Evaluation of Food Effect on Pharmacokinetics of Vismodegib

Phase 1

Completed

Conditions: Malignant Neoplasm

Interventions: Other: Pharmacological Study
Drug: Vismodegib

Registration Number: NCT01174264

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 63

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (vismodegib on empty stomach)	Pharmacological Study	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.
Arm II (vismodegib after high fat meal)	Pharmacological Study	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 (vismodegib after low fat meal)	Pharmacological Study	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.
Arm I (vismodegib on empty stomach)	Vismodegib	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.
Arm II (vismodegib after high fat meal)	Vismodegib	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 (vismodegib after low fat meal)	Vismodegib	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.

Primary Outcome Measures

Name	Time	Method
AUC Following Steady State Exposure for 14 Days	24 hours	Area under the curve from 0 to 24 hours.
Tmax'Following Single Dose of Drug	168 hours	Time of maximum drug concentration
Cmax Following Steady State Exposure for 14 Days	24 hours	Maximum drug concentration over 24 hours.
Tmax Following Steady State Exposure for 14 Days	24 hours	Time of maximum drug concentration.
Cmax Following Single Dose of Drug	168 hours	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.
AUC Following Single Dose of Drug	168 hours	Area under the curve from 0-168 hours.
Tlag Following Single Dose of Drug	168 hours	Time between drug administration and when it is first observed in the systemic circulation.
Ctrough Following Steady State Exposure for 14 Days	24 hours	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.

Secondary Outcome Measures

Name	Time	Method
Objective Responses in Patients With Solid Tumors	Up to 30 days	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.