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

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

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.

Study Overview

• Status: Completed
• Conditions: Non-Small-Cell Lung Cancer (NSCLC); Epidermal Growth Factor Receptor Mutations
• Intervention / Treatment: Drug: naquotinib; Drug: midazolam

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.

• Study Type: Interventional
• Enrollment (Actual): 133
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20007-2113
      • Site US10010
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Site US10006
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Site US10012
    • Boston, Massachusetts, United States, 02215
      • Site US10001
    • Boston, Massachusetts, United States, 02215
      • Site US10011
  • New York
    • New York, New York, United States, 10065
      • Site US10008
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Site US10004
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Site US10005
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Site US10009
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Site US10002
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Site US10003
  • Washington
    • Seattle, Washington, United States, 98104
      • Site US10007

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:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Astellas Pharma Global Development, Inc.

Publications and helpful links

Helpful Links

• Link to results on Astellas Clinical Study Results website

Study record dates

Study Major Dates

• Study Start (Actual): April 9, 2014
• Primary Completion (Actual): July 28, 2017
• Study Completion (Actual): February 11, 2019

Study Registration Dates

• First Submitted: April 4, 2014
• First Submitted That Met QC Criteria: April 11, 2014
• First Posted (Estimate): April 15, 2014

Study Record Updates

• Last Update Posted (Actual): January 18, 2020
• Last Update Submitted That Met QC Criteria: January 15, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: NSCLC; EGFR; Midazolam; Non-Small-Cell Lung Cancer; ASP8273; T790M resistance mutation; irreversible EGFR inhibitor; naquotinib; Epidermal Growth Factor Receptor mutations
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Antineoplastic Agents; Tranquilizing Agents; Psychotropic Drugs; Protein Kinase Inhibitors; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam; Naquotinib
• Other Study ID Numbers: 8273-CL-0102

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as compounds terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.
• IPD Sharing Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
• IPD Sharing Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No