A Multicenter, Open-Label Phase 1 Study of U3-1402 in Subjects with Metastatic or Unresectable EGFR-Mutant Non-Small Cell Lung Cancer

This study is designed to evaluate safety and antitumor activity of U3-1402 in two parts:
Dose Escalation and Dose Expansion.

In Dose Escalation, U3-1402 will be evaluated in participants with metastatic or unresectable
NSCLC with epidermal growth factor receptor (EGFR) activating mutation after disease
progression during/after EGFR tyrosine kinase inhibitor (TKI) therapy.

In Dose Expansion, U3-1402 will be evaluated in participants with metastatic or unresectable
NSCLC with EGFR activating mutation or squamous or non-squamous NSCLC (ie, without
EGFR-activating mutations) with disease progression during/after systemic treatment for
locally advanced or metastatic disease.

Inclusion Criteria for both Dose Escalation and Dose Expansion:

1. Has locally advanced or metastatic NSCLC, not amenable to curative surgery or
radiation

2. Has at least one measurable lesion per RECIST version 1.1

3. Has Eastern Cooperative Oncology Group performance status of 0 or 1 at Screening

Inclusion Criteria for Dose Escalation only:

1. Has histologically or cytologically documented adenocarcinoma NSCLC

2. Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011)

1. Historical confirmation that the tumor harbors an epidermal growth factor
receptor (EGFR) mutation known to be associated with EGFR tyrosine kinase
inhibitor (TKI) sensitivity (including G719X, exon 19 deletion, L858R, L861Q)

2. Has experienced clinical benefit from an EGFR TKI, followed by systemic
progression of disease [Response Evaluation Criteria in Solid Tumors (RECIST)
version 1.1] or World Health Organization (WHO)] while on continuous treatment
with an EGFR TKI

3. Is currently receiving and able to discontinue erlotinib, gefinitib, afatinib, or
osimertinib

4. Has been receiving erlotinib, gefitinib, afatinib, or osimertinib for at least 6 weeks
with well-controlled related toxicities less than Grade 3 in severity at the time of
Screening

5. Has radiological documentation of disease progression while receiving continuous
treatment with erlotinib, gefitinib, afatinib, or osimertinib

6. Is willing to provide archival tumor tissue from a biopsy performed within 6 months of
progression during treatment with erlotinib, gefitinib, afatinib, or osimertinib OR
has at least one lesion, not previously irradiated, amenable to core biopsy and is
willing to undergo screening tumor biopsy

7. Demonstrates absence of EGFR T790M mutation if treated with erlotinib, gefitinib, or
afatinib. No EGFR mutation testing is required if treated with osimertinib.

Inclusion Criteria for all cohorts of Dose Expansion only:

1. Has received systemic therapy for locally advanced or metastatic disease including at
least 1 platinum-based chemotherapy regimen

2. Has documented radiological disease progression during/after most recent treatment
regimen for locally-advanced or metastatic disease

3. For Cohorts 1, 2, 3a, and 3b: Is willing to provide archival tumor tissue from a
biopsy performed within 6 months of consent and performed after progression
during/after treatment with most recent cancer therapy regimen OR has at least 1
lesion, not previously irradiated, amenable to core biopsy and is willing to undergo
tumor biopsy. Tumor tissue must be of sufficient quantity as defined in the laboratory
manual and contain adequate tumor tissue content as confirmed by haematoxylin and
eosin (H&S) staining at central laboratory.

- For Cohort 4: Neither archival tumor tissue nor core tumor biopsy will be
collected

Inclusion Criteria specific to Cohorts 1, 3a, 3b, and 4 of Dose Expansion:

1. Has histologically or cytologically documented:

1. Cohort 1: Adenocarcinoma NSCLC

2. Cohorts 3a, 3b, and 4: NSCLC (including any histology other than small-cell or
combined small cell and non-small cell)

2. Has documentation of radiological disease progression following one or more lines of
EGFR TKI treatment. Participants with EGFR T790M mutation following treatment with
erlotinib, gefitinib afatinib, or dacomitinib must have received and have
documentation of radiological disease progression following treatment with osimertinib
unless unable or unwilling.

3. Has documentation of EGFR-activating mutation(s) detected from tumor tissue: G719X,
exon deletion 19, L858R, or L861Q. Participants with other EGFR-activating mutations
may be eligible following discussion with the Sponsor.

Inclusion Criteria specific to Cohort 2 of Dose Expansion:

1. Has histologically or cytologically documented squamous or non-squamous NSCLC (ie,
without EGFR-activating mutations).

2. Has received prior treatment with anti-PD-1 or anti-PD-L1 antibody-based regimen in
the locally advanced or metastatic setting unless unable or unwilling. Participants
with NSCLC known to harbor a genomic alteration(s) other than EGFR mutation(s) (eg,
ALK or ROS1 fusion) for which treatment is available must have also received prior
treatment with at least 1 genotype-directed therapy.

Exclusion Criteria for Dose Escalation and Dose Expansion:

1. Has any evidence of small cell histology, or combined small cell and non-small cell
histology, in original tumor biopsy or in Screening biopsy performed after progression

2. Treatment with any of the following:

1. Any cytotoxic chemotherapy, investigational agent or other anticancer drug(s)
from a previous cancer treatment regimen or clinical study (other than EGFR TKI
in Cohorts 1, 3a, 3b, and 4 only), within 14 days of the first dose of study
treatment

2. Immune checkpoint inhibitor therapy within 21 days of the first dose of study
treatment

3. Prior treatment with an anti-HER3 antibody (dose escalation only)

4. Prior treatment with a topoisomerase I inhibitor (dose escalation only)

5. Prior treatment with an antibody-drug conjugate (ADC) that consists of an
exatecan derivative that is a topoisomerase I inhibitor (eg, DS-8201a) (dose
escalation only)

6. Major surgery (excluding placement of vascular access) within 4 weeks of the
first dose of study drug treatment

7. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field
of radiation within 4 weeks of the first dose of study drug treatment, or
palliative radiation therapy within 2 weeks of the first dose of study drug
treatment, or stereotactic radiotherapy within 1 week prior to the first dose of
U3-1402

3. Has history of other active malignancy within 3 years prior to enrollment, except:

1. Adequately treated non-melanoma skin cancer OR

2. Superficial bladder tumors (Ta, Tis, T1) OR

3. Curatively treated in situ disease

4. Has spinal cord compression or clinically active central nervous system metastases,
defined as untreated and symptomatic, or requiring therapy with corticosteroids or
anticonvulsants to control associated symptoms. Participants with clinically inactive
brain metastases may be included in the study. Participants with treated brain
metastases that are no longer symptomatic and who require no treatment with
corticosteroids or anticonvulsants may be included in the study if they have recovered
from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed
between the end of whole brain radiotherapy and study enrollment (1 week for
stereotactic radiotherapy)

5. Has history of myocardial infarction within the past 6 months

6. Has symptomatic congestive heart failure[New York Heart Association (NYHA) Classes
II-IV], unstable angina within the past 6 months, or cardiac arrhythmia requiring
antiarrhythmic treatment

7. Has left ventricular ejection fraction (LVEF) < 50% by either echocardiogram (ECHO) or
multigated acquisition scan (MUGA)

8. Has any clinically important abnormalities in rhythm, conduction or morphology of
resting electrocardiogram (ECG), eg, complete left bundle branch block, third-degree
heart block, second-degree heart block, or PR interval > 250 milliseconds (ms)

9. Has a mean corrected QT interval using Fridericia's Correction Formula (QTcF)
prolongation to > 470 ms for females and > 450 ms for males in three successive
Screening measurements

10. Unable or unwilling to discontinue concomitant drugs that are known to prolong the QT
interval

11. Has any factors that increase the risk of corrected QT (QTc) interval prolongation or
risk of arrhythmic events, such as congenital long QT syndrome, family history of long
QT syndrome, or unexplained sudden death under 40 years of age in first-degree
relatives.

12. Has any history of interstitial lung disease (ILD) (including pulmonary fibrosis or
severe radiation pneumonitis), has current ILD/pneumonitis, or is suspected to have
such disease by imaging during screening

13. Has clinically significant corneal disease

Additional Exclusion Criteria for Dose Expansion Cohort 2:

1. Has documentation of one or more of the following EGFR-activating mutations: G719X, exon
19 deletion, L858R, or L861Q

Additional Exclusion Criteria for Dose Expansion Cohort 4:

1. Evidence of any leptomeningeal disease

2. Clinically severe respiratory compromise (based on Investigator's assessment)
resulting from intercurrent pulmonary illnesses including, but not limited to:

1. Any underlying pulmonary disorder

2. Any autoimmune, connective tissue or inflammatory disorders with pulmonary
involvement OR prior complete pneumonectomy

3. Is receiving chronic systemic corticosteroids dosed at >10 mg/day prednisone or
equivalent anti-inflammatory activity or any form of immunosuppressive therapy prior
to enrollment

4. Resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg

5. Prior or ongoing clinically relevant illness, medical condition, surgical history,
physical finding, or laboratory abnormality that could affect the safety of the
subject; alter the absorption, distribution, metabolism or excretion of the study
drug; or confound the assessment of study results.