Healthy Volunteer
Conditions
Brief summary
This is a Phase 1, single-center, open-label, randomized, 3-period, 2-sequence crossover study of cobimetinib in healthy participants to evaluate the effect of the proton-pump inhibitor (PPI) rabeprazole on the relative bioavailability of cobimetinib in healthy participants when administered in the fed or fasted states.
Interventions
DRUGCobimetinib
One 20-mg tablet of cobimetinib will be administered orally with 240 mL room temperature water after at least an 8-hour fast or approximately 30 minutes after starting the standardized FDA high-fat meal.
DRUGRabeprazole
Rabeprazole 20 mg will be administered orally once daily for 4 days starting on Day -4 and on Day 1 of the treatment period.
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* With a body mass index range of 18.5 to 29.9 kilograms per meter square (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 (does not include alcohol) and at each Check-in * Negative hepatitis panel (including hepatitis B virus surface antigen \[HBsAg\] and hepatitis C virus antibody \[anti-HCV\]) and negative human immunodeficiency virus (HIV) antibody screens * Healthy males and females of nonchildbearing potential 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/or cholecystectomy will be allowed * History or presence of an abnormal ECG * History of alcoholism or drug addiction within 1 year prior to Period 1 Check-in * Use of any tobacco- or nicotine-containing products within 6 months prior to Period 1 Check-in * Participation in any other investigational study drug trial in which receipt of an investigational study drug occurred within 30 days or 5 half-lives, whichever is longer, prior to Period 1 Check-in * Use of any prescription medications/products within 14 days prior to Period 1 Check-in * Use of any over-the-counter, non-prescription preparations within 7 days prior to Period 1 Check-in * Use of alcohol-, grapefruit-, or caffeine-containing foods or beverages within 72 hours prior to Period 1 Check-in * Poor peripheral venous access * Any acute or chronic condition that would limit the participant's ability to complete and/or participate in this clinical study * Female participant is pregnant, lactating, or breastfeeding * Use of PPIs or histamine H2 receptor antagonists within 1 month prior to Period 1 Check-in * Known hypersensitivity to rabeprazole or any of its components or to derived products of benzimidazoles * Predisposing factors to retinal vein occlusion (RVO)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Cobimetinib | Day 1 at 0 hour (predose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 hours postdose | AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - inf). It is obtained from AUC (0 - t) plus AUC (t - inf). |
| Maximum Observed Concentration of Cobimetinib | Day 1 at 0 hour (predose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 hours postdose | — |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population All participants randomized to any treatment. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 2 - Second Intervention | Physician Decision | 0 | 2 |
| Period 2 - Second Intervention | Protocol Violation | 0 | 1 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Continuous | 31 years |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 20 | 10 / 17 | 9 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 17 | 0 / 20 |
Outcome results
Primary
Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Cobimetinib
AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - inf). It is obtained from AUC (0 - t) plus AUC (t - inf).
Time frame: Day 1 at 0 hour (predose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 hours postdose
Population: Pharmacokinetic parameters populations included all enrolled participants. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cobimetinib [Fasted] | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Cobimetinib | 778 nanograms*hours/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 32.8 |
| Cobimetinib [Fasted] + Rabeprazole | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Cobimetinib | 864 nanograms*hours/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 39.1 |
| Cobimetinib [Fed] + Rabeprazole | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Cobimetinib | 846 nanograms*hours/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 48.2 |
90% CI: [98.02, 124.99]
90% CI: [85.06, 108.77]
90% CI: [94.53, 119.91]
Primary
Maximum Observed Concentration of Cobimetinib
Time frame: Day 1 at 0 hour (predose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 hours postdose
Population: Pharmacokinetic parameters populations included all enrolled participants. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cobimetinib [Fasted] | Maximum Observed Concentration of Cobimetinib | 17.0 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 35.3 |
| Cobimetinib [Fasted] + Rabeprazole | Maximum Observed Concentration of Cobimetinib | 17.2 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 36 |
| Cobimetinib [Fed] + Rabeprazole | Maximum Observed Concentration of Cobimetinib | 14.8 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 51.2 |
90% CI: [85.09, 118.03]
90% CI: [72.51, 101.33]
90% CI: [72.94, 101.17]