Stage IIIB/IV Non-small Cell Lung Cancer Tumors with EGFR Activating Mutations

Primary  To evaluate the progression free survival (PFS), based on independent radiologic review (IRR), of ASP8273 compared to erlotinib or gefitinib in patients with locally advanced, metastatic or unresectable stage IIIB/IV adenocarcinoma non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) activating mutations Secondary  Overall survival (OS)  Overall response rate (ORR) as assessed by IRR  PFS as assessed by the investigator  Disease control rate (DCR) as assessed by IRR  Safety of ASP8273 Exploratory  To evaluate potential biomarkers that may affect treatment outcome  Evaluation of the pharmacokinetics of ASP8273  To evaluate the impact of subsequent therapy on progression free survival on next-line therapy (PFS#2)  To evaluate Quality of Life (QoL) and patient-reported outcome (PRO) parameters as measured by FACT-EGFRI-18, EORTC-QLQ-LC13, EORTC-QLQ-C30 and EQ-5D-5L

ASP8273

ASP8273

capsule

100

Primary
 PFS as assessed by IRR
Secondary
 OS
 Best overall response rate (CR + PR) by IRR
 PFS by the investigator
 DCR (CR+PR+SD) by IRR
 Safety variables (e.g., adverse events [AEs], laboratory tests, vital sign measurements,
electrocardiograms [ECGs])
Exploratory
 Plasma T790M and other biomarkers related to EGFR TKI sensitivity and/or resistance
 Plasma pharmacokinetics of ASP8273
 PFS#2 on subsequent therapy
 QoL and PRO parameters as measured by FACT-EGFR-TKI, EORTC-QLQ-LC13,
EORTC-QLQ-C30 and EQ-5D-5L

Inclusion Criteria
Subject must meet all of the following inclusion criteria to be eligible for participation in this
study at enrollment:
1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written
informed consent and privacy language as per national regulations (e.g., HIPAA
Authorization for U.S. sites) must be obtained from the subject or legally authorized
representative prior to any study-related procedures.
2. Subject is ≥ 18 years of age and legally an adult according to local regulation at the time of
signing informed consent.
3. Subject agrees not to participate in another interventional study while on treatment.
4. Female subject must either:
 Be of nonchildbearing potential:
o postmenopausal (defined as at least 1 year without any menses) prior to Screening,
or
o documented surgically sterile
 Or, if of childbearing potential:
o Agree not to try to become pregnant during the study and for 28 days after the final
study drug administration
o And have a negative serum pregnancy test at Screening
o And, if heterosexually active, agree to consistently use 2 forms of highly effective
birth control* (at least 1 of which must be a barrier method) starting at Screening
and throughout the study period and for 28 days after the final study drug
administration
5. Female subject must not be breastfeeding at Screening or during the study period, and for
28 days after the final study drug administration.
6. Female subject must not donate ova starting at Screening and throughout the study period,
and for 28 days after the final study drug administration.
7. Male subject and their female spouse/partners who are of childbearing potential must be
using highly effective contraception consisting of 2 forms of birth control* (1 of which must
be a barrier method) starting at Screening and continue throughout the study period and for
90 days after the final study drug administration.
*Highly effective forms of birth control include:
 Consistent and correct usage of established oral, injected or implanted hormonal
methods of contraception
 Established intrauterine device (IUD) or intrauterine system (IUS)
 Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository (not applicable
in Japan)
 Calendar-based contraceptive methods (Knaus-Ogino or rhythm method [Japan only])
8. Male subject must not donate sperm starting at Screening and throughout the study period
and for 90 days after the final study drug administration.
9. Subject has Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
10. Subject has histologically confirmed locally advanced, metastatic or unresectable Stage
IIIB/IV adenocarcinoma NSCLC (newly diagnosed or recurrent). Subjects with mixed
histology are eligible if adenocarcinoma is the predominant histology.
11. Subject has predicted life expectancy  12 weeks in the opinion of the investigator.
12. Subject must meet all of the following criteria on the laboratory tests that will be analyzed
centrally within 7 days prior to the first dose of study drug. In case of multiple laboratory
data within this period, the most recent data should be used.
 Neutrophil count > 1,000/mm3
 Platelet count  7.5  104
/mm3
 Hemoglobin > 8.0 g/dL
 Serum creatinine  2.0 x upper limit of normal (ULN) or an estimated glomerular
filtration rate (eGFR) of > 50 mL/min as calculated by the Cockcroft Gault Method
 Total bilirubin  1.5  ULN (except for subjects with documented Gilbert’s syndrome)
 AST and ALT  3.0  ULN or ≤ 5  ULN if subject has documented liver metastases
 Serum sodium level is ≥ 130 mmol/L
13. Subject has an EGFR activating mutation (exon 19 deletion or exon 21 L858R), with or
without T790M mutation, by local or central testing on examination of a NSCLC FFPE
specimen. A tissue sample from the same block used to determine eligibility by local testing
should be available to send to the central lab for confirmatory testing.
14. Subject must have at least 1 measureable lesion based on RECIST V1.1.

Exclusion Criteria
Subject who meets any of the following exclusion criteria prior to enrollment is not eligible for
enrollment:
1. Subject has received intervening anticancer treatment or previous treatment with
chemotherapy for metastatic disease. The administration of neoadjuvant or adjuvant
chemotherapy is allowed as long as it has finalized ≥ 6 months before the first dose of study
drug.
2. Subject has received a prior treatment with a therapeutic agent targeting EGFR (e.g., afatinib,
dacomitinib, ASP8273, etc).
3. Subject has received investigational therapy within 28 days or 5 half-lives prior to the first
dose of study drug.
4. Subject has received radiotherapy within 1 week prior to the first dose of study drug. If the
subject received radiotherapy > 1 week prior to study treatment, the irradiated lesion cannot
be the only lesion used for evaluating response.
5. Subject has symptomatic central nervous system (CNS) metastasis. Subject with previously
treated brain or CNS metastases are eligible provided that the subject has recovered from any
acute effects of radiotherapy and is not requiring escalating doses of steroids, and any whole
brain radiation therapy was completed at least 2 weeks prior to study drug administration, or
any stereotactic radiosurgery (SRS) was completed at least 1 week prior to the first dose of
study drug.
6. Subject has received blood transfusions or hematopoietic factor therapy within 14 days prior
to the first dose of study drug.
7. Subject has had a major surgical procedure (other than a biopsy) within 14 days prior to the
first dose of study drug, or one is planned during the course of the study.
8. Subject has a known history of a positive test for human immunodeficiency virus (HIV)
infection.
9. Subject has known history of serious hypersensitivity reaction to a known ingredient of
ASP8273, erlotinib or gefitinib.
10. Subject has evidence of an active infection requiring systemic therapy within 14 days prior to
the planned first dose of study drug.
11. Subject has severe or uncontrolled systemic diseases including uncontrolled hypertension
(blood pressure > 150/100 mmHg) or active bleeding diatheses.
12. Subject has history of drug-induced interstitial lung disease (ILD) or any evidence of active
ILD.
13. Subject has ongoing cardiac arrhythmia that is Grade ≥ 2 or uncontrolled atrial fibrillation of
any grade.
14. Subject currently has Class 3 or 4 New York Heart Association congestive heart failure.
15. Subject has history of severe/unstable angina, myocardial infarction or cerebrovascular
accident within 6 months prior to the planned first dose of study drug.
16. Subject has history of gastrointestinal ulcer or gastrointestinal bleeding within 3 months prior
to the planned first dose of study drug.
17. Subject has concurrent corneal disorder or any ophthalmologic condition which, in the
investigator’s opinion, makes the subject unsuitable for study participation (i.e., advanced
cataracts, glaucoma).
18. Subject has difficulty taking oral medication or any digestive tract dysfunction or
inflammatory bowel disease that would interfere with the intestinal absorption of drug.
19. Subject has another malignancy which requires treatment.
20. Subject has any condition which, in the investigator’s opinion, makes the subject unsuitable
for study participation.
21. Subject has used the following drugs:
a. Potent CYP 3A4 inhibitors within 7 days prior to first dose of study drug
b. Proton pump inhibitors such as omeprazole within 14 days prior to first dose of study
drug