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
2. Severe renal impairment: eGFR subjects in all groups, the values of serum creatinine obtained at the two
screening visits should not be more than 20% different.
-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.