A Study to Investigate 14C-bemcentinib in Healthy Male Subjects

BerGenBio ASA6 enrolled

Overview

The aims of this Study were to determine: * How much of the Study Drug (bemcentinib) ends up in urine and faeces * How much of the Study Drug and its breakdown products get into the bloodstream * The breakdown products (metabolites) of the Study Drug * The safety of the Study Drug and any side effects that might be associated with it.

This was a Phase 1, open-label, nonrandomized, single oral dose study in up to 8 healthy male subjects (with 6 required to complete the study). Potential subjects were screened to assess their eligibility to enter the study within 28 days prior to dose administration. Up to 8 subjects were enrolled to ensure that 6 subjects completed the study. Subjects were admitted into the study site on Day -1. On the morning of Day 1, all subjects received a single oral dose of 200 mg containing approximately 32.8 μCi (1.21 MBq) of 14C-bemcentinib, 30 minutes after starting a standard high-fat breakfast. Subjects were confined to the study site until at least Day 8. Subjects were discharged from the study site on Day 8 if the following discharge criteria were met: ·≥90% mass balance recovery, and ·\<1% of the total radioactive dose is recovered in combined excreta (urine and feces)in 2 consecutive 24-hour periods. If these discharge criteria were not met by Day 8, subjects were required to remain resident until discharge criteria are met, up to Day 15. If criteria were not met by Day 15, subjects were asked to collect 24-hour excreta samples on up to 2 further occasions on a nonresidential basis to allow extrapolation of urinary and fecal excretion. If needed, the 2 additional 24-hour nonresidential collections started on the morning of Days 22 and 29 (to be brought into the study site at the end of the collection interval on Days 23 and 30, respectively). If on the second occasion the subject still did not meet the desired criterion, then the subject was discharged from the study, per investigator and sponsor decision. Subjects experiencing emesis during the first 4 hours post-dose were discharged on the same day from the study site, provided there were no safety concerns, and after discharge study procedures were performed. The total duration of study participation for each subject (from screening to outpatient visit \[if required\]) was anticipated to be a maximum of approximately 58 days.

Study Type

INTERVENTIONAL

Allocation

Eligibility

Sex: MALEMin age: 35 YearsMax age: 55 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: 1. Males of any race, between 35 and 55 years of age, inclusive. 2. Body mass index between 18.0 and 32.0 kg/m2, inclusive, and a total body weight between 50 and 100 kg, inclusive. 3. In good health, determined by no clinically significant findings from medical history, vital signs measurements, and clinical laboratory evaluations (congenital nonhemolytic hyperbilirubinemia \[eg, suspicion of Gilbert's syndrome based on total and direct bilirubin\] is not acceptable) at screening and check-in and from the physical examination at check-in, as assessed by the investigator (or designee). 4. No clinically significant abnormalities in 12-lead ECG determined within 28 days before dose of IMP including average PR \> 220 ms and QT interval corrected for heart rate using Fridericia's formula \>450 ms. 5. No history of clinically significant dysrhythmias (long QT features on ECG, sustained bradycardia, left bundle branch block, or ventricular arrhythmia), atrial fibrillation, or history of familial long QT syndromes. 6. Will agree to use contraception as detailed in the study protocol. 7. Able to comprehend and willing to sign an ICF and to abide by the study restrictions. 8. History of a minimum of 1 bowel movement per day. Exclusion Criteria: Medical conditions 1. Significant history or clinical manifestation of any metabolic, allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder, as determined by the investigator (or designee). 2. History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the investigator (or designee). 3. History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs (uncomplicated appendectomy and hernia repair will be allowed). 4. Positive hepatitis panel and/or positive human immunodeficiency virus test. Prior/concomitant therapy 5. Administration of a COVID-19 vaccine in the past 30 days prior to dosing. 6. Use or intend to use any medications/products known to alter drug absorption, metabolism, or elimination processes, including St. John's wort, within 30 days prior to check-in, unless deemed acceptable by the investigator (or designee). 7. Use or intend to use any prescription medications/products within 14 days prior to check-in, unless deemed acceptable by the investigator (or designee). 8. Use or intend to use slow-release medications/products considered to still be active within 14 days prior to check-in, unless deemed acceptable by the investigator (or designee). 9. Use or intend to use any nonprescription medications/products including vitamins, minerals, and phytotherapeutic/herbal/plant-derived preparations within 7 days prior to check-in, unless deemed acceptable by the investigator (or designee). Prior/concurrent clinical study experience 10. Participation in a clinical study involving administration of an investigational drug (new chemical entity) in the past 90 days prior to dosing. 11. Subjects who have participated in any clinical study involving a radiolabelled investigational product within 12 months prior to check-in. 12. Have previously completed or withdrawn from this study or any other study investigating bemcentinib, and have previously received bemcentinib. Diet and lifestyle 13. Alcohol consumption of \> 28 units per week for males. One unit of alcohol equals ½ pint (285 mL) of beer or lager, 1 glass (125 mL) of wine, or 1/6 gill (25 mL) of spirits. 14. Positive alcohol breath test result or positive urine drug screen (confirmed by repeat) at screening or check-in. 15. History of alcoholism or drug/chemical abuse within 2 years prior to check-in. 16. Use of tobacco- or nicotine-containing products within 3 months prior to check-in, or positive cotinine at screening or check-in. 17. Ingestion of poppy seed-, Seville orange-, or grapefruit-containing foods or beverages within 7 days prior to check-in. Other exclusions 18. Receipt of blood products within 2 months prior to check-in. 19. Donation of blood from 3 months prior to screening, plasma from 2 weeks prior to screening, or platelets from 6 weeks prior to screening. 20. Poor peripheral venous access. 21. Subjects with exposure to significant diagnostic or therapeutic radiation (eg, serial X-ray, computed tomography scan, barium meal) or current employment in a job requiring radiation exposure monitoring within 12 months prior to check-in. 22. Subjects who, in the opinion of the investigator (or designee), should not participate in this study. Subjects may previously have been screened on a generic basis to determine their eligibility for inclusion in Phase 1 clinical studies conducted at the study site. If generic screening was performed within the specified study screening window, selected study-specific procedures will be repeated either at an additional screening visit or on admission to the study site on Day -1.

Outcomes

Primary Outcomes

Total Radioactivity - Plasma Maximum Observed Concentration (Cmax)

This endpoint will report the relevant data for the parameters assessed in order to measure total radioactivity in plasma (based upon plasma samples collected at set timepoints during the study). Analysis was derived from obtaining plasma samples from participants at set timepoints described and deriving PK parameters through the use of noncompartmental procedures in validated software (WinNonlin Version 8.3.5).

Time frame: Samples collected over a 2-week period: Days 1-8: Predose, 15 and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours post-dose, Days 8-15: 192, 216, 240, 264, 288, 312, and 336 hours post-dose

Total Radioactivity - Whole Blood Maximum Observed Concentration (Cmax)

This endpoint will report the relevant data for the parameters assessed in order to measure total radioactivity in whole blood (based upon whole blood samples collected at set timepoints during the study). Analysis was derived from obtaining whole blood samples from participants at set timepoints described and deriving PK parameters through the use of noncompartmental procedures in validated software (WinNonlin Version 8.3.5).

Plasma Pharmacokinetic Parameters Bemcentinib - Maximum Observed Concentration (Cmax)

Plasma samples will be obtained in order to evaluate defined plasma pharmacokinetic parameters for 14C-bemcentinib. This endpoint will report the summary of derived pharmacokinetic parameters for the maximum observed concentration (Cmax) of 14C-bemcentinib in plasma. Analysis was derived from obtaining plasma samples from participants at set timepoints described and deriving PK parameters through the use of noncompartmental procedures in validated software (WinNonlin Version 8.3.5).

Plasma Pharmacokinetic Parameters Bemcentinib - Time to Maximum Observed Concentration (Tmax)

Plasma samples will be obtained in order to evaluate defined plasma pharmacokinetic parameters for 14C-bemcentinib. This endpoint will report the summary of derived pharmacokinetic parameters for the time to maximum observed concentration (Tmax) of 14C-bemcentinib in plasma. Analysis was derived from obtaining plasma samples from participants at set timepoints described and deriving PK parameters through the use of noncompartmental procedures in validated software (WinNonlin Version 8.3.5).

Plasma Pharmacokinetic Parameters Bemcentinib - Terminal Elimination Half-life (t1/2)

Plasma samples will be obtained in order to evaluate defined plasma pharmacokinetic parameters for 14C-bemcentinib. This endpoint will report the summary of derived pharmacokinetic parameters for the terminal elimination half-life (t1/2) of 14C-bemcentinib in plasma. Analysis was derived from obtaining plasma samples from participants at set timepoints described and deriving PK parameters through the use of noncompartmental procedures in validated software (WinNonlin Version 8.3.5).

Plasma Pharmacokinetic Parameters Bemcentinib - Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-∞)

Plasma samples will be obtained in order to evaluate defined plasma pharmacokinetic parameters for 14C-bemcentinib. This endpoint will report the summary of derived pharmacokinetic parameters for the area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-∞) of 14C-bemcentinib in plasma. Analysis was derived from obtaining plasma samples from participants at set timepoints described and deriving PK parameters through the use of noncompartmental procedures in validated software (WinNonlin Version 8.3.5).

Plasma Pharmacokinetic Parameters Bemcentinib - Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast)

Plasma samples will be obtained in order to evaluate defined plasma pharmacokinetic parameters for 14C-bemcentinib. This endpoint will report the summary of derived pharmacokinetic parameters for the area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC0-tlast) of 14C-bemcentinib in plasma. Analysis was derived from obtaining plasma samples from participants at set timepoints described and deriving PK parameters through the use of noncompartmental procedures in validated software (WinNonlin Version 8.3.5).

Secondary Outcomes

Number of Participants With Adverse Events

This secondary endpoint relates to the number of participants who report an adverse event (AE) during the study.

Time frame: Collection of AEs occurs through ad hoc reporting from the participants from the point of signature of informed consent through to study completion (up to 5 weeks).

Number of Participants Who Report a Change From Normal Range Values for Laboratory Safety Parameters (Serum Biochemistry, Serum Haematology or Urinalysis) From First Dose on Day 1 to Study Completion.

This secondary endpoint will report the number of participants who record a value which is deemed as outside of the normal range (clinically significant values only) for any of the serum biochemistry, serum haematology or urinalysis parameters as defined in the study protocol following first dose administration on Day 1 up to completion of the study.

Time frame: From Day 1 to study completion (up to 5 weeks)

Number of Participants Who Report a Change From Normal Range Values for Any of the Associated 12-Lead ECG Parameters From First Dose on Day 1 to Study Completion.

This secondary endpoint will report the number of participants who record a value which is deemed as outside of the normal range (clinically significant values only) for any of the 12-Lead ECG parameters as defined in the study protocol following first dose administration on Day 1 up to completion of the study.

Time frame: From Day 1 to study completion (up to 5 weeks)

Number of Participants Who Report a Change From Normal Range Values for Any of the Vital Signs Parameters From First Dose on Day 1 to Study Completion.

This secondary endpoint will report the number of participants who record a value which is deemed as outside of the normal range (clinically significant values only) for any of the vital signs parameters as defined in the study protocol following first dose administration on Day 1 up to completion of the study.

Time frame: From Day 1 to study completion (up to 5 weeks)

Number of Participants Who Report a Change From Normal With Respect to Physical Examination Parameters From First Dose on Day 1 to Study Completion.

A Study to Investigate 14C-bemcentinib in Healthy Male Subjects

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes