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A Study to Evaluate the Pharmacokinetics and Safety of Cobimetinib in Volunteers With and Without Liver Damage

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ClinicalTrials.gov Identifier: NCT02300025
Recruitment Status : Completed
First Posted : November 24, 2014
Results First Posted : February 19, 2016
Last Update Posted : February 19, 2016
Sponsor:
Information provided by (Responsible Party):
Genentech, Inc.

Brief Summary:
This study is an open-label, multi-center, single-dose, parallel group study to determine the pharmacokinetics, safety, and tolerability of cobimetinib administered at 10 mg to fasted male and female adult subjects with varying degrees of hepatic function. The study will be conducted based on the Child-Pugh classification of hepatic impairment. The anticipated duration of the study is 7.5 weeks. The target sample sizes are: 18 volunteers with varying degrees of hepatic function and up to 12 healthy control volunteers.

Condition or disease Intervention/treatment Phase
Healthy Volunteer Drug: cobimetinib Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 28 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Study Start Date : August 2014
Actual Primary Completion Date : January 2015
Actual Study Completion Date : January 2015

Resource links provided by the National Library of Medicine

Drug Information available for: Cobimetinib

Arm Intervention/treatment
Experimental: Cohort 1: Normal function Drug: cobimetinib
single oral 10-mg dose of cobimetinib

Experimental: Cohort 2: Mild Hepatic Impairment Drug: cobimetinib
single oral 10-mg dose of cobimetinib

Experimental: Cohort 3: Moderate Hepatic Impairment Drug: cobimetinib
single oral 10-mg dose of cobimetinib

Experimental: Cohort 4: Severe Hepatic Impairment Drug: cobimetinib
single oral 10-mg dose of cobimetinib




Primary Outcome Measures :
  1. Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Pre-dose (0 hours [hrs]), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose ]
  2. Time to Reach Maximum Observed Plasma Concentration (Tmax) [ Time Frame: Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose ]
  3. Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] [ Time Frame: Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose ]
    AUC (0-t) was defined as area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t).

  4. Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] [ Time Frame: Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose ]
    AUC (0 - ∞) was defined as AUC from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t- ∞).

  5. Extrapolated Area Under the Curve (AUC Percent [%] Extrapolated) [ Time Frame: Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose ]
    AUC% extrapolated was defined as the percentage of AUC [0-∞] obtained by forward extrapolation. It is calculated as [AUC (0-∞) minus AUC(0-t]*100/ AUC (0-∞), where AUC [0-∞] = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-∞) and AUC(0-t) is area under the plasma concentration time-curve from zero (pre-dose) to the last measured concentration.

  6. Apparent Terminal Elimination Rate Constant (λZ) [ Time Frame: Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose ]
    λZ was defined as the magnitude of the slope of the linear regression of the log concentration versus time profile during the terminal phase.

  7. Plasma Decay Half-Life (t1/2) [ Time Frame: Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose ]
    Plasma decay half-life is the time measured for the plasma concentration of cobimetinib to decrease by one half.

  8. Apparent Oral Clearance (CL/F) [ Time Frame: Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose ]
    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

  9. Apparent Volume of Distribution (Vz/F) [ Time Frame: Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose ]
    Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz/F after the oral dose is influenced by the fraction absorbed.



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Ages Eligible for Study:   18 Years to 74 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Male and female subjects between 18 and 74 years of age, inclusive
  • Body weight >/=45 kg and body mass index between 17 and 41 kg/m2, inclusive
  • Subjects with hepatic impairment must have a Child-Pugh score of 5 to 6 (mild), 7 to 9 (moderate), or 10 to 15 (severe) and have stable hepatic insufficiency within 1 month prior to Screening and a stable medication regimen for at least 1 month prior to Check-in
  • Agreement to use highly effective contraceptive methods as defined in the protocol

Exclusion Criteria:

  • Significant illness, including infections, or hospitalization within the 2 weeks prior to dosing, except for subjects with hepatic impairment who due to their liver disease may be affected by significant medical problems which require frequent hospitalizations. Invasive systemic fungal infections need to be fully treated prior to study entry
  • Significant history or clinical manifestations of any cardiac event that would put the subject at risk in the opinion of the Investigator
  • Use of drugs of abuse within 1 month of Screening or during the entire study
  • Any acute or chronic condition that, in the opinion of the Investigator, would limit the subject's ability to complete and/or participate in this clinical study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02300025


Locations
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United States, California
Anaheim, California, United States, 92801
United States, Florida
Miami, Florida, United States, 330014
Orlando, Florida, United States, 32809
Sponsors and Collaborators
Genentech, Inc.
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche

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Responsible Party: Genentech, Inc.
ClinicalTrials.gov Identifier: NCT02300025     History of Changes
Other Study ID Numbers: GP29342
First Posted: November 24, 2014    Key Record Dates
Results First Posted: February 19, 2016
Last Update Posted: February 19, 2016
Last Verified: January 2016