GDC-0449; in addition, these
patients are at increased risk of lethal infections when treated with
marrow-suppressive therapy; appropriate studies will be undertaken in patients
receiving combination antiretroviral therapy when indicated

- Patients with medical conditions that require the following medications will be
excluded due to potential drug-drug interactions

- Strong inhibitors of CYP3A4 (clarithromycin, itraconazole, ketoconazole,
nefazodone, erythromycin, grapefruit juice, verapamil, and diltiazem)

- Strong inhibitors of CYP2C9 (fluconazole and amiodarone)

- Inducers of CYP3A4 (carbamazepine, dexamethasone, modafinil, oxcarbazepine,
phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John's wort,

- Inducers of CYP2C9 (rifampin, and secobarbital)

- Patients who have a medical condition or dietary restrictions that prevent him or her
from fasting for at least 10 hours (overnight) or eating a high calorie meal

- Any ambiguity in the inclusion/exclusion criteria should be clarified and resolved by
communication with the study investigators

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Single dose pharmacokinetic parameters, including AUC, Tmax1, Tmax2, Cmax, and Tlag

Outcome Description:

Comparison of the food influence on the PK between prandial groups will be performed using analysis of variance. Outcome measures will be log-transformed if the data are highly skewed or non-normal in distribution.

Outcome Time Frame:

Up to 168 hours

Safety Issue:


Principal Investigator

Ezra Cohen

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Chicago Comprehensive Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

October 2009

Completion Date:

Related Keywords:

  • Hematopoietic/Lymphoid Cancer
  • Unspecified Adult Solid Tumor, Protocol Specific



University of Chicago Comprehensive Cancer CenterChicago, Illinois  60637-1470