Evaluation of Food Effect on Pharmacokinetics of Vismodegib

PRIMARY OBJECTIVES:

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

II. To evaluate the effect of fat content of meals on the pharmacokinetic parameters of
GDC-0449.

SECONDARY OBJECTIVES:

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
1-28.

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
1-28.

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
1-28.

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

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 X institutional upper limit of normal

- Creatinine =< 1.5 X institutional upper limit of normal

- 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 immediately

- 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
forward

- 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

- 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; breastfeeding should be discontinued if
the mother is treated with GDC-0449

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible

- Patients with medical conditions that require the following medications will be
excluded

- Strong inhibitors of cytochrome P450 3A4 (CYP3A4) (clarithromycin, itraconazole,
ketoconazole, nefazodone, erythromycin, grapefruit juice, verapamil, and
diltiazem)

- Strong inhibitors of cytochrome P450 2C9 (CYP2C9) (fluconazole and amiodarone)

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

- 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