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

NCT02113813 | Completed Phase 1 FDA Drug

• 1 other identifier: 8273-CL-0102
• Study Type: interventional
• Target: 133
• Locations: 1 country
• Sites: 12

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.

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

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (5)

• 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

Study Arms (6)

ASP8273 Dose Escalation cohort (part 1)

EXPERIMENTAL

oral

Drug: naquotinib

ASP8273 Response Expansion cohort (part 1)

EXPERIMENTAL

oral

Drug: naquotinib

ASP8273 and Midazolam RP2D Expansion cohort (part 2)

EXPERIMENTAL

oral

Drug: naquotinib; Drug: midazolam

Food Effect Fasted cohort (part 2)

EXPERIMENTAL

oral

Drug: naquotinib

Food Effect Fed cohort (part 2)

EXPERIMENTAL

oral

Drug: naquotinib

Exon 20 Cohort (part 2)

EXPERIMENTAL

oral

Drug: naquotinib

Interventions

naquotinib DRUG

oral

Also known as: ASP8273

ASP8273 Dose Escalation cohort (part 1); ASP8273 Response Expansion cohort (part 1); ASP8273 and Midazolam RP2D Expansion cohort (part 2); Exon 20 Cohort (part 2); Food Effect Fasted cohort (part 2); Food Effect Fed cohort (part 2)

midazolam DRUG

oral

ASP8273 and Midazolam RP2D Expansion cohort (part 2)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Astellas Pharma Global Development, Inc.: lead

Study Sites (12)

Site US10010

Washington D.C., District of Columbia, 20007-2113, United States

Location

Site US10006

Baltimore, Maryland, 21231, United States

Location

Site US10012

Boston, Massachusetts, 02114, United States

Location

Site US10001

Boston, Massachusetts, 02215, United States

Location

Site US10011

Boston, Massachusetts, 02215, United States

Location

Site US10008

New York, New York, 10065, United States

Location

Site US10004

Chapel Hill, North Carolina, 27599, United States

Location

Site US10005

Cleveland, Ohio, 44106, United States

Location

Site US10009

Philadelphia, Pennsylvania, 19104, United States

Location

Site US10002

Nashville, Tennessee, 37232, United States

Location

Site US10003

Fairfax, Virginia, 22031, United States

Location

Site US10007

Seattle, Washington, 98104, United States

Location

Related Links

• Link to results on Astellas Clinical Study Results website

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

naquotinib; Midazolam

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Senior Medical Director

  Astellas Pharma Global Development, Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 4, 2014
• First Posted: April 15, 2014
• Study Start: April 9, 2014
• Primary Completion: July 28, 2017
• Study Completion: February 11, 2019
• Last Updated: November 14, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• 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.
• 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.

Locations

US (12)