Trial design This is a prospective, multicenter, single-arm, window-of-opportunity study
evaluating the biological effect of patritumab deruxtecan in treatment naïve patients with
HR-positive/HER2-negative early breast cancer, whose primary tumors are ≥1 cm by ultrasound
evaluation. Patients will be enrolled in four cohorts according to the mRNA-based ERBB3
expression by central assessment. The objective of the study is to evaluate biological
activity of patritumab deruxtecan in patients with treatment naïve early breast cancer. The
primary endpoint is CelTIL score after one single-dose of U3-1402. A translational research
plan is also included to provide biological information and to evaluate secondary and
exploratory objectives of the study.
1. Written ICF for all study procedures according to local regulatory requirements prior
to beginning specific protocol procedures.
2. Premenopausal or postmenopausal women and men, age ≥ 18 years.
3. ECOG Performance Status 0 - 1.
4. Histologically confirmed non-metastatic primary invasive adenocarcinoma of the breast
untreated and recently diagnosed, with all the following characteristics:
- At least one lesion that can be measured in at least 1 dimension with ≥ 1 cm in
largest diameter measured by ultrasound.
- Absence of distant metastasis (M0) as determined by institutional practice.
- In the case of a multifocal tumor (defined as the presence of two or more foci of
cancer within the same breast quadrant), the largest lesion must be ≥ 1 cm and
designated the "target" lesion for all subsequent tumor evaluations and biopsies.
5. Patient must have biopsiable disease.
6. Estrogen (ER)-positive and/or Progesterone (PgR)-positive and HER2-negative tumor by
the most recent American Society of Clinical Oncology - College of American
Pathologists (ASCO-CAP) guidelines: ER and PgR defined as IHC nuclear staining >1% and
HER2 negative locally assessed.
7. Ki67% ≥ 10% locally assessed (Dowsset et al. Journal of the National Cancer Institute,
103 (22), 1656-1664. 2011).
8. Available pre-treatment FFPE core needle biopsy evaluable for PAM50 and ERBB3 mRNA
expression. Minimal sample requirements are to have at least 2 tumor cylinders with a
minimal tissue surface of 10 mm2 tissue, containing at least 50% tumor cells and
having enough tissue to do at least 20 cuts of 4 μm each. Macrodissection is allowed
when needed. If archival tissue is either insufficient or unavailable, a new biopsy
from the pretreated tumor must be obtained. Patients whose tumor tissue is not
evaluable for ERBB3 expression central testing are not eligible.
9. Baseline LVEF ≥ 50% measured by echocardiography (ECHO) or Multiple Gate Acquisition
10. Adequate organ function, as determined by the following laboratory tests prior to
- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
- Platelet count ≥ 100 x 109/L
- Hemoglobin ≥ 9 g/dL (red blood cell transfusion and/or erythropoietin
o Serum creatinine ≤ 1.5 x upper limit of normal (ULN), or 24-hour creatinine
clearance ≥ 60 mL/min for subject with creatinine levels > 1.5 x ULN. (Note:
Creatinine clearance does not need to be determined if the baseline serum
creatinine is within normal limits. Creatinine clearance should be calculated per
- Serum bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for a subject with
total bilirubin level > 1.5 x ULN
- Aspartate aminotransferase (AST) ≤ 3 x ULN
- Alanine aminotransferase (ALT) ≤ 3 x ULN
- Coagulation International normalization ratio (INR) or prothrombin time (PT)
≤ 1.5 x ULN
- Partial thromboplastin time (PTT) or activated PTT (aPTT) ≤ 1.5 x ULN
11. Absence of any psychological, familial, sociological or geographical condition
potentially hampering compliance with the study protocol and follow-up schedule; those
conditions should be discussed with the patient before registration in the trial.
12. Female subject of childbearing potential should have a negative urine or serum
pregnancy test within 7 days prior to enrollment. If urine pregnancy test is positive
or cannot be confirmed as negative, a serum pregnancy test will be required. Pregnancy
testing does not need to be pursued in patients who are judged as postmenopausal
before randomization, as determined by local practice, or who have undergone bilateral
oophorectomy, total hysterectomy, or bilateral tubal ligation. Women of childbearing
potential randomized to the treatment must use adequate contraception for the duration
of protocol treatment and after 7 months after the study drug administration (see
1. Inoperable locally advanced or inflammatory (i.e., inoperable Stage III) breast
2. Metastatic (Stage IV) breast cancer.
3. Bilateral invasive breast cancer.
4. Patients in whom a primary tumor excisional biopsy was performed.
5. Any prior treatment for primary actual invasive breast cancer.
6. Prior treatment with a HER3 antibody, topoisomerase I inhibitor, with an ADC which
consists of an exatecan derivative that is a topoisomerase I inhibitor (e.g., DS-8201)
and with a govitecan derivative (e.g., IMMU-132).
7. Medical history of symptomatic congestive heart failure (New York Heart Association
classes II-IV) or serious cardiac arrhythmia requiring treatment; myocardial
infarction within 6 months prior to randomization or unstable angina.
8. QT interval corrected using Fridericia's formula to > 450 millisecond (ms) in males
and > 470 ms in females.
9. 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.
10. Medical history of clinically significant lung diseases (e.g., interstitial pneumonia,
pneumonitis, pulmonary fibrosis, and severe radiation pneumonitis) or who are
suspected to have these diseases by imaging at screening period.
11. Clinically significant corneal disease.
12. Major surgical procedure or significant traumatic injury within 28 days prior to
13. Assessment by the investigator to be unable or unwilling to comply with the
requirements of the protocol.
14. History of other malignancy within the last 3 years, except for appropriately treated
carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer,
or other malignancies with an expected curative outcome.
15. Current severe, uncontrolled systemic disease (e.g. clinically significant
cardiovascular, pulmonary or metabolic disease; wound healing disorders; ulcers; bone
16. Concurrent, serious, uncontrolled infections or current known infection with HIV or
active hepatitis B and/or hepatitis C.
17. History of significant co-morbidities that, in the judgment of the investigator, may
interfere with the conduction of the study, the evaluation of response, or with ICF.
18. Known hypersensitivity to either the drug substance components (including an antibody,
a drug-linker, or a topoisomerase I inhibitor) or inactive ingredients in the drug
product or history of severe hypersensitivity reactions to other monoclonal
19. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses
including, but not limited to, any underlying pulmonary disorder (i.e. pulmonary
emboli within three months of the study enrollment, severe asthma, severe COPD,
restrictive lung disease, pleural effusion etc.), and any autoimmune, connective
tissue or inflammatory disorders with potential pulmonary involvement (i.e. rheumatoid
arthritis, Sjögren's syndrome, sarcoidosis etc.), or prior pneumonectomy.
20. 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