Evaluation of Food Effect on Pharmacokinetics of Vismodegib

Study Overview
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Brief Summary
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This randomized clinical trial studies the effect of food on the pharmacokinetics of vismodegib. Studying the effects of meals on the absorption of vismodegib may help doctors prescribe correct doses and label the drug accurately.

Detailed Description
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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.

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

Conditions
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Malignant Neoplasm

Intervention / Treatment
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* Other: Pharmacological Study
* Drug: Vismodegib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (vismodegib on empty stomach)<br>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. | Other: Pharmacological Study<br>* Correlative studies<br>Drug: Vismodegib<br>* Given PO<br>* Other names: Hedgehog Antagonist GDC-0449;|
| Experimental: Arm II (vismodegib after high fat meal)<br>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. | Other: Pharmacological Study<br>* Correlative studies<br>Drug: Vismodegib<br>* Given PO<br>* Other names: Hedgehog Antagonist GDC-0449;|
| Experimental: Arm III (vismodegib after low fat meal)<br>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. | Other: Pharmacological Study<br>* Correlative studies<br>Drug: Vismodegib<br>* Given PO<br>* Other names: Hedgehog Antagonist GDC-0449;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax Following Single Dose of Drug | Highest observed concentration over the 168 hour period. Blood samples were collected at j0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 24, 48, 120, and 168 hours. | 168 hours | 
| AUC Following Single Dose of Drug | Area under the curve from 0-168 hours. | 168 hours | 
| Tmax'Following Single Dose of Drug | Time of maximum drug concentration | 168 hours | 
| Tlag Following Single Dose of Drug | Time between drug administration and when it is first observed in the systemic circulation. | 168 hours | 
| Ctrough Following Steady State Exposure for 14 Days | Minimum blood concentration over 24-hour observation period. Blood sample collected at 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 24 hours. | 24 hours | 
| Cmax Following Steady State Exposure for 14 Days | Maximum drug concentration over 24 hours. | 24 hours | 
| AUC Following Steady State Exposure for 14 Days | Area under the curve from 0 to 24 hours. | 24 hours | 
| Tmax Following Steady State Exposure for 14 Days | Time of maximum drug concentration. | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Responses in Patients With Solid Tumors | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | Up to 30 days |