Evaluation of Food Effect on Pharmacokinetics of GDC-0449

• Single dose pharmacokinetic parameters, including AUC, Tmax1, Tmax2, Cmax, and Tlag [ Time Frame: Up to 168 hours ] [ Designated as safety issue: No ]
  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.
• Steady state pharmacokinetic analysis, including steady state drug concentration, ss Cmax, ss Tmax, and cumulative AUC [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
  The data will again be log transformed if appropriate and compared between the fasting and fed groups using a two-sample t test. Relationship between AAG and GDC-0449 PK will be conducted by regression analysis. The effect of prandial states and fat content of meals on the safety profile of GDC-0449, a secondary objective, will be evaluated using a two sample t test.

• Rate of adverse events (AEs) in the fasting and fed groups [ Time Frame: Up to 30 days ] [ Designated as safety issue: Yes ]
  AEs will be summarized by type and severity and compared between groups using Fisher's exact test.
• Objective responses in patients with solid tumors [ Time Frame: Up to 30 days ] [ Designated as safety issue: No ]
• Anticancer activity [ Time Frame: Up to 30 days ] [ Designated as safety issue: No ]
  Will be reported descriptively.

• Effect of food on toxicity of GDC-0449 [ Time Frame: 9 weeks ] [ Designated as safety issue: Yes ]
• Antitumor effects of GDC-0449 [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]

The purpose of this trial is to determine the effect of food on the pharmacokinetics of GDC-0449

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.

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

• Drug: vismodegib
  Given PO
  Other Names:

  • Erivedge
  • GDC-0449
  • Hedgehog antagonist GDC-0449
• Other: pharmacological study
  Correlative studies
  Other Name: pharmacological studies

• Experimental: Arm I (vismodegib on empty stomach)
  Patients receive a single dose of vismodegib PO on an empty stomach. Beginning 7 days later, patients receive vismodegib PO on an empty stomach daily on days 1-28.
  Interventions:

  • Drug: vismodegib
  • Other: pharmacological study
• Experimental: Arm II (vismodegib after high fat meal)
  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.
  Interventions:

  • Drug: vismodegib
  • Other: pharmacological study
• Experimental: Arm III (vismodegib after low fat meal)
  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.
  Interventions:

  • Drug: vismodegib
  • Other: pharmacological study

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 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 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 (http://medicine.iupui.edu/clinpharm/ddis/ClinicalTable.asp)

  • 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, 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