A Phase 1 Study To Evaluate The Effect Of Glasdegib On The Cardiac Repolarization In Healthy Subjects (B1371023)

A PHASE 1, SINGLE CENTER, RANDOMIZED, 4-WAY CROSSOVER, DOUBLE BLINDED, PLACEBO AND MOXIFLOXACIN CONTROLLED STUDY TO EVALUATE THE EFFECT OF GLASDEGIB ON THE CARDIAC REPOLARIZATION IN HEALTHY SUBJECTS

This is a Thorough QT study intended to estimate the effect of glasdegib at therapeutic exposure and at supra-therapeutic exposure on cardiac repolarization in healthy subjects. This is a randomized, double blind, positive and placebo controlled study with a 6 day washout between successive periods.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: Glasdegib Therapeutic Exposure; Drug: Positive Control (Moxifloxacin); Other: Placebo Control; Drug: Glasdegib Supra-therapeutic Exposure

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, B-1070
    • Pfizer Clinical Research Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 51 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 1. Healthy male and/or female subjects of non child bearing potential who, at the time of screening, are between the ages of 18 and 55 years, inclusive. Healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12 lead ECG or clinical laboratory tests.

Female subjects of nonchildbearing potential must meet at least 1 of the following criteria:

1. Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; with a serum follicle stimulating hormone (FSH) level confirming the postmenopausal state;
2. Have undergone a documented hysterectomy and/or bilateral oophorectomy;

3. Have medically confirmed ovarian failure. All other female subjects (including females with tubal ligations and females that do NOT have a documented hysterectomy, bilateral oophorectomy and/or ovarian failure) are considered to be of childbearing potential.

   2. Body mass index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb).

   3. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.

   4. Subjects who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and other study procedures.

   Exclusion Criteria:

   • Screening supine 12 lead ECG demonstrating a corrected QT (QTc) interval >450 msec or a QRS interval >120 msec. If QTc exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be repeated 2 more times and the average of the 3 QTc or QRS values should be used to determine the subject's eligibility.

   Subjects with family history of myocardial infarction, congenital long QT syndrome, torsades de pointes or clinically significant ventricular arrhythmias. Subjects should be within normal range of potassium, magnesium and corrected calcium calculation at screening.

   Pregnant female subjects; breastfeeding female subjects; female subjects of childbearing potential; male subjects with partners currently pregnant; male subjects who are unwilling or unable to use atleast one highly effective methods of contraception as outlined in this protocol for the duration of the study and for at least 90 days after the last dose of investigational product and, refrain from sperm donation for the duration of the Study and for at least 90 days after the last dose of investigational product.

   History of known QTc prolongation or ECG abnormalities.

   Self-reported history of risk factors for QT prolongation or torsades de pointes (eg, organic heart disease, congestive heart failure, hypokalemia, hypomagnesemia,congenital long QT syndrome, myocardial ischemia or infarction, congenital deafness, and family history of sudden death, or a family history of congenital QT syndrome).

   Self-reported history of sick sinus syndrome, first, second, or third degree atrioventricular (AV) block, myocardial infarction, pulmonary congestion, cardiac arrhythmia, prolonged QT interval or conduction abnormalities, or any other clinically significant cardiovascular disease history.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Glasdegib QT Therapeutic Exposure; Randomized sequence of Glasdegib clinical exposure, Placebo and moxifloxacin active control administration. This treatment will be in four separate sequences with four periods per sequence. Each period will be separated by a washout of atleast 6 days.	Drug: Glasdegib Therapeutic Exposure; Subjects Receive a single 150 mg dose of Glasdegib followed by ECG and PK assessments.; Drug: Positive Control (Moxifloxacin); Subjects will receive a single 400 mg dose of moxifloxacin followed by ECG and PK assessments.; Other: Placebo Control; Subjects will receive placebo dose followed by ECG and PK assessments.
Experimental: Glasdegib QT Supra-therapeutic Exposure; Randomized sequence of glasdegib supra-therapeutic exposure, Placebo and moxifloxacin active control administration. This treatment will be in four separate sequences with four periods per sequence. Each period will be separated by a washout of atleast 6 days.	Drug: Glasdegib Supra-therapeutic Exposure; Subjects receive a single 300 mg dose of glasdegib followed by ECG and PK assessments.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
QTcF interval	Post-dose placebo corrected QTcF intervals from ECG traces following glasdegib dosing.	120 hours per period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
QTcF interval (Moxifloxacin)	Post-dose placebo corrected QTcF intervals from ECG traces following moxifloxacin dosing.	120 hours

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• Masters JC, Shaik N, Mendes da Costa L, Hee B, LaBadie RR. Clinical and Model-Based Evaluation of the Effect of Glasdegib on Cardiac Repolarization From a Randomized Thorough QT Study. Clin Pharmacol Drug Dev. 2021 Mar;10(3):272-282. doi: 10.1002/cpdd.862. Epub 2020 Aug 12.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): June 9, 2017
• Primary Completion (Actual): September 23, 2017
• Study Completion (Actual): October 16, 2017

Study Registration Dates

• First Submitted: May 18, 2017
• First Submitted That Met QC Criteria: May 18, 2017
• First Posted (Actual): May 22, 2017

Study Record Updates

• Last Update Posted (Actual): September 6, 2019
• Last Update Submitted That Met QC Criteria: September 3, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: Pharmacokinetics; TQT; QTc; Glasdegib; PF-04449913
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Moxifloxacin
• Other Study ID Numbers: B1371023; 2017-001295-38 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Drug and device information, study documents

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