This study includes a Dose Escalation Part to identify the recommended combination dose (RCD)
and a Dose Expansion Part to further evaluate efficacy and safety.
The primary objectives:
Dose Escalation: To assess the safety and tolerability of patritumab deruxtecan (U3-1402) and
osimertinib in subjects with locally advanced or metastatic non-small cell lung cancer
(NSCLC) with an EGFR exon 19 deletion or L858R mutation with tumor progression after
treatment with osimertinib, and to determine the recommended combination dose (RCD).
Second-Line Dose Expansion Arm 1 and Arm 1b: To assess the preliminary antitumor activity of
patritumab deruxtecan and osimertinib in subjects with locally advanced or metastatic NSCLC
with an EGFR exon 19 deletion or L858R mutation with tumor progression after treatment with
osimertinib. Note: One or both of the study arms may open with one or two distinct dosing
Second-Line Dose Expansion Arm 2: To assess the preliminary antitumor activity of patritumab
deruxtecan monotherapy in subjects with locally advanced or metastatic NSCLC with an EGFR
exon 19 deletion or L858R mutation with tumor progression after treatment with osimertinib.
First-Line Dose Expansion: To assess the safety and tolerability of patritumab deruxtecan and
osimertinib in subjects with locally advanced or metastatic NSCLC with an EGFR exon 19
deletion or L858R mutation without prior systemic treatment for locally advanced or
Inclusion Criteria Specific to Dose Escalation and Second-Line Dose Expansion:
- Documentation of EGFR exon 19 deletion or L858R mutation detected from tumor tissue
- Must have received osimertinib for locally advanced or metastatic disease at a dose of
80 mg once daily (QD) for at least 6 weeks and must not miss more than two doses
during the 2 weeks prior to the first day of study treatment (Cycle 1, Day 1)
- Must not have received any other prior systemic cancer therapies in the locally
- Has documentation of radiological disease progression following first-line treatment
with osimertinib in the locally advanced or metastatic setting
Inclusion Criteria Specific to First-line Dose Expansion:
- The tumor tissue harbors one of the 2 common EGFR mutations occurring in NSCLC known
to be associated with EGFR-TKI sensitivity (exon 19 deletion or L858R) as assessed by
Clinical Laboratory Improvement Amendments (CLIA)-certified (United States [US]
sites), accredited (outside of the US), local laboratory or central laboratory. Only
tissue-based testing will be accepted.
- Participants must have previously untreated locally advanced or metastatic NSCLC and
must be eligible to receive first-line treatment with osimertinib, according to the
judgment of the investigator. Prior adjuvant or neo-adjuvant therapy (chemotherapy,
radiotherapy, investigational agents; except with osimertinib) is permitted.
Participants must meet all criteria to be eligible for inclusion in this study:
- Histologically or cytologically documented locally advanced or metastatic NSCLC not
amenable to curative surgery or radiation.
- At least 1 measurable lesion as assessed by Investigator as per Response Evaluation
Criteria in Solid Tumors (RECIST v1.1)
- Willing to provide required tumor tissue of sufficient quantity (as defined in the
laboratory manual) and contain adequate tumor tissue content (as confirmed by
hematoxylin and eosin (H&E) staining at central laboratory). Required tumor tissue can
be provided as either:
- Pre-treatment tumor biopsy from at least 1 lesion not previously irradiated and
amenable to core biopsy OR
- Archival tissue collected from a biopsy performed within 3 months prior to
signing of the tissue consent and since progression while on the most recent
cancer therapy regimen.
- On-study tumor biopsies are required for the first 15 participants in Dose
- Has adequate bone marrow reserve and organ function based on local laboratory data
within 14 days prior to Cycle 1, Day 1:
- Platelet count: ≥100 000/mm^3 or ≥100 × 10^9/L (platelet transfusions are not
allowed up to 14 days prior to Cycle 1, Day 1 to meet eligibility)
- Hemoglobin: ≥9.0 g/dL (transfusion and/or growth factor support is allowed)
- Absolute neutrophil count ; 1500/mm^3 or ≥1.5 × 10^9/L
- Serum creatinine (SCr) OR creatinine clearance (CrCl): SCr ≤1.5 × ULN, OR CrCl
≥30 mL/min as calculated using the Cockcroft-Gault equation or measured CrCl;
confirmation of CrCl is only required when creatinine is >1.5 × ULN
- Aspartate aminotransferase/ alanine aminotransferase: ≤3 × ULN (if liver metastases
are present, ≤5 × ULN)
- Total bilirubin: ≤1.5 × ULN if no liver metastases (<3 × ULN in the presence of
documented Gilbert's syndrome [unconjugated hyperbilirubinemia] or liver metastases)
- Serum albumin ; ≥2.5 g/dL
- Prothrombin time (PT) or PT-international normalized ratio (INR) and Activated partial
thromboplastin time (aPTT) / Partial thromboplastin time (PTT): ≤1.5 × ULN, except for
subjects on coumarin-derivative anticoagulants or other similar anticoagulant therapy,
who must have PT-INR within therapeutic range as deemed appropriate by the
- Any previous histologic or cytologic evidence of small cell OR combined small
cell/non-small cell disease in the archival tumor tissue or pretreatment tumor biopsy.
- Any history of interstitial lung disease (including pulmonary fibrosis or radiation
pneumonitis), has current interstitial lung disease (ILD), or is suspected to have
such disease by imaging during screening.
- Clinically severe pulmonary compromise (based on Investigator's assessment) resulting
from intercurrent pulmonary illnesses including, but not limited to:
- Any underlying pulmonary disorder (eg, pulmonary emboli within three months of
the study enrollment, severe asthma, severe chronic obstructive pulmonary
disease, restrictive lung disease, pleural effusion);
- Any autoimmune, connective tissue or inflammatory disorders with pulmonary
involvement (eg, rheumatoid arthritis, Sjogren's syndrome, sarcoidosis); OR prior
- Is receiving chronic systemic corticosteroids dosed at >10 mg prednisone or equivalent
or any form of immunosuppressive therapy prior to Cycle 1, Day 1. Participants who
require use of bronchodilators, inhaled steroids, or local steroid injections may be
included in the study.
- Evidence of any leptomeningeal disease.
- Evidence of clinically active spinal cord compression or brain metastases, defined as
untreated and symptomatic, or requiring therapy with corticosteroids or
anticonvulsants to control associated symptoms. Participants with clinically inactive
or treated brain metastases who are asymptomatic (ie, without neurologic signs or
symptoms and do not require treatment with corticosteroids or anticonvulsants) may be
included in the study.
- Inadequate washout period prior to Cycle 1, Day 1, defined as:
- Whole brain radiation therapy <14 days or stereotactic brain radiation therapy <7
- Any systemic anticancer (excluding osimertinib in all Dose Escalation Cohorts and
in Second-Line Dose Expansion [Arms 1, 2, and 1b]), including investigational
agents, <14 days or 5 half-lives, whichever is longer
- Immune checkpoint inhibitor therapy <5 half-lives
- Major surgery (excluding placement of vascular access) <4 weeks
- Radiotherapy treatment to more than 30% of the bone marrow or with a wide field
of radiation < 28 days or palliative radiation therapy <14 days
- Chloroquine or hydroxychloroquine ≤14 days
- Medications or herbal supplemented known to be strong inducers of cytochrome P450
(CYP) 3A4 <21 days.
- Has unresolved toxicities from previous anticancer therapy, defined as toxicities
(other than alopecia) not yet resolved to National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI-CTCAE) version 5.0, Grade ≤1 or baseline. Subjects
with chronic Grade 2 toxicities may be eligible per the discretion of the Investigator
after consultation with the Sponsor Medical Monitor or designee.
- Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to
swallow osimertinib, or previous significant bowel resection that would preclude
adequate absorption of osimertinib.
- Has any primary malignancy other than locally advanced or metastatic NSCLC within 3
years prior to Cycle 1, Day 1, except adequately resected non-melanoma skin cancer,
curatively treated in situ disease, or other solid tumors curatively treated.
- Uncontrolled or significant cardiovascular disease prior to Cycle 1, Day 1, including:
- Mean corrected QT interval using Fridericia's formula (QTcF) prolongation
interval of >470 ms for females and >450 ms for males in 3 successive screening
- Left ventricular ejection fraction (LVEF) <50% by either echocardiogram (ECHO) or
multigated acquisition (MUGA) scan
- Uncontrolled hypertension (resting systolic blood pressure >180 mmHg or diastolic
blood pressure >110 mmHg)
- Myocardial infarction within 6 months
- New York Heart Association (NYHA) Classes 2 to 4 congestive heart failure within
- Uncontrolled angina pectoris within 6 months
- Has cardiac arrhythmia requiring antiarrhythmic treatment
- Complete left or right bundle branch block within 6 months
- History of second- or third-degree heart block or PR interval >250 ms within 6
- History of clinically relevant ventricular arrhythmias, such as ventricular
tachycardia, ventricular fibrillation, or Torsade de Pointes
- Has any factors that increase the risk of corrected QT (QTc) prolongation or risk
of arrhythmic events, such as heart failure, hypokalemia, congenital long QT
syndrome, family history of long QT syndrome, or unexplained sudden death under
40 years of age in first-degree relatives, or any concomitant medication known to
prolong the QT interval
- Has clinically significant corneal disease
- Any evidence of severe or uncontrolled diseases including active bleeding diatheses,
active infection, psychiatric illness/social situations, geographical factors,
substance abuse, or other factors which in the Investigator's opinion makes it
undesirable for the subject to participate in the study or which would jeopardize
compliance with the protocol. Screening for chronic conditions is not required.