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An Absolute Bioavailability Study in Healthy Participants Comparing Oral to Intravenous Administration of GDC-0973 (Cobimetinib)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Genentech, Inc.
ClinicalTrials.gov Identifier:
NCT01249118
First received: November 24, 2010
Last updated: April 4, 2017
Last verified: April 2017
  Purpose
The primary objective of Part 1 of this study is to evaluate the safety and tolerability of the intravenous (IV) dose of GDC-0973. The primary objectives of Part 2 of this study are to evaluate the absolute bioavailability of GDC-0973 and to evaluate the pharmacokinetic (PK) of GDC-0973 following IV and oral administration. The secondary objective of Part 2 of this study is to evaluate the safety of GDC-0973 administered orally and intravenously.

Condition Intervention Phase
Healthy Volunteers Drug: GDC-0973 IV Infusion Drug: GDC-0973 Oral Capsules Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: No masking
Primary Purpose: Basic Science
Official Title: A Phase 1, Single Dose, Randomized, Cross-over Absolute Bioavailability Study in Healthy Subjects Comparing Oral to Intravenous Administration of GDC-0973

Resource links provided by NLM:


Further study details as provided by Genentech, Inc.:

Primary Outcome Measures:
  • Maximum Observed Plasma Concentration (Cmax) of IV and Oral GDC-0973 [ Time Frame: Part 2: 0 hours (Hrs) (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 ]
  • Dose Normalized Cmax [Cmax(dn)] of IV and Oral GDC-0973 [ Time Frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 ]
    Cmax(dn) is Cmax divided by dose.

  • Minimum Observed Plasma Trough Concentration (Cmin) of IV and Oral GDC-0973 [ Time Frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 ]
  • Time to Reach Maximum Observed Plasma Concentration (Tmax) of IV and Oral GDC-0973 [ Time Frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 ]
  • Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] of IV and Oral GDC-0973 [ Time Frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 ]
    AUC (0-t)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t).

  • Dose Normalized AUC (0-t) [AUC (0-t)dn] of IV and Oral GDC-0973 [ Time Frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 ]
    AUC (0-t)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t). AUC (0-t)dn is AUC (0-t) divided by dose.

  • Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] of IV and Oral GDC-0973 [ Time Frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 ]
    AUC (0 - ∞)= Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞).

  • Dose Normalized AUC (0 - ∞) [AUC (0 - ∞)dn] of IV and Oral GDC-0973 [ Time Frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 ]
    AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞). AUC (0 - ∞)dn is AUC(0 - ∞) divided by dose.

  • Plasma Decay Half-Life (t1/2) of IV and Oral GDC-0973 [ Time Frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 ]
    t1/2 is the time measured for the plasma concentration of GDC-0973 to decrease by one half.

  • Systemic Clearance (CL) of IV GDC-0973 [ Time Frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 ]
    CL is a quantitative measure of the rate at which a drug substance is removed from the body.

  • Apparent Oral Clearance (CL/F) of Oral GDC-0973 [ Time Frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 ]
    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. Clearance was estimated from population PK modelling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

  • Volume of Distribution at Steady State (Vss) of IV GDC-0973 [ Time Frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose of Day 1 ]
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steady-state.

  • Apparent Volume of Distribution (Vz/F) of Oral GDC-0973 [ Time Frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 ]
    Volume of distribution is 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 is influenced by the fraction absorbed.

  • Absolute Oral Bioavailability (F) of GDC-0973 [ Time Frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 ]
    Absolute oral bioavailability is the amount of drug from a formulation that reaches the systemic circulation relative to an IV dose. F = [AUC (0-∞), oral multiplied by Dose IV] divided by [AUC (0-∞), IV multiplied by Dose oral]. Absolute oral bioavailability is determined for drugs which are administered orally. IV dose is 100% in systemic circulation (dosed directly) and hence no estimation is required.

  • Mean Absorption Time (MAT) [ Time Frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 ]
    MAT is mean time required for the drug to reach the central compartment. MAT was estimated from the mean resident time (MRT) from oral and IV administration. MAT was calculated as MRT last of oral dose minus MRT last of IV dose. MAT is analyzed when drug is administered orally (only for non-IV routes of administration).

  • Amount of Drug Excreted in the Urine (Aeu) of IV and Oral GDC-0973 [ Time Frame: Part 2: 0 to 12, 12 to 24, 24 to 48, 48 to 72, and 72 to 96 Hrs post-dose on Day 1 ]
    The cumulative amount of drug excreted in urine over the entire collection interval of 96 hrs was calculated by adding the Aeu of the intervals 0 to 12, 12 to 24, 24 to 48, 48 to 72, and 72 to 96 hrs where Aeu was calculated by multiplying the urine volume within the collection interval by the associated drug concentration.

  • Renal Clearance (CLR) of IV and Oral GDC-0973 [ Time Frame: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 for plasma; 0 to 12, 12 to 24, 24 to 48, 48 to 72, and 72 to 96 Hrs post-dose for urine ]
    CLR was calculated as Aeu divided by AUC (0 - ∞), where Aeu was amount of drug excreted in urine from time 0 to 96 hrs post-dose and AUC(0 - ∞) was area under the concentration-time curve of the analyte in plasma over the time interval from zero extrapolated to infinity hrs post-dose.

  • Percent of GDC-0973 Excreted in the Urine (% Excreted) for IV and Oral GDC-0973 [ Time Frame: Part 2: 0 to 12, 12 to 24, 24 to 48, 48 to 72, and 72 to 96 Hrs post-dose ]
    % Excreted is the mean percentage of dose recovery in urine and calculated as: (Aeu divided by dose) multiplied by 100, where Aeu was amount of drug excreted in urine from time 0 to 96 hrs post-dose.


Enrollment: 13
Study Start Date: November 2010
Study Completion Date: January 2011
Primary Completion Date: January 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part 1: GDC-0973 IV Infusion First, Then GDC-0973 Capsules
Participants will receive single dose of GDC-0973 2 milligrams (mg) IV infusion in first intervention period followed by single dose of GDC-0973 20 mg oral capsules (four 5-mg capsules) in second intervention period. The washout period between each period will be a minimum of 10 days.
Drug: GDC-0973 IV Infusion
IV infusion.
Other Name: XL518
Drug: GDC-0973 Oral Capsules
Oral dose.
Other Name: XL518
Experimental: Part 2: GDC-0973 IV Infusion First, Then GDC-0973 Capsules
Participants will receive single dose of GDC-0973 2 mg IV infusion in first intervention period followed by single dose of GDC-0973 20 mg oral capsules (four 5-mg capsules) in second intervention period. The washout period between each period will be a minimum of 10 days.
Drug: GDC-0973 IV Infusion
IV infusion.
Other Name: XL518
Drug: GDC-0973 Oral Capsules
Oral dose.
Other Name: XL518
Experimental: Part 2: GDC-0973 Capsules First, Then GDC-0973 IV Infusion
Participants will receive single dose of GDC-0973 20 mg oral capsules (four 5-mg capsules) in first intervention period followed by single dose of GDC-0973 2 mg IV infusion in second intervention period. The washout period between each period will be a minimum of 10 days.
Drug: GDC-0973 IV Infusion
IV infusion.
Other Name: XL518
Drug: GDC-0973 Oral Capsules
Oral dose.
Other Name: XL518

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria

  • Within body mass index range 18.5 to 29.9 kilograms per square meter (kg/m^2)
  • In good health, determined by no clinically significant findings from medical history, 12-lead electrocardiogram (ECG), and vital signs
  • Clinical laboratory evaluations within the reference range for the test laboratory
  • Negative test for selected drugs of abuse at Screening and at each Check-in
  • Negative hepatitis panel and anti-hepatitis C virus and negative human immunodeficiency virus (HIV) antibody screens
  • Healthy males and females of non-child-bearing potential or who agree to use effective contraception

Exclusion Criteria

  • Significant history or clinical manifestation of any significant metabolic, allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, or psychiatric disorder
  • History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance
  • History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs except that appendectomy, hernia repair, and cholecystectomy will be allowed
  • History or presence of an abnormal ECG
  • History of alcoholism or drug addiction prior to period 1 check-in
  • Use of any tobacco-containing or nicotine-containing products prior to period 1 check-in
  • Participation in any other investigational study drug trial in which receipt of an investigational study drug occurred within 28 days or 5 half-lives, whichever is longer, prior to period 1 check-in
  • Use of any prescription medications/products, including proton pump inhibitors, within 14 days prior to period 1 check-in
  • Poor peripheral venous access
  • Any acute or chronic condition that would limit the participants ability to complete and/or participate in this clinical study
  • Female participant is pregnant, lactating, or breastfeeding
  • Predisposing factors to retinal vein occlusion (RVO)
  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: NCT01249118

Sponsors and Collaborators
Genentech, Inc.
Investigators
Study Director: Isabelle Rooney, M.D., PhD Genentech, Inc.
  More Information

Responsible Party: Genentech, Inc.
ClinicalTrials.gov Identifier: NCT01249118     History of Changes
Other Study ID Numbers: MEK4952g
Study First Received: November 24, 2010
Results First Received: September 6, 2016
Last Updated: April 4, 2017

ClinicalTrials.gov processed this record on June 26, 2017