Clinical trial NCT02113813: A Dose Escalation Study of ASP8273 in Subjects With Non-Small-Cell Lung Cancer (NSCLC) Who Have Epidermal Growth Factor Receptor (EGFR) Mutations
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Non-Small-Cell Lung Cancer (NSCLC)
Epidermal Growth Factor Receptor Mutations
Keywords: irreversible EGFR inhibitor
Non-Small-Cell Lung Cancer
Midazolam
T790M resistance mutation
EGFR
NSCLC
naquotinib
Epidermal Growth Factor Receptor mutations
ASP8273
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2014-04-15
Enrollment: 133
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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)
  * 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

Primary outcomes:
measure: Safety and tolerability as assessed by Dose Limiting Toxicities (DLTs)
timeFrame: up to 18 months
measure: Safety and tolerability as assessed by adverse events (AEs)
timeFrame: up to 18 months
measure: Safety and tolerability as assessed by laboratory tests
timeFrame: up to 18 months
measure: Safety and tolerability as assessed by vital signs
timeFrame: up to 18 months
measure: Safety and tolerability as assessed by 12-lead electrocardiograms (ECGs)
timeFrame: up to 18 months
Secondary outcomes:
measure: Composite of pharmacokinetics of ASP8273 concentration and its metabolites (plasma): Cmax, tmax, AUClast, AUCinf, t1/2, CL/F, and Vz/F
timeFrame: 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
measure: Composite of pharmacokinetics of midazolam concentration and its metabolites (plasma): Cmax, tmax, AUClast, AUCinf, t1/2, CL/F, and Vz/F
timeFrame: Day -1 and Day 1 of cycle 1; Day 1 and Day 2 of cycle 2
measure: Best overall response rate
timeFrame: Up to 18 months
measure: Disease control rate
timeFrame: Up to 18 months
measure: Progression free survival
timeFrame: Up to 18 months
Other outcomes:
Locations:
city: Washington
country: United States
facility: Site US10010
state: District of Columbia
city: Baltimore
country: United States
facility: Site US10006
state: Maryland
city: Boston
country: United States
facility: Site US10012
state: Massachusetts
city: Boston
country: United States
facility: Site US10001
state: Massachusetts
city: Boston
country: United States
facility: Site US10011
state: Massachusetts
city: New York
country: United States
facility: Site US10008
state: New York
city: Chapel Hill
country: United States
facility: Site US10004
state: North Carolina
city: Cleveland
country: United States
facility: Site US10005
state: Ohio
city: Philadelphia
country: United States
facility: Site US10009
state: Pennsylvania
city: Nashville
country: United States
facility: Site US10002
state: Tennessee
city: Fairfax
country: United States
facility: Site US10003
state: Virginia
city: Seattle
country: United States
facility: Site US10007
state: Washington
Study officials:
affiliation: Astellas Pharma Global Development, Inc.
name: Senior Medical Director
role: STUDY_DIRECTOR
References: