Open, Single-dose/-Period Study to Assess Mass Balance Recovery, Metabolite Profile/Identification of 14C-Varlitinib

Study Overview
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Brief Summary
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This is a single-centre, open-label, non-randomised, single oral dose study in healthy male subjects. It is planned to enrol a single cohort of 6 healthy male subjects to ensure data in 4 evaluable subjects. Each subject will receive a single administration of 120 mg [14C] varlitinib oral suspension containing not more than (NMT) 2.9 MBq (79 µCi), in the fed state.

Detailed Description
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Subjects will be screened for eligibility to participate in the study up to 28 days before dosing. Subjects will be admitted to the clinical unit on the evening prior to IMP administration (Day 1) and will fast overnight for a minimum of 8 h. Subjects will be dosed on the morning of Day 1 following a light breakfast, and will remain resident in the clinic until up to 240 h after dosing (Day 11). It is planned that subjects will be released as a group when all subjects have achieved a mass balance cumulative recovery of >90%, or if <1% of the dose administered has been collected in urine and faeces within 2 separate, consecutive 24 h periods. In this case, collection of all samples (blood, urine and faeces) will cease and the subjects will undergo discharge assessments. If this criterion has not been met by all subjects on Day 11, the residency period may be extended by a further 48 h maximum (up to Day 13). If the criterion is still not met by Day 13, or if additional residency is not considered appropriate or necessary, then home collections of urine and/or faeces may be requested at the discretion of the investigator for individual subjects.

Official Title
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An Open Label, Single-dose, Single-period Study Designed to Assess the Mass Balance Recovery, Metabolite Profile and Metabolite Identification of [14C]-Varlitinib in Healthy Male Subjects

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Varlitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy males of non-Asian descent Aged 30 to 65 years Body mass index of 18.0 to 35.0 kg/m2 or, if outside the range, considered not clinically significant by the investigator Must be willing and able to communicate and participate in the whole study Must provide written informed consent Must agree to use an adequate method of contraception (as defined in Section 9.4) Must have regular bowel movements (ie, average stool production of ≥1 and ≤3 stools per day) Subject is considered healthy on the basis of medical history, physical examination, ECG, vital signs and clinical laboratory assessments. Exclusion Criteria: Subjects who have received any IMP in a clinical research study within the previous 3 months Subjects who are study site employees, or immediate family members of a study site or sponsor employee Subjects with pregnant partners Subjects who have previously been enrolled in this study History of any drug or alcohol abuse in the past 2 years Regular alcohol consumption in males >21 units per week (1 unit = ½ pint beer, 25 mL of 40% spirit or a 125 mL glass of wine) Current smokers and those who have smoked within the last 12 months. A breath carbon monoxide reading of greater than 10 ppm at screening and admission Users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months Radiation exposure, including that from the present study, excluding background radiation but including diagnostic x-rays and other medical exposures, exceeding 5 mSv in the last 12 months or 10 mSv in the last 5 years. No occupationally exposed worker, as defined in the Ionising Radiation Regulations 1999, shall participate in the study Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator at screening Clinically significant abnormal biochemistry, haematology or urinalysis as judged by the investigator (laboratory parameters are listed in Appendix 1) Neutrophil count <1.8 x109/L at screening ALT and AST >1.25 x upper limit of normal range at screening QT interval corrected for heart rate using Fridericia's formula (QTcF) > 450 msec at screening Positive drugs of abuse test result (drugs of abuse tests are listed in Appendix 1) Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results Evidence of renal impairment at screening, as indicated by an estimated creatinine clearance (CLcr) of <80 mL/min using the Cockcroft-Gault equation History of clinically relevant cardiovascular, renal, hepatic, chronic respiratory or Gl disease, neurological or psychiatric disorder, as judged by the investigator History of clinically relevant dermatological disease (eg eczema, psoriasis, drug rashes) or the presence of dermatological conditions at screening (eg acne, eczema, dermatitis etc) Subjects with a history of cholecystectomy or gall stones Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hayfever is allowed unless it is active Donation or loss of greater than 400 mL of blood within the previous 3 months Subjects who are taking, or have taken, any prescribed or over-the-counter drug or herbal remedies in the 14 days before IMP administration; with the exception of 4 g per day paracetamol [see Section 11.4]). Further exceptions may apply on a case by case basis, if considered not to interfere with the objectives of the study, as agreed by the PI and sponsor's medical monitor. Failure to satisfy the investigator of fitness to participate for any other reason

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: [14C]-Varlitinib<br> | Drug: Varlitinib<br>* [14C]-Varlitinib<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mass balance recovery after a single oral dose of [14C] varlitinib | Mass balance recovery of [14C] varlitinib recovered in urine, faeces, and all excreta | Assessments will be made up to 13 days postdose | 
| Metabolite profiling and structural identification of metabolites in plasma, urine and faeces | Identification of the chemical structure of metabolites | Assessments will be made up to 13 days postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Routes and rates of elimination of [14C] varlitinib | Amount [14C] varlitinib excreted for urine and faeces | Assessments will be made up to 13 days postdose | 
| Determination of the chemical structure of the major metabolites of [14C] varlitinib | Identification of the chemical structure of each metabolite accounting for greater than 10% | Assessments will be made up to 13 days postdose | 
| Evaluation of whole blood:plasma concentration ratios for total radioactivity |  | Assessments will be made up to 13 days postdose | 
| PK of total radioactivity and varlitinib in plasma following a single oral dose of [14C] varlitinib | Peak Plasma Concentration (Cmax) | Assessments will be made up to 13 days postdose | 
| PK of total radioactivity and varlitinib in plasma following a single oral dose of [14C] varlitinib | Area under the plasma concentration versus time curve (AUC) | Assessments will be made up to 13 days postdose | 
| PK of total radioactivity and varlitinib in plasma following a single oral dose of [14C] varlitinib | Half life | Assessments will be made up to 13 days postdose | 
| PK of total radioactivity and varlitinib in plasma following a single oral dose of [14C] varlitinib | The time from dosing at which Cmax was apparent | Assessments will be made up to 13 days postdose | 
| Collect additional information on the safety and tolerability of varlitinib | Number of participants with abnormal laboratory values and/or adverse events | Assessments will be made up to 13 days postdose |