A Phase Ib Open-Label Pharmacokinetics and Safety Study of the Hedgehog Pathway Inhibitor Vismodegib in Patients With Advanced Solid Malignancies Including Hepatocellular Carcinoma With Varying Degrees of Renal or Hepatic Function
Overview
- Phase
- Phase 1
- Intervention
- Vismodegib
- Conditions
- Cancer
- Sponsor
- Genentech, Inc.
- Enrollment
- 31
- Primary Endpoint
- Maximum Observed Plasma Concentration and Concentration at Steady-state Following Multiple Doses of Vismodegib
- Status
- Completed
- Last Updated
- 9 years ago
Overview
Brief Summary
This is a Phase Ib, open-label, multiple-center, multiple-dose study designed to evaluate the pharmacokinetics and safety of vismodegib in patients with advanced solid malignancies (including hepatocellular carcinoma and lymphoma) that are refractory to standard therapy or for whom no standard therapy exists.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically or cytologically confirmed advanced solid malignancy (including hepatocellular carcinoma and lymphoma) that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective
- •Eastern Cooperative Oncology Group (ECOG) performance status \</= 2 (Karnofsky \>/=60%)
- •Acceptable bone marrow functions
- •Normal or varying degrees of renal or hepatic impairment according to NCI Organ Dysfunction Working Group criteria.
- •Organ function should be stable for at least 2 weeks before Day
- •In addition, there should be no evidence of acute exacerbation of hepatic/renal disease.
- •Patients with gliomas or known brain metastases who require corticosteroids or anticonvulsants must be on a stable dose of corticosteroids and seizure free for 1 month prior to enrollment. Patients with known brain metastases must be at least 4 weeks out from any radiation before starting the protocol (Day 1).
- •Documented negative serum pregnancy test for women of childbearing potential
- •For women of childbearing potential, agreement to the use of two acceptable methods of contraception during the study and for 7 months after discontinuation of vismodegib
- •For men with female partners of childbearing potential, agreement to use a latex, non-latex, or any other male condom and to advise their female partners to use an additional acceptable method of birth control during the study and for 2 months after discontinuation of study drug
Exclusion Criteria
- •Pregnancy or lactation
- •Chemotherapy, biologic therapy, immunotherapy, 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
- •Investigational agents within 28 days prior to study entry (Day 1)
- •Use of Pgp inhibitors within 7 days of Day 1
- •Use of gastric pH altering drugs except antacids within 7 days of Day 1
- •Major surgery within 14 days prior to treatment (Day 1). Patients with recent major surgery must have recovered from that surgery. Patients who are expected to have any major surgery during the study treatment period should not be enrolled.
- •Uncontrolled concurrent 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. History of other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of vismodegib or that might affect interpretation of the results from this study or renders the patient at high risk from treatment complications.
- •Severely impaired renal function (Cohort 2 only) should not have active hemolysis, and should not be on hemodialysis or peritoneal dialysis during the screening and study treatment period (Days 1-9).
Arms & Interventions
4
Moderate hepatic impairment and normal renal function
Intervention: Vismodegib
5
Severe hepatic impairment and normal renal function
Intervention: Vismodegib
1
Control cohort with normal renal and normal hepatic function
Intervention: Vismodegib
2
Severe renal impairment and normal hepatic function
Intervention: Vismodegib
3
Mild hepatic impairment and normal renal function
Intervention: Vismodegib
Outcomes
Primary Outcomes
Maximum Observed Plasma Concentration and Concentration at Steady-state Following Multiple Doses of Vismodegib
Time Frame: Day 1,2,4 and 0, 0.5, 1, 2, 4, 8 and 24 hours post dose on Day 8
Maximum observed plasma Concentration (Cmax) \& Concentration at steady-state (Css) following multiple doses of vismodegib (150 mg QD) were analyzed. At steady state the amount of drug administered (in a given time period) is equal to the amount of drug eliminated. Blood samples for assessing Cmax and Css for analysis were collected following multiple oral doses of vismodegib at pre-dose and at 0.5, 1, 2, 4, 8 and 24 hours post-dose on Day 8. From the plasma concentration-time curve, the PK parameter Cmax and Css were determined by standard non-compartmental analysis using WinNonlin
The Area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUC[0-24hours]) Following Multiple Doses of Vismodegib
Time Frame: Day 1, 2, 4 and 0, 0.5, 1, 2, 4, 8 and 24 hours postdose on Day 8
The steady state pharmacokinetic profile following oral administration of multiple doses of vismodegib included determining the area under the curve over the dosing interval (AUC\[0-24 hours\]). The AUC\[0-24 hrs\]) was determined by standard non-compartmental analysis using WinNonlin. Blood samples were collected at pre-dose and at 0.5, 1, 2, 4, 8 and 24 hours post-dose on Day 8 to estimate AUC(0-24 hrs).
Secondary Outcomes
- Amount of Vismodegib Excreted Into Urine in 24 Hours (Ae0-24hr)(24 hr total interval on Day 8)
- The Percentage of Dose of Vismodegib in 24-hour Total Urine(24 hr total interval on Day 8)
- Minimum Plasma Concentration (Cmin) of Vismodegib(Up to 8 days)
- Renal Clearance of Vismodegib(0, 0.5, 1, 2, 4, 8 and 24 hours postdose on Day 8)
- Time to Maximum Plasma Concentration (Tmax) of Vismodegib(Up to 8 days)
- Apparent Clearance (CL/F) of Vismodegib(Up to 8 days)
- Apparent Non-renal Clearance (CLNR/F) of Vismodegib(Up to 8 days)