Effect of Food, Rabeprazole, Methotrexate and Formulation on the Pharmacokinetics (PK) of GDC-0853 and the Effect of GDC-0853 on the PK of Methotrexate in Healthy Subjects (QCL117578)

A Phase I, Single Center, Randomized, Open-Label, Study Investigating the Effect of Food, Rabeprazole, Methotrexate and Formulation on the Pharmacokinetics of GDC-0853 and the Effect of GDC-0853 on the Pharmacokinetics of Methotrexate in Healthy Subjects

This study is a Phase I, single center, randomized (Parts 1 and 2 only), open-label, 3 part study. Parts 1 and 2 are 2-way crossover, with 1-fixed sequence, 3-period designs to investigate the effect of formulation, food and rabeprazole on the PK of GDC-0853 in healthy male and female (of non-childbearing potential) participants. Part 3 is a fixed-sequence study with 3 treatments to characterize the steady-state PK of the GDC-0853 tablet; the effect of simultaneous administration of a single dose of methotrexate on the steady-state kinetics of GDC-0853; and the effect of dosing GDC-0853 to steady-state on the single dose PK of methotrexate in healthy male participants.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteer
• Intervention / Treatment: Drug: GDC-0853; Drug: Rabeprazole; Drug: Folic Acid; Drug: Methotrexate

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Nottingham, United Kingdom, NG11 6JS
    • Quotient Clinical Ltd, Clinical Research Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Within body mass index range of 18.0 to 31.0 kilograms per square meter (kg/m^2), inclusive
• For women who are not postmenopausal (greater than or equal to [>/=] 12 months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): these participants will be excluded
• For men: agreement to use a condom plus an additional contraceptive method with their partner during the treatment period and for at least 93 days after the last dose of study drug and agreement to refrain from donating sperm during this same period

Exclusion Criteria:

• Significant history or clinical manifestation of any significant metabolic, allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, or psychiatric disorder (as determined by the investigator)
• History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the investigator
• Participants previously enrolled in this study or participation in any other investigational study drug trial in which receipt of an investigational study drug occurred within 90 days prior to Period 1 Check-in (Day -1)
• History of malignancy, except for completely excised basal cell carcinoma or squamous cell carcinoma of the skin or cervical carcinoma in situ
• Female participant is pregnant, lactating or breastfeeding
• Current treatment with medications that are well known to prolong the QT interval
• Failure to satisfy the investigator of fitness to participate for any other reason

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Part 1: GDC-0853, Rabeprazole (Fasting State); Participants will receive single dose of GDC-0853 (200 milligrams [mg]) in a crossover design as either the capsule or tablet formulation in the fasted state with the final fixed treatment consisting of the tablet formulation administered in the fasted state after prior administration of rabeprazole (20 mg twice daily [BID]) for 3 days.	Drug: GDC-0853; GDC-0853 will be administered orally as tablet or capsule at a dose of 200 mg.; Drug: Rabeprazole; Rabeprazole will be administered orally as tablet at a dose of 20 mg.
EXPERIMENTAL: Part 2: GDC-0853, Rabeprazole (Fasting or Fed State); Participants will receive single dose of GDC-0853 (200 mg) tablet formulation in the fasted or fed state in a crossover design with the final fixed treatment consisting of the tablet formulation administered in the fed state after prior administration of rabeprazole (20 mg BID) for 3 days.	Drug: GDC-0853; GDC-0853 will be administered orally as tablet or capsule at a dose of 200 mg.; Drug: Rabeprazole; Rabeprazole will be administered orally as tablet at a dose of 20 mg.
EXPERIMENTAL: Part 3: GDC-0853, Methotrexate; Participants will receive single dose of methotrexate (7.5 mg) under fasting conditions on Day 1 (5 mg folic acid will be administered the following day [Day 2]) and then GDC-0853 (200 mg) tablet formulation twice daily (BID) under fasting conditions (an overnight fast for the morning dose and a 2 hour fast for the evening dose) from Days 15 to 20 after washout period from Days 2 to 14. On Day 21, participants will receive single dose of methotrexate (7.5 mg) with single dose of GDC-0853 (200 mg) tablet formulation under fasting conditions, and folic acid (5 mg) will be administered on Day 22.	Drug: GDC-0853; GDC-0853 will be administered orally as tablet or capsule at a dose of 200 mg.; Drug: Folic Acid; Folic acid will be administered orally as tablet at a single dose of 5 mg.; Drug: Methotrexate; Methotrexate will be administered orally as tablet at a single dose of 7.5 mg.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Part 1: Relative Bioavailability of GDC-0853 tablet Compared to GDC-0853 Capsule	Part 1 (Periods 1 to 2 [Period length=5 days]): Predose (</=1 hour before dosing), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose on Day 1; 24, 36 hours postdose on Day 2; 48 hours postdose on Day 3; 72 hours postdose on Day 4
Part 1: Area Under the Concentration Time-Curve From Time 0 to Infinity (AUC0-inf) of GDC-0853 Capsule	Part 1 (Periods 1 to 2 [Period length=5 days]): Predose (</=1 hour before dosing), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose on Day 1; 24, 36 hours postdose on Day 2; 48 hours postdose on Day 3; 72 hours postdose on Day 4
Part 1: Area Under the Concentration Time-Curve From Time 0 to Last Reported Plasma Concentration (AUC0-t) of GDC-0853 Capsule	Part 1 (Periods 1 to 2 [Period length=5 days]): Predose (</=1 hour before dosing), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose on Day 1; 24, 36 hours postdose on Day 2; 48 hours postdose on Day 3; 72 hours postdose on Day 4
Part 1: Maximum Plasma Concentration (Cmax) of GDC-0853 Capsule	Part 1 (Periods 1 to 2 [Period length=5 days]): Predose (</=1 hour before dosing), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose on Day 1; 24, 36 hours postdose on Day 2; 48 hours postdose on Day 3; 72 hours postdose on Day 4
Part 1: Time to Maximum Plasma Concentration (Tmax) of GDC-0853 Capsule	Part 1 (Periods 1 to 2 [Period length=5 days]): Predose (</=1 hour before dosing), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose on Day 1; 24, 36 hours postdose on Day 2; 48 hours postdose on Day 3; 72 hours postdose on Day 4
Part 1: Apparent half-life (t1/2) of GDC-0853 Capsule	Part 1 (Periods 1 to 2 [Period length=5 days]): Predose (</=1 hour before dosing), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose on Day 1; 24, 36 hours postdose on Day 2; 48 hours postdose on Day 3; 72 hours postdose on Day 4
Parts 1 and 2: AUC0-inf of GDC-0853 Tablet	Parts 1 and 2 (Periods 1 to 2 [Period length=5 days]): Predose (</=1 hour before dosing), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose on Day 1; 24, 36 hours postdose on Day 2; 48 hours postdose on Day 3; 72 hours postdose on Day 4
Parts 1 and 2: AUC0-t of GDC-0853 Tablet	Parts 1 and 2 (Periods 1 to 2 [Period length=5 days]): Predose (</=1 hour before dosing), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose on Day 1; 24, 36 hours postdose on Day 2; 48 hours postdose on Day 3; 72 hours postdose on Day 4
Parts 1 and 2: Cmax of GDC-0853 Tablet	Parts 1 and 2 (Periods 1 to 2 [Period length=5 days]): Predose (</=1 hour before dosing), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose on Day 1; 24, 36 hours postdose on Day 2; 48 hours postdose on Day 3; 72 hours postdose on Day 4
Parts 1 and 2: Tmax of GDC-0853 Tablet	Parts 1 and 2 (Periods 1 to 2 [Period length=5 days]): Predose (</=1 hour before dosing), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose on Day 1; 24, 36 hours postdose on Day 2; 48 hours postdose on Day 3; 72 hours postdose on Day 4
Parts 1 and 2: Apparent t1/2 of GDC-0853 Tablet	Parts 1 and 2 (Periods 1 to 2 [Period length=5 days]): Predose (</=1 hour before dosing), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose on Day 1; 24, 36 hours postdose on Day 2; 48 hours postdose on Day 3; 72 hours postdose on Day 4
Parts 1 and 2: AUC0-inf of GDC-0853 Tablet When Administered With Rabeprazole	Parts 1 and 2 (Period 3 [Period length=8 days]): Predose (</=1 hour before dosing), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose on Day 1; 24, 36 hours postdose on Day 2; 48 hours postdose on Day 3; 72 hours postdose on Day 4
Parts 1 and 2: AUC0-t of GDC-0853 Tablet When Administered With Rabeprazole	Parts 1 and 2 (Period 3 [Period length=8 days]): Predose (</=1 hour before dosing), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose on Day 1; 24, 36 hours postdose on Day 2; 48 hours postdose on Day 3; 72 hours postdose on Day 4
Parts 1 and 2: Cmax of GDC-0853 Tablet When Administered With Rabeprazole	Parts 1 and 2 (Period 3 [Period length=8 days]): Predose (</=1 hour before dosing), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose on Day 1; 24, 36 hours postdose on Day 2; 48 hours postdose on Day 3; 72 hours postdose on Day 4
Parts 1 and 2: Tmax of GDC-0853 Tablet When Administered With Rabeprazole	Parts 1 and 2 (Period 3 [Period length=8 days]): Predose (</=1 hour before dosing), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose on Day 1; 24, 36 hours postdose on Day 2; 48 hours postdose on Day 3; 72 hours postdose on Day 4
Parts 1 and 2: Apparent t1/2 of GDC-0853 Tablet When Administered With Rabeprazole	Parts 1 and 2 (Period 3 [Period length=8 days]): Predose (</=1 hour before dosing), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose on Day 1; 24, 36 hours postdose on Day 2; 48 hours postdose on Day 3; 72 hours postdose on Day 4
Part 3: Area Under the Concentration Time-Curve From Time 0 to 24 Hours, Steady State (AUC0-24, ss) of GDC0853 Tablet	Part 3: Predose (</=1 hour before dosing) on Days 17, 18, 19, 20, 21; 0.5, 1, 2, 3, 4, 6, 8, 10, 12 hours postdose on Days 20, 21; 16 hours postdose on Day 21; 24 hours postdose on Day 22
Part 3: Maximum Plasma Concentration, Steady State (Cmax, ss) of GDC-0853 Tablet	Part 3: Predose (</=1 hour before dosing) on Days 17, 18, 19, 20, 21; 0.5, 1, 2, 3, 4, 6, 8, 10, 12 hours postdose on Days 20, 21; 16 hours postdose on Day 21; 24 hours postdose on Day 22
Part 3: Time to Maximum Plasma Concentration, Steady State (Tmax, ss) of GDC-0853 Tablet	Part 3: Predose (</=1 hour before dosing) on Days 17, 18, 19, 20, 21; 0.5, 1, 2, 3, 4, 6, 8, 10, 12 hours postdose on Days 20, 21; 16 hours postdose on Day 21; 24 hours postdose on Day 22
Part 3: Area Under the Concentration Time-Curve From Time 0 to 12 Hours (AUC0-12) of GDC-0853 Tablet When Administered With Methotrexate	Part 3: Predose (</=1 hour before dosing) on Days 17, 18, 19, 20, 21; 0.5, 1, 2, 3, 4, 6, 8, 10, 12 hours postdose on Days 20, 21; 16 hours postdose on Day 21; 24 hours postdose on Day 22
Part 3: Cmax of GDC-0853 Tablet When Administered with Methotrexate	Part 3: Predose (</=1 hour before dosing) on Days 17, 18, 19, 20, 21; 0.5, 1, 2, 3, 4, 6, 8, 10, 12 hours postdose on Days 20, 21; 16 hours postdose on Day 21; 24 hours postdose on Day 22
Part 3: Tmax of GDC-0853 Tablet When Administered with Methotrexate	Part 3: Predose (</=1 hour before dosing) on Days 17, 18, 19, 20, 21; 0.5, 1, 2, 3, 4, 6, 8, 10, 12 hours postdose on Days 20, 21; 16 hours postdose on Day 21; 24 hours postdose on Day 22
Part 3: Area Under the Concentration Time-Curve From Time 0 to 24 Hours (AUC0-24) of Methotrexate When Administered With GDC-0853	Part 3: Predose (</=1 hour before dosing) on Days 1, 21; 0.5, 1, 2, 3, 4, 6, 8, 10, 12 hours postdose on Days 1, 21; 16 hours postdose on Days 1, 21; 24 hours postdose on Days 2, 22
Part 3: Cmax of Methotrexate When Administered with GDC-0853 Tablet	Part 3: Predose (</=1 hour before dosing) on Days 1, 21; 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16 hours postdose on Days 1, 21; 24 hours postdose on Days 2, 22
Part 3: Tmax of Methotrexate When Administered with GDC-0853 Tablet	Part 3: Predose (</=1 hour before dosing) on Days 1, 21; 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16 hours postdose on Days 1, 21; 24 hours postdose on Days 2, 22
Part 3: Apparent t1/2 of Methotrexate When Administered With GDC-0853	Part 3: Predose (</=1 hour before dosing) on Days 1, 21; 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16 hours postdose on Days 1, 21; 24 hours postdose on Days 2, 22

Secondary Outcome Measures

Outcome Measure	Time Frame
Percentage of Participants With Adverse Events	From Baseline up to approximately 9 months

Collaborators and Investigators

• Sponsor: Genentech, Inc.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 3, 2015
• Primary Completion (ACTUAL): May 26, 2016
• Study Completion (ACTUAL): May 26, 2016

Study Registration Dates

• First Submitted: March 1, 2016
• First Submitted That Met QC Criteria: March 1, 2016
• First Posted (ESTIMATE): March 4, 2016

Study Record Updates

• Last Update Posted (ACTUAL): March 2, 2020
• Last Update Submitted That Met QC Criteria: February 27, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Dermatologic Agents; Micronutrients; Vitamins; Reproductive Control Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Vitamin B Complex; Hematinics; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Rabeprazole; Methotrexate; Folic Acid
• Other Study ID Numbers: GP29832; 2015-002471-25 (EUDRACT_NUMBER); QCL117578 (OTHER: Genentech, Inc.)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No