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

Non-Small-Cell Lung Cancer (NSCLC) Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02113813
• Other study ID #: 8273-CL-0102
• Status: Completed
• Phase: Phase 1
• Start date: April 9, 2014
• Est. completion date: February 11, 2019

Study information

• Verified date: January 2020
• Source: Astellas Pharma Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 133
• Est. completion date: February 11, 2019
• Est. primary completion date: July 28, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Epidermal Growth Factor Receptor Mutations
• Lung Neoplasms
• Non-Small-Cell Lung Cancer (NSCLC)

Intervention

Drug:
• naquotinib
oral
• midazolam
oral

Locations

Country	Name	City	State
United States	Site US10006	Baltimore	Maryland
United States	Site US10001	Boston	Massachusetts
United States	Site US10011	Boston	Massachusetts
United States	Site US10012	Boston	Massachusetts
United States	Site US10004	Chapel Hill	North Carolina
United States	Site US10005	Cleveland	Ohio
United States	Site US10003	Fairfax	Virginia
United States	Site US10002	Nashville	Tennessee
United States	Site US10008	New York	New York
United States	Site US10009	Philadelphia	Pennsylvania
United States	Site US10007	Seattle	Washington
United States	Site US10010	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Astellas Pharma Global Development, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	Safety and tolerability as assessed by vital signs	Vital signs to be measured includes blood pressure, pulse rate and temperature.	up to 18 months
Primary	Safety and tolerability as assessed by 12-lead electrocardiograms (ECGs)		up to 18 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   Link to results on Astellas Clinical Study Results website