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

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

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).

Study Overview

• Status: Withdrawn
• Conditions: Solid Tumors; Epidermal Growth Factor Receptor (EGFR) Mutations
• Intervention / Treatment: Drug: radio-labeled naquotinib; Drug: naquotinib

Detailed Description

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.

• Study Type: Interventional
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

    1. Postmenopausal (defined as at least 1 year without any menses) prior to screening, or
    2. Documented surgically sterile or status post hysterectomy (at least 1 month prior to screening).

  • Or, if of childbearing potential:

    1. Agree not to try to become pregnant during the study and for 28 days after the final study drug administration,
    2. Must have a negative serum pregnancy test at screening and day -1, and
    3. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: ASP8273; Two Parts - Part A: 14C-radio labeled; Part B: non radio labeled (optional)	Drug: radio-labeled naquotinib; Oral administration; Other Names: ASP8273; Drug: naquotinib; Oral administration; Other Names: ASP8273

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Astellas Pharma Global Development, Inc.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 15, 2016
• Primary Completion (ACTUAL): November 15, 2016
• Study Completion (ACTUAL): November 15, 2016

Study Registration Dates

• First Submitted: January 21, 2016
• First Submitted That Met QC Criteria: February 2, 2016
• First Posted (ESTIMATE): February 4, 2016

Study Record Updates

• Last Update Posted (ACTUAL): July 28, 2017
• Last Update Submitted That Met QC Criteria: July 26, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Phase 1; Oncology; Absorption; Metabolism; Excretion; naquotinib; [14C]-radioactivity
• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Naquotinib
• Other Study ID Numbers: 8273-CL-0104

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED