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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02113813
Recruitment Status : Completed
First Posted : April 15, 2014
Last Update Posted : January 18, 2020
Information provided by (Responsible Party):
Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

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.

Condition or disease Intervention/treatment Phase
Non-Small-Cell Lung Cancer (NSCLC) Epidermal Growth Factor Receptor Mutations Drug: naquotinib Drug: midazolam Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 133 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : April 9, 2014
Actual Primary Completion Date : July 28, 2017
Actual Study Completion Date : February 11, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arm Intervention/treatment
Experimental: ASP8273 Dose Escalation cohort (part 1)
Drug: naquotinib
Other Name: ASP8273

Experimental: ASP8273 Response Expansion cohort (part 1)
Drug: naquotinib
Other Name: ASP8273

Experimental: ASP8273 and Midazolam RP2D Expansion cohort (part 2)
Drug: naquotinib
Other Name: ASP8273

Drug: midazolam

Experimental: Food Effect Fasted cohort (part 2)
Drug: naquotinib
Other Name: ASP8273

Experimental: Food Effect Fed cohort (part 2)
Drug: naquotinib
Other Name: ASP8273

Experimental: Exon 20 Cohort (part 2)
Drug: naquotinib
Other Name: ASP8273

Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. Safety and tolerability as assessed by 12-lead electrocardiograms (ECGs) [ Time Frame: up to 18 months ]

Secondary Outcome Measures :
  1. Composite of pharmacokinetics of ASP8273 concentration and its metabolites (plasma): Cmax, tmax, AUClast, AUCinf, t1/2, CL/F, and Vz/F [ Time Frame: 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 ]
    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)

  2. Composite of pharmacokinetics of midazolam concentration and its metabolites (plasma): Cmax, tmax, AUClast, AUCinf, t1/2, CL/F, and Vz/F [ Time Frame: Day -1 and Day 1 of cycle 1; Day 1 and Day 2 of cycle 2 ]
  3. Best overall response rate [ Time Frame: Up to 18 months ]
    Defined as proportion of subjects whose best overall response is Complete Response (CR) or Partial Response (PR) among all analyzed subjects.

  4. Disease control rate [ Time Frame: Up to 18 months ]
    Defined as the proportion of subjects whose best overall response is rated as CR, PR or Stable Disease (SD) among all analyzed subjects.

  5. Progression free survival [ Time Frame: Up to 18 months ]
    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.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02113813

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United States, District of Columbia
Site US10010
Washington, District of Columbia, United States, 20007-2113
United States, Maryland
Site US10006
Baltimore, Maryland, United States, 21231
United States, Massachusetts
Site US10012
Boston, Massachusetts, United States, 02114
Site US10001
Boston, Massachusetts, United States, 02215
Site US10011
Boston, Massachusetts, United States, 02215
United States, New York
Site US10008
New York, New York, United States, 10065
United States, North Carolina
Site US10004
Chapel Hill, North Carolina, United States, 27599
United States, Ohio
Site US10005
Cleveland, Ohio, United States, 44106
United States, Pennsylvania
Site US10009
Philadelphia, Pennsylvania, United States, 19104
United States, Tennessee
Site US10002
Nashville, Tennessee, United States, 37232
United States, Virginia
Site US10003
Fairfax, Virginia, United States, 22031
United States, Washington
Site US10007
Seattle, Washington, United States, 98104
Sponsors and Collaborators
Astellas Pharma Global Development, Inc.
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Study Director: Senior Medical Director Astellas Pharma Global Development, Inc.
Additional Information:
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Responsible Party: Astellas Pharma Global Development, Inc.
ClinicalTrials.gov Identifier: NCT02113813    
Other Study ID Numbers: 8273-CL-0102
First Posted: April 15, 2014    Key Record Dates
Last Update Posted: January 18, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (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.
URL: https://www.clinicalstudydatarequest.com/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. ):
irreversible EGFR inhibitor
Non-Small-Cell Lung Cancer
T790M resistance mutation
Epidermal Growth Factor Receptor mutations
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors