A Phase 1 Study to Assess the Mass Balance, Pharmacokinetics, and Metabolism of Oral [14C-ZIPALERTINIB in Healthy Adult Male Subjects

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Taiho Oncology Inc.

Participant type

Healthy volunteers

Age range

18-64 years, 65+ years

Gender

Male

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

5 Jul 2023 → 23 Aug 2023

Decision date (initial)

2023-06-09

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Taiho Oncology, Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic

• To assess the mass balance of zipalertinib following a single oral dose of [14C]-zipalertinib
• To quantify TRA concentration equivalents in plasma and whole blood following a single oral dose of [14C]-zipalertinib in healthy adult subjects
• To characterize the PK profile of zipalertinib in plasma and urine following a single oral dose of [14C]-zipalertinib in healthy adult subjects
• To determine the percentage of 14C radioactivity associated with cellular components in whole blood over time (eg, whole blood:plasma partitioning ratio)

Secondary objectives 2

1. To determine the safety and tolerability of a single dose of [14C]-zipalertinib in healthy adult subjects
2. To investigate the metabolism of zipalertinib following a single oral dose of [14C]-zipalertinib in healthy adult subjects and identify metabolites in biological specimens

Conditions and MedDRA coding

Cancer

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Sex : male
2. Age : 18 years to 67 years; inclusive, at screening.
3. Body mass index (BMI): 18.0 kg/m2 to 32.0 kg/m2, inclusive, at screening.
4. Male subjects, if not surgically sterilized (vasectomy performed at least 4 months prior to dosing), must agree to use adequate contraception and not donate sperm from entry to the clinical research center until 90 days after follow¬up. Adequate contraception for the male subject (and his female partner, if she is of childbearing potential) 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 from heterosexual intercourse, in accordance with the lifestyle of the subject, is also acceptable.
5. All prescribed medication, and all over-the-counter medication, vitamin preparations and other food supplements, or herbal medications must have been stopped at least 14 days prior to admission to the clinical research center. With accidental use, subjects can still be eligible for participation after discussion with the medical monitor. An exception is also made for paracetamol, which is allowed up to admission to the clinical research center (up to 2 g per day). Milk of Magnesia (ie, magnesium hydroxide) (≤30 mL per day) may be administered 24 hours after dosing at the discretion of the Investigator.
6. Any drugs known to be strong inducers of cytochrome P450 (CYP)3A, enzymes and/or P-glycoprotein, including St. John’s Wort, must have been stopped at least 28 days prior admission and throughout the study. Appropriate sources (eg, Flockhart Table™) will be consulted by the Investigator or authorized designee, to confirm lack of PK/pharmacodynamic interaction with study drug. The Sponsor’s study director should be contacted with any questions.
7. Ability and willingness to abstain from alcohol from 48 hours (2 days) prior to screening and admission to the clinical research center and until discharge.
8. Able to fast for at least 14 hours (ie, at least 10 hours prior to dosing and at least 4 hours after dosing).
9. Ability and willingness to abstain from methylxanthine-containing beverages or food (coffee, tea, cola, chocolate, and energy drinks) and grapefruit (juice) from 48 hours (2 days) prior to admission to the clinical research center.
10. Good physical and mental health on the basis of medical history, physical examination, clinical laboratory, electrocardiogram (ECG), and vital signs, as judged by the Investigator.
11. Willing and able to sign the ICF.

Exclusion criteria 17

1. Employee of ICON or the Sponsor.
2. History of relevant drug and/or food allergies.
3. Using tobacco products within 30 days prior to drug administration.
4. History of alcohol abuse or drug addiction (including soft drugs like cannabis products) within 2 years prior to dosing.
5. Positive drug and alcohol screen (opiates, methadone, cocaine, amphetamines [including ecstasy], cannabinoids, barbiturates, benzodiazepines, tricyclic antidepressants, cotinine, and alcohol) at screening or 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. History or presence of hypersensitivity or idiosyncratic reaction to the study drug or related compounds.
8. History and/or current evidence of any of the following disorders: • Ventricular dysfunction or risk factors for Torsades de Pointes (eg, heart failure, cardiomyopathy, family history of Long QT Syndrome); • QTcF >470 ms; • Unable to take medications by mouth due to medical conditions or previous surgery that may affect gastrointestinal function, including but not limited to inflammatory bowel diseases (eg, Crohn's disease, and ulcerative colitis) or malabsorption syndrome, or procedures that may affect gastrointestinal function, such as gastrectomy, enterectomy, or colectomy.
9. For a study with a radiation burden of >0.1 mSv, the subject will be excluded if he participated in another study with a radiation burden of >0.1 mSv and ≤1 mSv in the period of 1 year prior to screening; a radiation burden of >1.1 mSv and ≤2 mSv in the period of 2 years prior to screening; a radiation burden of >2.1 mSv and ≤3 mSv in the period of 3 years prior to screening, etc (add 1 year per 1 mSv).
10. 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.
11. Recent history of abnormal bowel movements, such as diarrhea, loose stools, or constipation (defined as less than 1 bowel movement every 2 days and/or requires treatment for constipation), within 2 weeks of dosing.
12. Positive screen for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibodies, or human immunodeficiency virus (HIV) 1 and 2 antibodies at screening.
13. Participation in a drug study within 30 days prior to drug administration in the current study. Participation in 4 or more other drug studies in the 12 months prior to drug administration in the current study.
14. Donation or loss of more than 450 mL of blood within 60 days prior to drug administration.
15. Plasma donation within 7 days prior to dosing.
16. Significant and/or acute illness within 5 days prior to drug administration that may impact safety assessments, in the opinion of the Investigator.
17. Unsuitable veins for blood sampling.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 6

1. Mass balance will be calculated as the sum of the percent of total radioactivity (TRA) recovered in urine and feces relative to the administered radioactive dose minus any radioactivity lost due to emesis (if any occurred): Aeurine, Aefeces, Aetotal, feurine, fefeces, fetotal
2. TRA concentration equivalents in plasma and whole blood and the following pharmacokinetics (PK) parameters: AUC0-last, AUC0-inf, Cmax, Tmax, t½, and time matched AUC0-t (where t is the last common time point at which both TRA concentration equivalents and plasma zipalertinib concentrations are quantifiable in all subjects)
3. Zipalertinib concentrations in plasma and the PK parameters: AUC0-last, AUC0 inf, Cmax, Tmax, Kel, t½, AUC0-t, CL/F, and Vz/F
4. Ratio of plasma zipalertinib to TRA at time-matched AUC0-t
5. Zipalertinib concentrations in urine, and the following PK parameters: CLR, Aeurine and feurine
6. The fraction of 14C radioactivity associated with cellular components in whole blood will be determined by using the 14C radioactivity concentrations in whole blood and plasma, and the whole blood:plasma concentration ratio will be calculated

Secondary endpoints 2

1. Safety endpoints will include adverse events (AEs), vital signs measurements, 12-lead ECGs, clinical laboratory tests, and physical examination findings
2. Zipalertinib metabolic profiling and identification in plasma, urine, and feces containing sufficient amounts of radioactivity, and the percentage of each identified metabolite to TRA in plasma

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Taiho Oncology Inc.

Sponsor organisation

Taiho Oncology Inc.

Address

101 Carnegie Center Suite 101

City

Princeton

Postcode

08540-6231

Country

United States

Scientific contact point

Organisation

Taiho Oncology Inc.

Contact name

Trial Information Desk

Public contact point

Organisation

Taiho Oncology Inc.

Contact name

Trial Information Desk

Third parties 1

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 2 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications