A Dose Escalation Study of ASP8273 in Subjects With Non-Small-Cell Lung Cancer (NSCLC) Who Have Epidermal Growth Factor Receptor (EGFR) Mutations

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and tolerability of ASP8273 and to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). This study will also determine the pharmacokinetics (PK) of ASP8273, evaluate the potential inhibition of CYP3A4 by ASP8273 and the antitumor activity of ASP8273 as well as determine the effect of food on the bioavailability of ASP8273.

Detailed Description
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This study is composed of 2 parts: part 1 is the dose escalation phase and part 2 is the recommended Phase 2 dose (RP2D) phase, Food Effect (FE) cohort and Exon 20 cohort.

Official Title
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An Open-label, Phase 1 Dose Escalation Study of Oral ASP8273 in Subjects With Non-Small-Cell Lung Cancer (NSCLC) Who Have Epidermal Growth Factor Receptor (EGFR) Mutations

Conditions
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Non-Small-Cell Lung Cancer (NSCLC), Epidermal Growth Factor Receptor Mutations

Intervention / Treatment
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* Drug: naquotinib
* Drug: midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Non-child bearing potential or able to follow birth control requirements Eastern Cooperative Oncology Group (ECOG) ≤ 1 Life expectancy ≥ 12 weeks Laboratory criteria as: Neutrophil count ≥ 1,500/mm3 Platelet count ≥ 7.5 x 104 /mm3 Hemoglobin ≥ 9.0 g/dL Lymphocyte count ≥ 500/mm3 Serum creatinine < 1.5 x institutional Upper Limit of Normal (ULN) or an estimated glomerular filtration rate (eGFR) of > 50 ml/min as calculated by the Modification of Diet in Renal Disease (MDRD) equation Total bilirubin < 1.5 x ULN (except for subjects with documented Gilbert's syndrome) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x ULN Dose escalation subjects: Epidermal Growth Factor Receptor (EGFR) activating mutation by local testing: exon 18 G719X, exon 19 deletion, exon 21 L861Q, exon 21 L858R or exon 20 insertion; and received prior treatment with EGFR Tyrosine Kinase Inhibitor (TKI) Response expansion/RP2D expansion/ FE Cohort subjects: disease progression on or was intolerant to prior EGFR TKI; activating mutation as above AND T790M mutation; tumor sample subsequent to EGFR TKI is available for central testing; at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Inclusion Criteria for Exon 20 cohort: Subject on any line of treatment and has an EGFR exon 20 insertion mutation on examination of an NSCLC tissue or cellular specimen. Local testing may determine eligibility and a tumor sample should also be sent for central testing. Subjects must have at least 1 measurable lesion based on RECIST version 1.1. Exclusion Criteria: Any ongoing toxicity ≥ Grade 2 attributable to prior Non-Small-Cell Lung Cancer (NSCLC) treatment Prior EGFR inhibitor within 6 days; received prior treatment with any other agent with antitumor activity chemotherapy, radiotherapy, or immunotherapy within 14 days; any investigational therapy within 28 days or 5 half-lives, whichever is shorter; blood transfusion or hemopoietic factor within 14 days; major surgery within 14 days; any strong CYP3A4 inhibitors within 7 days Positive hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-HCV) or Human Immunodeficiency Virus (HIV) Symptomatic Central Nervous System (CNS) metastasis Active infection requiring systemic therapy within 14 days Severe or uncontrolled systemic diseases including uncontrolled hypertension History of or active interstitial lung disease Screening QTcF >450 msec or current medication known to prolong QT ≥ Grade 2 cardiac arrhythmia or uncontrolled atrial fib of any grade; Class 3 or 4 New York Heart Association congestive heart failure; history of severe/unstable angina, myocardial infarction or cerebrovascular accident within 6 months History of gastrointestinal ulcer or bleeding within 3 months; any digestive tract dysfunction Concurrent corneal disorder or ophthalmologic condition making subject unsuitable RP2D cohort subjects: contraindications to midazolam, any other midazolam within 7 days, or any medications or supplements known to be strong CYP3A inhibitors within 7 days or inducers within 12 days Any other malignancy requiring treatment

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ASP8273 Dose Escalation cohort (part 1)<br>oral | Drug: naquotinib<br>* oral<br>* Other names: ASP8273;|
| Experimental: ASP8273 Response Expansion cohort (part 1)<br>oral | Drug: naquotinib<br>* oral<br>* Other names: ASP8273;|
| Experimental: ASP8273 and Midazolam RP2D Expansion cohort (part 2)<br>oral | Drug: naquotinib<br>* oral<br>* Other names: ASP8273;Drug: midazolam<br>* oral<br>|
| Experimental: Food Effect Fasted cohort (part 2)<br>oral | Drug: naquotinib<br>* oral<br>* Other names: ASP8273;|
| Experimental: Food Effect Fed cohort (part 2)<br>oral | Drug: naquotinib<br>* oral<br>* Other names: ASP8273;|
| Experimental: Exon 20 Cohort (part 2)<br>oral | Drug: naquotinib<br>* oral<br>* Other names: ASP8273;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability as assessed by Dose Limiting Toxicities (DLTs) | A DLT is defined as any pre-determined toxicity that is related to study drug per the investigator and which occurs during Cycle 0 and Cycle 1 using NCI CTCAE v4.03. | up to 18 months | 
| Safety and tolerability as assessed by adverse events (AEs) | An AE is defined as any untoward medical occurrence in a subject administered a study drug or has undergone study procedures and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. | up to 18 months | 
| Safety and tolerability as assessed by laboratory tests | Laboratory tests to be conducted are hematology, biochemistry, urinalysis, coagulation profile, lipid panel and lymphocyte subpopulation. | up to 18 months | 
| Safety and tolerability as assessed by vital signs | Vital signs to be measured includes blood pressure, pulse rate and temperature. | up to 18 months | 
| Safety and tolerability as assessed by 12-lead electrocardiograms (ECGs) |  | up to 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of pharmacokinetics of ASP8273 concentration and its metabolites (plasma): Cmax, tmax, AUClast, AUCinf, t1/2, CL/F, and Vz/F | Maximum concentration (Cmax), the time after dosing when Cmax occurs (tmax), area under the concentration - time curve from time 0 up to the last quantifiable concentration (AUClast), area under the concentration - time curve from time 0 extrapolated to infinity (AUCinf), apparent terminal elimination half-life (t1/2), apparent oral systemic clearance (CL/F), Apparent volume of distribution (Vz/F) | Cycle 0: Dose Escalation Days 1-2, FE Days 1-6; Cycle 1: Dose Escalation/Response Expansion/RP2D/FE Days 1,8,15, RP2D Day 21, Exon 20 Days 8,15; Cycle 2 & 3: Dose Escalation/Response Expansion/RP2D Days 1,2, FE Day 1; Exon 20 days 1, 2 & Cycle 3 | 
| Composite of pharmacokinetics of midazolam concentration and its metabolites (plasma): Cmax, tmax, AUClast, AUCinf, t1/2, CL/F, and Vz/F |  | Day -1 and Day 1 of cycle 1; Day 1 and Day 2 of cycle 2 | 
| Best overall response rate | Defined as proportion of subjects whose best overall response is Complete Response (CR) or Partial Response (PR) among all analyzed subjects. | Up to 18 months | 
| Disease control rate | Defined as the proportion of subjects whose best overall response is rated as CR, PR or Stable Disease (SD) among all analyzed subjects. | Up to 18 months | 
| Progression free survival | Defined as the time from the start of the study treatment until death from any cause or radiographic disease progression assessed according to RECIST 1.1, whichever occurs first. | Up to 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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irreversible EGFR inhibitor, EGFR, NSCLC, naquotinib, Epidermal Growth Factor Receptor mutations, ASP8273, Non-Small-Cell Lung Cancer, Midazolam, T790M resistance mutation