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

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2016 by Astellas Pharma Inc
Information provided by (Responsible Party):
Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )
ClinicalTrials.gov Identifier:
First received: April 4, 2014
Last updated: February 5, 2016
Last verified: February 2016
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 Intervention Phase
Non-Small-Cell Lung Cancer (NSCLC)
Epidermal Growth Factor Receptor Mutations
Drug: ASP8273
Drug: midazolam
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:

Further study details as provided by Astellas Pharma Inc:

Primary Outcome Measures:
  • Safety and tolerability as assessed by Dose Limiting Toxicities (DLTs) [ Time Frame: up to 18 months ] [ Designated as safety issue: Yes ]
    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.

  • Safety and tolerability as assessed by adverse events (AEs) [ Time Frame: up to 18 months ] [ Designated as safety issue: Yes ]
    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.

  • Safety and tolerability as assessed by laboratory tests [ Time Frame: up to 18 months ] [ Designated as safety issue: Yes ]
    Laboratory tests to be conducted are hematology, biochemistry, urinalysis, coagulation profile, lipid panel and lymphocyte subpopulation.

  • Safety and tolerability as assessed by vital signs [ Time Frame: up to 18 months ] [ Designated as safety issue: Yes ]
    Vital signs to be measured includes blood pressure, pulse rate and temperature.

  • Safety and tolerability as assessed by 12-lead electrocardiograms (ECGs) [ Time Frame: up to 18 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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)

  • 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 ] [ Designated as safety issue: No ]
  • Best overall response rate [ Time Frame: Up to 18 months ] [ Designated as safety issue: No ]
    Defined as proportion of subjects whose best overall response is Complete Response (CR) or Partial Response (PR) among all analyzed subjects.

  • Disease control rate [ Time Frame: Up to 18 months ] [ Designated as safety issue: No ]
    Defined as the proportion of subjects whose best overall response is rated as CR, PR or Stable Disease (SD) among all analyzed subjects.

  • Progression free survival [ Time Frame: Up to 18 months ] [ Designated as safety issue: No ]
    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.

Estimated Enrollment: 110
Study Start Date: March 2014
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ASP8273 Dose Escalation cohort (part 1) Drug: ASP8273
Experimental: ASP8273 Response Expansion cohort (part 1) Drug: ASP8273
Experimental: ASP8273 and Midazolam RP2D Expansion cohort (part 2) Drug: ASP8273
Drug: midazolam
Experimental: Food Effect Fasted cohort (part 2) Drug: ASP8273
Experimental: Food Effect Fed cohort (part 2) Drug: ASP8273
Experimental: Exon 20 Cohort (part 2) Drug: 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.

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02113813

Contact: Astellas Pharma Global Development 800-888-7704 ext 5473 Astellas.registration@astellas.com

United States, District of Columbia
Site US10010 Recruiting
Washington, District of Columbia, United States, 20007-2113
United States, Maryland
Site US10006 Recruiting
Baltimore, Maryland, United States, 21231
United States, Massachusetts
Site US10001 Recruiting
Boston, Massachusetts, United States, 02215
United States, New York
Site US10008 Recruiting
New York City, New York, United States, 10065
United States, North Carolina
Site US10004 Recruiting
Chapel Hill, North Carolina, United States, 27599
United States, Ohio
Site US10005 Recruiting
Cleveland, Ohio, United States, 44106
United States, Pennsylvania
Site US10009 Recruiting
Philadelphia, Pennsylvania, United States, 19104
United States, Tennessee
Site US10002 Recruiting
Nashville, Tennessee, United States, 37232-7415
United States, Virginia
Site US10003 Recruiting
Fairfax, Virginia, United States, 22031
United States, Washington
Site US10007 Recruiting
Seattle, Washington, United States, 98104
Sponsors and Collaborators
Astellas Pharma Global Development, Inc.
Study Director: Senior Medical Director Astellas Pharma Global Development, Inc.
  More Information

Responsible Party: Astellas Pharma Global Development, Inc.
ClinicalTrials.gov Identifier: NCT02113813     History of Changes
Other Study ID Numbers: 8273-CL-0102 
Study First Received: April 4, 2014
Last Updated: February 5, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by Astellas Pharma Inc:
Non-Small-Cell Lung Cancer
Epidermal Growth Factor Receptor mutations
irreversible EGFR inhibitor
T790M resistance mutation

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Bronchial Neoplasms
Lung Diseases
Neoplasms by Site
Respiratory Tract Neoplasms
Thoracic Neoplasms
Carcinoma, Bronchogenic
Respiratory Tract Diseases
Adjuvants, Anesthesia
Anesthetics, General
Anesthetics, Intravenous
Anti-Anxiety Agents
Central Nervous System Depressants
GABA Agents
GABA Modulators
Hypnotics and Sedatives
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Physiological Effects of Drugs
Psychotropic Drugs
Tranquilizing Agents

ClinicalTrials.gov processed this record on May 26, 2016