Glasdegib Renal Impairment Study

A PHASE 1, OPEN-LABEL, SINGLE DOSE, PARALLEL GROUP STUDY TO EVALUATE THE PHARMACOKINETICS OF GLASDEGIB (PF-04449913) IN SUBJECTS WITH IMPAIRED RENAL FUNCTION

The goal of this study is to administer single dose (100 mg) glasdegib tablet to subjects with normal, moderate and severe renal impairment and estimate the effect, if any, of this renal impairment on glasdegib pharmacokinetics.

Study Overview

• Status: Completed
• Conditions: Renal Impairment
• Intervention / Treatment: Drug: Glasdegib single 100 mg dose in normal healthy subjects; Drug: Glasdegib single 100 mg dose in moderate renal impairment subjects; Drug: Glasdegib single 100 mg dose in severe renal impairment subjects

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami, Sylvester Comprehensive Cancer Center
    • Miami, Florida, United States, 33136
      • University of Miami Division of Clinical Pharmacology
  • Minnesota
    • Saint Paul, Minnesota, United States, 55114
      • Prism Clinical Research LLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Healthy female subjects of non child bearing potential and/or male subjects who, at the time of screening, are between the ages of 18 and 75 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.

2. 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) are considered to be of childbearing potential.
3. Body mass index (BMI) of 17.5 to 40 kg/m2; and a total body weight >50 kg (110 lb).
4. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study.
5. Subjects who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and other study procedures.

Subjects with Normal Renal Function will Need to Meet the Following Criteria in addition -

1. Normal renal function, eGFR=>90 mL/min, based on the MDRD equation.
2. Matched for age (+/-10years) weight +/-15kg, and gender to subjects in the impaired renal function groups

Subjects with Impaired Renal Function will Need to Meet the Following Criteria in Addition to Those Above

1. Good general health commensurate with the population with chronic kidney disease (renal impairment). 'Health' is defined as no clinically relevant abnormalities (with the exception of hypertension, diabetes mellitus, hyperparathyroidism, ischemic heart disease, etc. as long as, in the opinion of the investigator, the subject is medically stable, is on a stable drug regimen and can abide by the meals and dietary restrictions outlined in protocol identified by a detailed medical history, full physical examination, measurement of pulse rate and 12 lead ECG as well as clinical laboratory tests (except serum creatinine and eGFR).
2. Stable drug regimen defined as not starting a new drug or changing dosage within seven days or five half lives (whichever is longer) before dosing the study drug.
3. Any form of renal impairment except acute nephritic syndrome (subjects with history of previous nephritic syndrome but in remission can be included).

4. Meet one of the following eGFR criteria during the screening period based on the MDRD equation:

   1. Moderate renal impairment: eGFR 30 mL/min and <60 mL/min, or

   2. Severe renal impairment: eGFR <30 mL/min, but not requiring hemodialysis. For subjects in all groups, the values of serum creatinine obtained at the two screening visits should not be more than 20% different.

      Exclusion Criteria:

      -Any condition possibly affecting drug absorption (eg, gastrectomy, achlorhydria).

      Renal allograft recipients

      Urinary incontinence without catheterization.

      Concurrent use of any of the following food or drugs known to inhibit CYP3A4 (consult the Sponsor if in doubt whether a food or a drug falls into any of the above categories) within 7 days or 5 half lives (whichever is longer) prior to the dose of glasdegib, until the completion of the last PK sample collection.

      Concurrent use of any of the following food or drugs known to induce CYP3A4 (consult the Sponsor if in doubt whether a food or a drug falls into any of the above categories) within 12 days or 5 half lives (whichever is longer) prior to the first dose of trial medication until the completion of the last PK sample collection.

      Pregnant female subjects; breastfeeding female subjects; fertile male subjects who are unwilling or unable to use two 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.

      Subjects with ANY of the following abnormalities in clinical laboratory tests at Screening, as assessed by the study specific laboratory and confirmed by a single repeat test, if deemed necessary:

      • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level > upper limit of normal (ULN);
      • Total bilirubin level 1.5 × ULN; subjects with a history of Gilbert's syndrome may have direct bilirubin measured and would be eligible for this study provided the direct bilirubin level is not greater than 0.5 mg/dL.

      For subjects with renal impairment, the following important additional criteria are:

      Subjects with other clinically significant disease that may affect the safety of the subject or that may affect the pharmacokinetics of glasdegib (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing). Subjects with any significant hepatic, cardiac, or pulmonary disease or subjects who are clinically nephrotic. Hypertension, diabetes mellitus, hyperparathyroidism, ischemic heart disease, etc is not cause for exclusion as long as the subject is medically stable and any drugs that are administered for these conditions are not expected to interfere with the pharmacokinetics of glasdegib.

      Screening blood pressure =>180mm Hg (systolic) or>=110 mm Hg (diastolic), following at least 5 minutes of supine rest. If initial blood pressure (BP) is 180 mm Hg (systolic) or 110 mm Hg (diastolic), the BP should be repeated two more times and the average of the three BP values should be used to determine the subject's eligibility.

      Screening supine 12 lead ECG demonstrating QTcF >470 msec or a QRS interval >120 msec. If initial QTcF exceeds 470 msec, or QRS exceeds 120 msec, the ECG should be repeated two more times and the average of the three QTcF or QRS values should be used to determine the subject's eligibility.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Normal Renal Function Group; Subjects with estimated glomerular filtration rate (eGFR) of => 90 ml/min	Drug: Glasdegib single 100 mg dose in normal healthy subjects; A single dose of 100 mg glasdegib tablet will be administered after an overnight fast, followed by serial PK collection, discharge and follow -up.
EXPERIMENTAL: Moderate Renal Impairment Group; Subjects with estimated glomerular filtration rate (eGFR) of => 30ml/min and < 60 ml/min	Drug: Glasdegib single 100 mg dose in moderate renal impairment subjects; A single dose of 100 mg glasdegib tablet will be administered to subjects with moderate renal impairment, after an overnight fast, followed by serial PK collection, discharge and follow -up.
EXPERIMENTAL: Severe Renal Impairment Group; Subjects with estimated glomerular filtration rate (eGFR) of < 30 ml/min and not requiring dialysis	Drug: Glasdegib single 100 mg dose in severe renal impairment subjects; A single dose of 100 mg glasdegib tablet will be administered to subjects with severe renal impairment, after an overnight fast, followed by serial PK collection, discharge and follow -up.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Plasma Concentration (Cmax)		6 days
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - 8)]	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 - ∞).	6 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]).	concomitant medication and adverse event monitoring.	34 days
PR/ECGs	PR interval (msec),	34 days
Hematology Lab Panel	Platelet count (10^3/mm^3)	34 days
BUN /Chemistry Lab Panel	BUN (mg/dL)	34 days
pH/Urinalysis Lab Panel	pH (no unit)	34 days
Blood Pressure	Supine Systolic and Diastolic blood pressure (mm of Hg). Reported as Systolic/Diastolic	34 days
Pulse Rate	Pulse Rate will be reported in beats per minute.	34 days
ECGs	Heart Rate (beats per minute)	34 days
Hemoglobin /Hematology Lab Panel	Hemoglobin (g/dL)	34 days
Hematology Lab Panel	Hematocrit (%)	34 days
Hematology Lab Panel	RBC Count (10^6/mm^3)	34 days
Hematology Lab Panel	MCV (femto Liters)	34 days
Hematology Lab Panel	MCH (pictograms/cell)	34 days
Potassium/Chemistry Lab Panel	Potassium (Meq/L)	34 days
AST/Chemistry Lab Panel	AST (U/L)	34 days
Albumin/Chemistry Lab Panel	Albumin (g/dL)	34 days
MCHC/Hematology Lab Panel	MCHC (10^3/mm^3)	34 days
WBC count/Hematology Lab Panel	WBC count (10^3/mm^3),	34 days
Total neutrophils/Hematology Lab Panel	Total neutrophils (Abs)(10^3/mm^3),	34 days
Eosinophils/Hematology Lab Panel	Eosinophils (Abs)(10^3/mm^3	34 days
Monocytes/Hematology Lab Panel	Monocytes (Abs)(10^3/mm^3)	34 days
Basophils/Hematology Lab Panel	Basophils (Abs) (10^3/mm^3)	34 days
Lymphocytes/Hematology Lab Panel	Lymphocytes (Abs) (10^3/mm^3)	34 days
Total Protein/Chemistry Lab Panel	Total Protein (g/dL)	34 days
ALT/Chemistry Lab Panel	ALT (U/L)	34 days
Alkaline Phosphate/Chemistry Lab Panel	Alkaline Phosphate (U/L)	34 days
Sodium/Chemistry Lab Panel	Sodium (Meq/L)	34 days
Chloride/Chemistry Lab Panel	Chloride (Meq/L)	34 days
Creatinine/Chemistry Lab Panel	Creatinine (mg/dL),	34 days
Glucose/Chemistry Lab Panel	Glucose (mg/dL),	34 days
Calcium/Chemistry Lab Panel	Calcium (mg/dL),	34 days
Total Bilirubin/Chemistry Lab Panel	Total Bilirubin (mg/dL),	34 days
Uric acid/Chemistry Lab Panel	Uric acid (mg/dL)	34 days
Magnesium/Chemistry Lab Panel	Magnesium (mg/dL)	34 days
QTc/ECGs	QTc interval (msec)	34 days
QRS/ECGs	QRS interval (msec)	34 days
Glucose/Urinalysis Lab Panel	Glucose (qual) (no unit)	34 days
Protein/Urinalysis Lab Panel	Protein (qual) (no unit)	34 days
Blood/Urinalysis Lab Panel	Blood (qual) (no units)	34 days
Ketones/Urinalysis Lab Panel	Ketones (no units)	34 days
Nitrites/Urinalysis Lab Panel	Nitrites (no units)	34 days
Leukocyte /Urinalysis Lab Panel	Leukocyte esterase (no units)	34 days
Urobilinogen/Urinalysis Lab Panel	Urobilinogen (no unit)	34 days
Urine bilirubin/Urinalysis Lab Panel	Urine bilirubin (no unit)	34 days

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• Shaik N, LaBadie RR, Hee B, Chan G. Evaluation of the impact of renal impairment on the pharmacokinetics of glasdegib in otherwise healthy volunteers. Cancer Chemother Pharmacol. 2021 Feb;87(2):241-250. doi: 10.1007/s00280-020-04207-9. Epub 2021 Jan 3.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 17, 2018
• Primary Completion (ACTUAL): August 28, 2018
• Study Completion (ACTUAL): September 19, 2018

Study Registration Dates

• First Submitted: April 2, 2018
• First Submitted That Met QC Criteria: July 12, 2018
• First Posted (ACTUAL): July 24, 2018

Study Record Updates

• Last Update Posted (ACTUAL): August 29, 2019
• Last Update Submitted That Met QC Criteria: August 27, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Renal Impairment; Glasdegib; PF-04449913
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency
• Other Study ID Numbers: B1371017

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