A Study of Vismodegib in Patients With Advanced Solid Malignancies Including Hepatocellular Carcinoma With Varying Degrees of Renal or Hepatic Function

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Genentech, Inc.
ClinicalTrials.gov Identifier:
NCT01546519
First received: March 2, 2012
Last updated: April 14, 2016
Last verified: April 2016
  Purpose
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.

Condition Intervention Phase
Cancer
Drug: Vismodegib
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Genentech, Inc.:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 Outcome Measures:
  • The Percentage of Dose of Vismodegib in 24-hour Total Urine [ Time Frame: 24 hr total interval on Day 8 ] [ Designated as safety issue: No ]
    The percentage of dose vismodegib excreted in urine over a 24-hr total interval was estimated

  • Renal Clearance of Vismodegib [ Time Frame: 0, 0.5, 1, 2, 4, 8 and 24 hours postdose on Day 8 ] [ Designated as safety issue: No ]
    Renal clearance (CLR) is defined as the apparent total clearance of the drug from plasma after oral administration.

  • Amount of Vismodegib Excreted Into Urine in 24 Hours (Ae0-24hr) [ Time Frame: 24 hr total interval on Day 8 ] [ Designated as safety issue: No ]
    The amount of total vismodegib excreted in urine over a 24-hr total interval (Ae0-24hr) was estimated.

  • Time to Maximum Plasma Concentration (Tmax) of Vismodegib [ Time Frame: Up to 8 days ] [ Designated as safety issue: No ]
    Tmax is the time to reach maximum plasma concentration of vismodegib. This was a pre-specified PK parameter. However, due to minimal fluctuation of Vismodegib concentrations at steady state, this parameter could not be determined.

  • Minimum Plasma Concentration (Cmin) of Vismodegib [ Time Frame: Up to 8 days ] [ Designated as safety issue: No ]
    Cmin is defined as the minimum observed plasma concentration of Vismodegib. This was a pre-specified PK parameter. However, due to minimal fluctuation of Vismodegib concentrations at steady state, this parameter could not be determined.

  • Apparent Clearance (CL/F) of Vismodegib [ Time Frame: Up to 8 days ] [ Designated as safety issue: No ]
    CL/F is apparent clearance of the drug from the plasma, calculated as the drug dose divided AUC (0-inf), expressed in liter/hour (L/hr). This was a pre-specified PK parameter. However, due to minimal fluctuation of vismodegib concentrations at steady state, this parameter could not be determined.

  • Apparent Non-renal Clearance (CLNR/F) of Vismodegib [ Time Frame: Up to 8 days ] [ Designated as safety issue: No ]
    Apparent Non-Renal Clearance (CLNR) describes the removal of vismodegib by organs other than the kidneys. This was a pre-specified PK parameter. However, due to minimal fluctuation of vismodegib concentrations at steady state, this parameter could not be determined.


Enrollment: 31
Study Start Date: March 2012
Study Completion Date: April 2014
Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Control cohort with normal renal and normal hepatic function
Drug: Vismodegib
oral repeating dose of 150 mg once daily
Experimental: 2
Severe renal impairment and normal hepatic function
Drug: Vismodegib
oral repeating dose of 150 mg once daily
Experimental: 3
Mild hepatic impairment and normal renal function
Drug: Vismodegib
oral repeating dose of 150 mg once daily
Experimental: 4
Moderate hepatic impairment and normal renal function
Drug: Vismodegib
oral repeating dose of 150 mg once daily
Experimental: 5
Severe hepatic impairment and normal renal function
Drug: Vismodegib
oral repeating dose of 150 mg once daily

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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 1. 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
  • Agreement not to donate blood/blood products during the study and for 7 months after discontinuing study drug
  • For men with normal renal and hepatic function, agreement to provide semen during the vismodegib treatment period for study assessment (optional), but otherwise NOT to donate semen during the vismodegib treatment period 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).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01546519

Locations
United States, Illinois
Chicago, Illinois, United States, 60637
United States, Maryland
Baltimore, Maryland, United States, 21201
United States, Michigan
Detroit, Michigan, United States, 48201
United States, New Hampshire
Lebanon, New Hampshire, United States, 03756
United States, New York
New York, New York, United States, 10017
Sponsors and Collaborators
Genentech, Inc.
Investigators
Study Director: Clinical Trials Genentech, Inc.
  More Information

Responsible Party: Genentech, Inc.
ClinicalTrials.gov Identifier: NCT01546519     History of Changes
Other Study ID Numbers: GP27839 
Study First Received: March 2, 2012
Results First Received: October 13, 2015
Last Updated: April 14, 2016
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Carcinoma, Hepatocellular
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases

ClinicalTrials.gov processed this record on August 29, 2016