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

• ClinicalTrials.gov Identifier: NCT02113813
• Recruitment Status: Completed
• First Posted: April 15, 2014
• Last Update Posted: January 18, 2020
• Sponsor: Astellas Pharma Global Development, Inc.
• Information provided by (Responsible Party): Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

Study Description

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.

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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.

Eligibility Criteria

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

Criteria

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

Locations

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.

Investigators

• Study Director: Senior Medical Director; Astellas Pharma Global Development, Inc.

More Information

Additional Information:

Link to results on Astellas Clinical Study Results website 

• Responsible Party: Astellas Pharma Global Development, Inc.
• ClinicalTrials.gov Identifier: NCT02113813
• Other Study ID Numbers: 8273-CL-0102
• First Posted: April 15, 2014
• 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/

• 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; Midazolam; T790M resistance mutation; EGFR; NSCLC; naquotinib; Epidermal Growth Factor Receptor mutations; ASP8273

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Naquotinib; Midazolam; Adjuvants, Anesthesia; Hypnotics and Sedatives; Central Nervous System Depressants; Physiological Effects of Drugs; Anti-Anxiety Agents; Tranquilizing Agents; Psychotropic Drugs; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; GABA Modulators; GABA Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors