To identify and quantify the main excretion pathways of E7727.
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
Myelodysplastisch syndroom
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To identify and quantify the main excretion pathways of E7727.
Secondary outcome
To determine the F of E7727 after single dose administration in the fasted
condition.
To determine the Fa of E7727.
To determine the PK of E7727 following oral and IV administration.
To determine the safety and tolerability of E7727 following oral and IV
administration.
To identify the metabolites of E7727 in plasma, urine, and feces, if possible.
Background summary
E7727 is a new compound that may eventually be used in combination with another
product for the treatment of myelodysplastic syndromes (MDS), which are a group
of cancers in which blood cells in the bone marrow do not mature and therefore
do not become healthy blood cells. Hypomethylating agents (HMAs), have proven
to be an effective treatment against MDS. However, effective oral
administration of not worked because HMAs are broken down in the gut and liver,
specifically by the enzyme cytidine deaminase (CDA). E7727 is a new compound
that suppresses CDA in the gut and liver, which could help HMAs be better
absorbed in the body.
Study objective
To identify and quantify the main excretion pathways of E7727.
Study design
The study consists of 3 phases: pre-treatment, treatment and follow-up. The
pre-treatment lasts a maximum of 21 days and will consist of a screening phase
and a baseline phase, in which the suitability of each volunteer will be
determined.
The treatment period consists of 2 periods. During period 1 the volunteers
receive unlabeled E7727 orally in combination with intravenous radioactive
E7727. During period 2 the volunteers receive radioactive E7727 orally. Period
2 will start after a complete wash-out of E7727.
The subject remains in the clinic for 5 days (4 nights) (Period 1) and up to 11
days (10 nights) (Period 2) in the research center with at least 4 days between
each period.
Each period has a Day 1, this is the day on which the research product is
administered.
Finally, the volunteers will come back for a follow-up visit.
Intervention
E7727 will be given as oral capsules with 240 milliliters (mL) of (tap) water
and an intravenous infusion (solution of the compound that will be administered
directly in a blood vessel).
Day 1, Period 1 E7727, 100 mg Oral capsule - Once
Day 1, Period 1 E7727, 100 microgram (µg) containing 14C radiolabeled E7727
Intravenous solution - Once
Day 1, Period 2 E7727, 100 mg containing 14C-radiolabeled E7727 Oral capsule -
Once
Study burden and risks
Study compound
The study compound may cause side effects.
E7727 has not yet been administered to healthy volunteers. E7727 has only been
administered to MDS patients in combination with decitabine. It was found that
the adverse events that were reported in the combination with 100 mg E7727 and
35 mg decitabine were similar to 35 mg decitabine alone. Decitabine will not be
administered in this study.
E7727 has been studied extensively in the laboratory and in animals. The E7727
dose to be used in this study (100 mg) is 1/40th of the dose in human
equivalent terms that was evaluated in animals in studies; i.e. an
approximately 40-fold higher dose of E7727 when dosed daily to monkeys or mice
for 7 consecutive days did not cause any significant toxicities. You will
receive only 2 doses of E7727, approximately 9 days apart.
Possible discomforts due to procedures
Drawing blood and/or insertion of the indwelling cannula (tube in an arm vein)
may be painful or cause some bruising.
In total, we will take about 272 mL of blood from the subject. This amount does
not cause any problems in adults. To compare: a blood donation involves 500 mL
of blood being taken.
To make a heart tracing, electrodes (small, plastic patches) will be pasted at
specific locations onto your arms, chest and legs. Prolonged use of these
electrodes can cause skin irritation (rash and itching).
Exposure to radiation
This study involves using radioactive markers. The additional radiation burden
in this study due to the administration of radiolabeled E7727 is calculated to
be approximately 1 mSv and is considered acceptable. The average environmental
background radiation burden in The Netherlands is approximately 2.5 mSv per
year.
4420 Rosewood Drive Suite 200
Pleasanton CA94588
US
4420 Rosewood Drive Suite 200
Pleasanton CA94588
US
Listed location countries
Age
Inclusion criteria
1. Gender: male or female; females must be postmenopausal
2. Age: >=65 years, at screening.
3. Body mass index (BMI): 18.0 to 32.0 kg/m2, inclusive.
4. Status: healthy subjects
5. Male subjects, if not surgically sterilized, with a female partner of childbearing potential must agree to use adequate contraception and not donate sperm from first admission to the clinical research center until 90 days after the follow-up visit. Adequate contraception for the male subject (and his female partner) is defined as using hormonal contraceptives or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm, a cervical cap, or a condom. Total abstinence, in accordance with the lifestyle of the subject, is also acceptable.
6. All prescribed medication must have been stopped at least 30 days prior to each admission to the clinical research center.
7. All over-the-counter medication, vitamin preparations and other food supplements, or herbal medications (eg, St. John*s Wort) must have been stopped at least 14 days prior to each admission to the clinical research center. An exception is made for paracetamol, which is allowed up to each admission to the clinical research center.
8. Ability and willingness to abstain from alcohol, methylxanthine-containing beverages or food (coffee, tea, soft drinks, chocolate, energy drinks), and grapefruit (juice) and tobacco products from 48 hours prior to each admission to the clinical research center.
9. Satisfactory physical and mental health on the basis of medical history, physical examination, clinical laboratory, 12-lead electrocardiogram (ECG), and vital signs, as judged by the PI.
10. Willing and able to sign the ICF.
11. Subject is able to understand and comply with the study procedures and understands the risks involved in the study
Exclusion criteria
1. Employee of PRA or the Sponsor.
2. History of relevant drug and/or food allergies.
3. Using tobacco products and/or alcohol in the 48 hours (2 days) prior to first admission to the clinical research center is not allowed.
4. Known significant mental illness or other condition, such as active alcohol or other substance abuse or addiction, that in the opinion of the investigator predisposes the subject to high risk of noncompliance with the protocol.
5. Positive drug and alcohol screen (opiates, methadone, cocaine, amphetamines [including ecstasy], cannabinoids, barbiturates, benzodiazepines, tricyclic antidepressants, and alcohol ) at screening and each admission to the clinical research center.
6. Average intake of more than 24 units of alcohol per week (1 unit of alcohol equals approximately 250 mL of beer, 100 mL of wine, or 35 mL of spirits).
7. Positive screen for hepatitis B surface antigen (HBsAg), antihepatitis C virus (HCV) antibodies, or antihuman immunodeficiency virus (HIV) 1 and 2 antibodies.
8. Participation in an investigational drug study within 60 days prior to the first drug administration in the current study. Participation in more than 4 other drug studies in the year prior to the first drug administration in the current study.
9. Donation or loss of more than 100 mL of blood within 60 days prior to the first drug administration. Donation or loss of more than 1.5 liters of blood (for male subjects)/more than 1.0 liter of blood (for female subjects) in the 10 months prior to the first drug administration in the current study.
10. Significant and/or acute illness within 5 days prior to the first drug administration that may impact safety assessments, in the opinion of the Investigator.
11. Unsuitable peripheral veins for infusion or blood sampling.
12. Participation in another ADME study with a radiation burden >0.1 mSv in the period of 1 year prior to screening.
13. Exposure to radiation for diagnostic reasons (except dental X-rays and plain X-rays of thorax and bony skeleton [excluding spinal column]), during work, or during participation in a clinical study in the period of 1 year prior to screening.
14. Irregular defecation pattern (less than once per 2 days).
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-004366-33-NL |
| CCMO | NL68882.056.19 |