A Phase 1, Open-label Study of the Absorption, Metabolism, Excretion of [14C]-Resminostat

Study Overview
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Brief Summary
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Resminostat is a potent, orally available inhibitor of Class I, IIb and IV histone deacetylases (HDACs), including a pronounced activity against HDAC6. Resminostat targets epigenetic changes observed in tumour cells and has the potential to provide significant benefit to patients with advanced malignancies by inhibiting tumour progression and metastasis or even inducing tumour regression. This will be a Phase 1, open-label, non-randomized, single dose study of the absorption, metabolism, excretion of [14C] resminostat following a single oral dose in healthy male participants. The purpose of this study is to determine the absorption, metabolism, and excretion (AME) of [14C] resminostat and to characterize and determine the metabolites present in plasma, urine, and, where possible, faeces in healthy male participants following a single oral administration. Knowledge of the metabolism and excretion of parent drug and its metabolites is useful for evaluating the Metabolites in Safety Testing requirements elucidated in the International Conference on Harmonisation (ICH) M3, and the likelihood of effects of renal or hepatic impairment on the disposition of resminostat, and the likelihood for drug-drug interactions with resminostat. The results from this study may guide future study designs using special populations or evaluating the potential for drug-drug interactions.

Official Title
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A Phase 1, Open-label Study of the Absorption, Metabolism, Excretion of [14C]-Resminostat Following a Single Oral Dose in Healthy Male Subjects

Conditions
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Cutaneous T Cell Lymphoma, Mycosis Fungoides, Sezary Syndrome

Intervention / Treatment
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* Drug: [14C]-resminostat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male Age between 35 (inclusive) and 55 years of age (inclusive) Body mass index between 18.0 and 28.0 kg/m2, inclusive but at least 60 kg of body weight. Healthy, as determined by no clinically significant findings from medical history, physical examination, 12-lead ECG, vital signs measurements, and clinical laboratory evaluations (congenital nonhemolytic hyperbilirubinemia [eg, suspicion of Gilbert Meulengracht's syndrome based on total and direct bilirubin] is not acceptable) at screening and/or check-in as assessed by the investigator (or designee). Subjects must agree to use contraception Able to comprehend and willing to sign an ICF and to abide by the study restrictions History of a minimum of 1 bowel movement per day. Subjects must agree not to donate sperm from check-in until 90 days after discharge. Exclusion Criteria: 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). Any of the following abnormalities in laboratory test values and/or ECG at screening and/or check-in, confirmed by repeat: hemoglobin, white blood cell count, total platelets, and QTcF outside of normal range; alanine aminotransferase, aspartate aminotransferase, and creatinine values > upper limit of normal; and estimated glomerular filtration rate (calculated using Cockcroft-Gault formula) <60 mL/min. History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the investigator (or designee). 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). Confirmed (eg, 2 consecutive measurements) systolic blood pressure >150 or <90 mmHg, diastolic blood pressure >90 or <50 mmHg, and pulse rate >90 or <40 beats per minute. History of alcoholism or drug/chemical abuse within 2 years prior to screening. Alcohol consumption of > 21 units per week. 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. Positive alcohol breath test result or positive urine drug screen (confirmed by repeat) at screening or check-in. Positive hepatitis panel and/or positive human immunodeficiency virus test Participation in a clinical study involving administration of an investigational drug (new chemical entity) in the past 90 days or 5 half-lives, whichever is longer prior to dosing. Administration of any vaccination (including vaccines currently being deployed in the UK for SARS-CoV-27) within the past 90 days prior to dosing. Use or intend to use any medications/products known to alter drug absorption, metabolism, and excretion processes, including St. John's wort, within 30 days prior to check-in, unless deemed acceptable by the investigator (or designee). Use or intend to use any prescription medications/products within 14 days prior to check-in, unless deemed acceptable by the investigator (or designee). 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). 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). Use of tobacco- or nicotine-containing products within 3 months prior to check-in, or positive cotinine test at screening or check-in. Ingestion of poppy seed-, Seville orange-, or grapefruit-containing foods or beverages within 7 days prior to check-in. Receipt of blood products within 2 months prior to check-in. Donation of blood from 3 months prior to screening, plasma from 2 weeks prior to screening, or platelets from 6 weeks prior to screening. Poor peripheral venous access 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. Subjects who have participated in any clinical study involving a radiolabeled investigational product within 12 months prior to check-in. Subjects who, in the opinion of the investigator (or designee), should not participate in this study.

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 55 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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: [14C]-resminostat<br>single dose of 400 mg [14C]-resminostat | Drug: [14C]-resminostat<br>* 1 single dose of 400 mg [14C]-resminostat<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-tlast | AUC from time zero to the last quantifiable concentration derived from the whole blood and plasma concentration-time profiles following oral administration of [14C]-resminostat | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| AUC0-∞ | AUC from time zero extrapolated to infinity derived from the whole blood and plasma concentration-time profiles following oral administration of [14C]-resminostat | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| Cmax | maximum observed concentration derived from the whole blood and plasma concentration-time profiles following oral administration of [14C]-resminostat | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| tmax | time to reach Cmax derived from the whole blood and plasma concentration-time profiles following oral administration of [14C]-resminostat | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| tlag | time to the first quantifiable concentration in plasma derived from the whole blood and plasma concentration-time profiles following oral administration of [14C]-resminostat | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| λz | terminal elimination rate constant derived from the whole blood and plasma concentration-time profiles following oral administration of [14C]-resminostat | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| t1/2 | apparent terminal elimination half-life derived from the whole blood and plasma concentration-time profiles following oral administration of [14C]-resminostat | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| CL/F | apparent total clearance derived from the whole blood and plasma concentration-time profiles following oral administration of [14C]-resminostat | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| Vz/F | apparent volume of distribution derived from the whole blood and plasma concentration-time profiles following oral administration of [14C]-resminostat | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| AUC0-∞ Plasma resminostat/Total Radioactivity Ratio | AUC0-∞ of plasma resminostat relative to AUC0-∞ of plasma total radioactivity derived from the whole blood and plasma concentration-time profiles following oral administration of [14C]-resminostat | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| AUC0-∞ Blood/Plasma Ratio | AUC0-∞ of whole blood total radioactivity to AUC0-∞ of plasma total radioactivity derived from the whole blood and plasma concentration-time profiles following oral administration of [14C]-resminostat | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| Aeu | amount excreted in urine derived from urine collections at each sampling interval | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| cumulative Aeu | cumulative amount excreted in urine derived from urine collections at each sampling interval | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| feu | percentage excreted in urine derived from urine collections at each sampling interval | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| cumulative feu | cumulative percentage excreted in urine derived from urine collections at each sampling interval | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| Aef | amount excreted in feces derived from feces collections at each sampling interval | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| cumulative Aef | cumulative amount excreted in feces derived from feces collections at each sampling interval | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| fef | percentage excreted in feces derived from feces collections at each sampling interval | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| cumulative fef. | cumulative percentage excreted in feces derived from feces collections at each sampling interval | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability | AE reporting including relatedness and severity | from study drug intake until 28 days after study drug administration | 
| Heart rhythm | ECG analysis by 12-lead ECG | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| Ventricular rate | ECG analysis by 12-lead ECG | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| PR-interval (synonymous: PQ interval) | ECG analysis by 12-lead ECG | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| QRS complex | ECG analysis by 12-lead ECG | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| QT interval | ECG analysis by 12-lead ECG | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| QTcF interval | ECG analysis by 12-lead ECG | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| Vital Signs (Body Temperature) | Body temperature will be measured after a 5 minute rest in supine position | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| Vital Signs (Blood pressure) | Systolic and diastolic blood pressure will be measured after a 5 minute rest in supine position | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| Physical Examination | A full physical examination covering at least head, eyes, ears, nose and throat, lungs, heart, neurological status, abdomen, extremities, skin, and lymph nodes | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| metabolic profiles of resminostat | identification and quantification of metabolites in serum and urin samples by HPLC | From day -1 until maximum 15 days after single dose of [14C]-resminostat | 
| identification and quantification of resminostat metabolites | identification and quantification of metabolites in serum and urin samples by HPLC | From day -1 until maximum 15 days after single dose of [14C]-resminostat |