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
Overview
- Phase
- Phase 1
- Intervention
- naquotinib
- Conditions
- Non-Small-Cell Lung Cancer (NSCLC)
- Sponsor
- Astellas Pharma Global Development, Inc.
- Enrollment
- 133
- Locations
- 12
- Primary Endpoint
- Safety and tolerability as assessed by Dose Limiting Toxicities (DLTs)
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
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
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.
Investigators
Eligibility Criteria
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)
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
Arms & Interventions
ASP8273 Dose Escalation cohort (part 1)
oral
Intervention: naquotinib
ASP8273 Response Expansion cohort (part 1)
oral
Intervention: naquotinib
ASP8273 and Midazolam RP2D Expansion cohort (part 2)
oral
Intervention: naquotinib
ASP8273 and Midazolam RP2D Expansion cohort (part 2)
oral
Intervention: midazolam
Food Effect Fasted cohort (part 2)
oral
Intervention: naquotinib
Food Effect Fed cohort (part 2)
oral
Intervention: naquotinib
Exon 20 Cohort (part 2)
oral
Intervention: naquotinib
Outcomes
Primary Outcomes
Safety and tolerability as assessed by Dose Limiting Toxicities (DLTs)
Time Frame: up to 18 months
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.
Safety and tolerability as assessed by adverse events (AEs)
Time Frame: up to 18 months
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.
Safety and tolerability as assessed by laboratory tests
Time Frame: up to 18 months
Laboratory tests to be conducted are hematology, biochemistry, urinalysis, coagulation profile, lipid panel and lymphocyte subpopulation.
Safety and tolerability as assessed by vital signs
Time Frame: up to 18 months
Vital signs to be measured includes blood pressure, pulse rate and temperature.
Safety and tolerability as assessed by 12-lead electrocardiograms (ECGs)
Time Frame: up to 18 months
Secondary Outcomes
- Composite of pharmacokinetics of ASP8273 concentration and its metabolites (plasma): Cmax, tmax, AUClast, AUCinf, t1/2, CL/F, and 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(Up to 18 months)
- Disease control rate(Up to 18 months)
- Progression free survival(Up to 18 months)