A Study to Investigate the Absorption, Metabolism and Excretion of [14C]ASP8273 in Subjects With Solid Tumors

Study Overview
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Brief Summary
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This is a study to investigate the absorption, metabolism and excretion of [14C] labeled ASP8273 in subjects with solid tumors harboring EGFR mutations (per local testing). This study consists of two parts (A and B).

Detailed Description
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This study consists of two parts (A and B). In Part A, eligible subjects will be admitted to the site on day -1 and remain confined at the site until postdosing discharge criteria are met. Subjects will receive a single dose of [14C] ASP8273 solution on study day 1. Once Part A has been completed, subjects may elect to continue participation in Part B. Subjects will receive oral administration of ASP8273 (nonradiolabeled) once daily in 28-day cycles.

Official Title
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A Phase 1 Study to Investigate the Absorption, Metabolism and Excretion of [14C]ASP8273 in Subjects With Solid Tumors Harboring Epidermal Growth Factor Receptor (EGFR) Mutations

Conditions
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Epidermal Growth Factor Receptor (EGFR) Mutations, Solid Tumors

Intervention / Treatment
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* Drug: radio-labeled naquotinib
* Drug: naquotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has histologically or cytologically confirmed metastatic or locally advanced, unresectable solid tumors harboring EGFR mutations. Subject has Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1. Subject must meet all of the following criteria on the laboratory tests that will be performed within 7 days prior to enrollment. In case of multiple laboratory data within this period, the most recent data should be used. Neutrophil count ≥ 1,000/mm3 Platelet count ≥ 7.5 × 104/mm3 Hemoglobin ≥ 9.0 g/dL Lymphocyte count ≥ 500/mm3 Estimated glomerular filtration rate (eGFR) of > 50 ml/min as calculated by the Cockcroft-Gault Method Total bilirubin (TBL) < 1.5 × upper limit of normal (ULN; except for subjects with documented Gilbert's syndrome) Aspartate aminotransferase (AST) and ALT < 3.0 × ULN Serum sodium level is ≥ 130 mmol/L Female subject must either be: Of nonchild bearing potential: Postmenopausal (defined as at least 1 year without any menses) prior to screening, or Documented surgically sterile or status post hysterectomy (at least 1 month prior to screening). Or, if of childbearing potential: Agree not to try to become pregnant during the study and for 28 days after the final study drug administration, Must have a negative serum pregnancy test at screening and day -1, and If heterosexually active must use two forms of birth control* (at least one of which must be a barrier method) starting at screening and throughout the study period and for 28 days after the final study drug administration. Female subject must not be breastfeeding at screening or during the study period, and for 28 days after the final study drug administration. Female subject must not donate ova starting at screening and throughout the study period, and for 28 days after the final study drug administration. Male subject and his female spouse/partner who is of childbearing potential must be using highly effective contraception consisting of two forms of birth control* (one of which must be a barrier method) starting at screening and continue throughout the study period and for 90 days after the final study drug administration. Male subject must not donate sperm starting at screening and throughout the study period and for 90 days after the final study drug administration. *Acceptable forms of birth control include: Established use of oral, injected or implanted hormonal methods of contraception. Placement of an intrauterine device (IUD) or intrauterine system (IUS). Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository. Exclusion Criteria: Subject has an ongoing toxicity ≥ Grade 2 (Common Terminology Criteria for Adverse Event [CTCAE] v4.03) attributable to prior medication to treat solid tumor (except alopecia) at the time of screening. Subject has known history of serious hypersensitivity reaction to ASP8273, or any component of the formulation used. Subject has received investigational therapy within 28 days or 5 half-lives, whichever is shorter, prior to the first dose of study drug. Subject has received a prior EGFR inhibitor within 6 days prior to the first dose of study drug. Subject has had any of the following within 14 days prior to the first dose of study drug: A treatment with any other agent with antitumor activity including chemotherapy, radiotherapy, or immunotherapy A major surgical procedure (other than study related biopsy), or a major surgical is planned to occur during the study Blood transfusions or hemopoietic factor therapy Evidence of active infection requiring systemic therapy Subject has symptomatic central nervous system (CNS) metastasis. Subject with previously treated brain or CNS metastases are eligible provided that the subject has recovered from any acute effects of radiotherapy and is not requiring steroids, and any whole brain radiation therapy was completed at least 2 weeks prior to study drug administration, or any stereotactic radiosurgery (SRS) was completed at least 1 week prior the first dose of study drug. Subject has ≥ CTCAE v4.03 Grade 2 neuropathy. Subject has a known history of a positive test for hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-HCV). Subject has a known history of a positive test for human immunodeficiency virus (HIV) infection. Subject has history of drug-induced interstitial lung disease (ILD) or any evidence of active ILD. Subject has severe or uncontrolled systemic diseases including uncontrolled hypertension (blood pressure > 150/100 mmHg) or active bleeding diatheses. Subject has ongoing cardiac arrhythmia that is Grade ≥ 2 or uncontrolled atrial fibrillation of any grade. Subject currently has Class 3 or 4 New York Heart Association congestive heart failure. Subject has history of severe/unstable angina, myocardial infarction, or cerebrovascular accident within 6 months prior to the first dose of study drug. Subject has concurrent corneal disorder or any ophthalmologic condition which, in the Investigator's opinion, makes the subject unsuitable for study participation (e.g., advanced cataracts, glaucoma, or subject is unable to undergo a comprehensive ophthalmologic exam). Subject has history of gastrointestinal ulcer or gastrointestinal bleeding within 3 months prior to the first dose of study drug. Subject has difficulty taking oral medication or any digestive tract dysfunction or inflammatory bowel disease that would interfere with the intestinal absorption of drug. Subject who has received strong/moderate inhibitors or inducers of CYP3A4 within 14 days prior to the first dose of study drug.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: ASP8273<br>Two Parts - Part A: 14C-radio labeled; Part B: non radio labeled (optional) | Drug: radio-labeled naquotinib<br>* Oral administration<br>* Other names: ASP8273;Drug: naquotinib<br>* Oral administration<br>* Other names: ASP8273;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Radioactivity in whole blood: AUCinf | AUCinf: area under the concentration-time curve from the time of dosing extrapolated to time infinity | Up to 14 days | 
| Part A: Radioactivity in whole blood: AUClast | AUClast: area under the concentration-time curve from the time of dosing to the last measurable concentration | Up to 14 days | 
| Part A: Radioactivity in whole blood: Cmax | Cmax: maximum concentration | Up to 14 days | 
| Part A: Radioactivity in whole blood: tmax | tmax: time to maximum concentration | Up to 14 days | 
| Part A: Radioactivity in whole blood: t1/2 | t1/2: apparent terminal elimination half-life | Up to 14 days | 
| Part A: Radioactivity in plasma: AUCinf |  | Up to 14 days | 
| Part A: Radioactivity in plasma: AUClast |  | Up to 14 days | 
| Part A: Radioactivity in plasma: Cmax |  | Up to 14 days | 
| Part A: Radioactivity in plasma: tmax |  | Up to 14 days | 
| Part A: Radioactivity in plasma: t1/2 |  | Up to 14 days | 
| Part A: Radioactivity ratio for whole blood/plasma concentration (per time point.) |  | Up to 14 days | 
| Part A: Radioactivity ratio for whole blood/plasma AUCinf |  | Up to 14 days | 
| Part A: Radioactivity ratio for whole blood/plasma AUClast |  | Up to 14 days | 
| Part A: Excretion ratio of radioactivity in urine |  | Up to 14 days | 
| Part A: Cumulative excretion of radioactivity in urine |  | Up to 14 days | 
| Part A: Excretion ratio of radioactivity in feces |  | Up to 14 days | 
| Part A: Cumulative excretion of radioactivity in feces |  | Up to 14 days | 
| Part A: Total excretion ratio of radioactivity in urine and feces |  | Up to 14 days | 
| Part A: Total cumulative excretion of radioactivity in urine and feces |  | Up to 14 days | 
| Part A: Radioactivity in emesis (if applicable) |  | Up to 14 days | 
| Part A: Pharmacokinetics of ASP8273 and possible metabolites in plasma: AUCinf |  | Up to 14 days | 
| Part A: Pharmacokinetics of ASP8273 and possible metabolites in plasma: AUClast |  | Up to 14 days | 
| Part A: Pharmacokinetics of ASP8273 and possible metabolites in plasma: Cmax |  | Up to 14 days | 
| Part A: Pharmacokinetics of ASP8273 and possible metabolites in plasma: tmax |  | Up to 14 days | 
| Part A: Pharmacokinetics of ASP8273 and possible metabolites in plasma: t1/2 |  | Up to 14 days | 
| Part A: Pharmacokinetics of ASP8273 and possible metabolites in urine: (Aelast) | Aelast: cumulative amount of drug excreted from time of dosing up to the collection time of the last measurable concentration | Up to 14 days | 
| Part A: Pharmacokinetics of ASP8273 and possible metabolites in urine CLr | CLr: renal clearance | Up to 14 days | 
| Part A: Pharmacokinetics of ASP8273 and possible metabolites in urine: % of dose excreted (Aelast%) |  | Up to 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Profiling of possible metabolites of ASP8273 in plasma | Identification and possible quantification of metabolites in plasma | Up to 14 days | 
| Part A: Profiling of possible metabolites of ASP8273 in urine | Identification and possible quantification of metabolites in urine | Up to 14 days | 
| Part A: Profiling of possible metabolites of ASP8273 in feces | Identification and possible quantification of metabolites in feces | Up to 14 days | 
| Part A and Part B: Safety profile assessed by adverse event reporting, vital signs, electrocardiograms (ECG), clinical laboratory tests, and physical examinations | Vital signs include oral temperature, pulse, and blood pressure. Clinical laboratory evaluations include hematology, chemistry and urinalysis. | Up to 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 1, Metabolism, Excretion, Absorption, [14C]-radioactivity, Pharmacokinetics, naquotinib, Oncology