Patritumab Deruxtecan (U3-1402) in Unresectable Locally Advanced or Metastatic Breast Cancer

Inclusion Criteria:

• Adults with histologically-confirmed HER2 negative, unresectable locally advanced ormetastatic breast cancer that is hormone receptor positive (HR+) at the time of thefirst breast cancer diagnosis

• Participants with a documented radiologic unresectable or metastatic progression

• Participants may have received anthracyclines and taxanes as (neo) adjuvanttreatment and must have received one line of chemotherapy for Advanced breast cancer (ABC), but not more than one line. Participants must have a clinically orradiologically documented evidence of tumor progression on or after cyclin dependentkinase 4/6 (CDK 4/ 6) inhibitor combined with endocrine therapy. Previous treatmentswith PI3K inhibitors, mTOR inhibitors, AKT-inhibitors and poly ADP ribose polymerase (PARP)-inhibitors are allowed

• Participants must have a tumor site easily accessible to biopsy (with exception ofbone metastasis)

• Participants must have at least one radiologically measurable lesion (different fromthe biopsy site)

• Participants must have an ECOG PS equals to 0 or 1

• Participants must have a life expectancy of 12 weeks or more

• Participants must have adequate bone marrow reserve and organ function, based onlocal laboratory data within 14 days prior to Cycle 1, Day 1

• Females of reproductive/childbearing potential must have a negative pregnancy testat screening and must agree to use a highly effective form of contraception or avoidintercourse during the study and for at least 7 months after the last dose of studydrug.

Contraceptive methods considered highly effective:

1. Intrauterine device (IUD)

2. Bilateral tubal occlusion

3. Vasectomized partner

4. Complete sexual abstinence during and upon completion of the study and for at least 7 months for females after the last dose of study drug

Female participants must not donate, or retrieve for their own use, ova from the time of screening and for at least 7 months after the final study drug administration

-If male, the participant must be surgically sterile, must withhold heterosexual intercourse, or must be willing to use a highly effective birth control upon enrollment, and for at least 4 months following the last dose of study drug

Male participants must not freeze or donate sperm starting at screening and throughout the study period, and for at least 4 months after the final study drug administration

• Participant must understand, sign, and date the written ICF prior to anyprotocol-specific procedures performed. Participant should be able and willing tocomply with study visits and procedure as per protocol

• Participant must be affiliated to a social security system or beneficiary of thesame

Exclusion Criteria:

• Breast cancer amenable for resection or radiation therapy with curative intent

• Any history of interstitial lung disease (ILD), actual ILD, or a suspicion of an ILD

• Clinically severe pulmonary 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 disorder with pulmonaryinvolvement

3. OR prior pneumonectomy

• The use of chronic systemic corticosteroids at a dose superior to 10 mg ofprednisone or equivalent or any form of immunosuppressive therapy prior to Cycle 1Day 1. Participants who require use of bronchodilators, inhaled steroids, or localsteroid injections may be included in the study

• Evidence of any leptomeningeal disease

• Evidence of corneal disease

• Any evidence of severe or uncontrolled systemic diseases including active bleedingdiatheses, active infection, psychiatric illness/social situations, geographicalfactors, substance abuse, or other factors which in the investigator's opinion makesit undesirable for the participant to participate in the study or which wouldjeopardize compliance with the protocol

• Evidence of clinically active spinal cord compression or brain metastases defined asuntreated and symptomatic, or requiring therapy with corticosteroids oranticonvulsants to control associated symptoms

• Inadequate washout period prior to Cycle 1 Day 1, defined as:

1. Whole brain radiation therapy within 14 days before treatment or stereotacticbrain radiation therapy, within 7 days before treatment

2. Any cytotoxic chemotherapy, investigational agents or other anticancer drug(s)from a previous cancer treatment regimen or clinical study, within 14 daysbefore treatment or 5 half-lives, whichever is longer

3. Immune checkpoint inhibitor therapy, within 21 days before treatment

4. Endocrine therapy within 21 days of treatment

5. Major surgery (excluding placement of vascular access) within 28 days oftreatment

6. Radiotherapy treatment to more than 30% of the bone marrow or with a wide fieldof radiation within 28 days or palliative radiation therapy within 14 days oftreatment

7. Chloroquine or hydroxychloroquine within 14 days before treatment

8. Live virus vaccination, within 28 days before treatment

• Prior treatment with an anti-HER3 antibody and/or ADC containing an exatecanderivative that is a topoisomerase I inhibitor

• Participants with a grade equals or greater than 2 unresolved toxicities fromprevious anticancer therapy (other than alopecia)

• A history of severe hypersensitivity reactions to either the drug substances orinactive ingredients of U3-1402, or to other monoclonal antibodies

• Any evidence of primary malignancy other than locally advanced or metastatic lungcancer within three years prior to Cycle 1 Day 1, except adequately resectednon-melanoma skin cancer, curatively treated in-situ disease, or other solid tumorscuratively treated

• Uncontrolled or significant cardiovascular disease prior to Cycle 1 Day :

1. Corrected QT interval higher than 470 ms for females and 450 ms for malesaccording to Fridericia's formula (QTcF) and assessed based on triplicate ECGs,approximately 1 minute apart

2. Left ventricular ejection fraction (LVEF) less than 50% by either ECHO orcardiac MRI or multigated acquisition scan (MUGA)

3. Resting systolic blood pressure higher than 140 mmHg or diastolic bloodpressure higher than 90 mmHg

4. Myocardial infarction within six months

5. Symptomatic congestive heart failure (NYHA Classes 2 to 4 within 28 days beforetreatment)

6. Uncontrolled angina pectoris within six months.

7. Cardiac arrhythmia requiring antiarrhythmic treatment

• Active hepatitis B and/or hepatitis C infection, such as those with serologicevidence of viral infection within 28 days of Cycle 1, Day 1.

1. Hepatitis surface antigen (HBsAg) negative and hepatitis B core antibody (anti-HBc) positive; OR

2. HBsAg positive and HBV DNA viral load is documented to be equal or less than 2,000 IU/mL in the absence of anti-viral therapy and during the previous 12weeks prior to the viral load evaluation with normal transaminases (in theabsence of liver metastasis); OR

3. HBsAg positive and HBV DNA viral load is documented to be equal or less than 2,000 IU/mL in the absence of anti-viral therapy and during the previous 12weeks prior to the viral load evaluation with liver metastasis and abnormaltransaminases AST/ALT less than 3 ULN

Participants with a history of Hepatitis C infection will be eligible for enrollment only if the viral load according to local standards of detection, is documented to be below the level of detection in the absence of anti-viral therapy during the previous 12 weeks (ie, sustained viral response according to the local product label but no less than 12 weeks, whichever is longer)

• Known human immunodeficiency virus (HIV) or active COVID-19 infection

• Participants under guardianship or deprived of his/her liberty by a judicial oradministrative decision or incapable of giving his/her consent

• Female participants who are pregnant or breastfeeding or intend to become pregnantduring the study

• Participation in another clinical trial evaluating an experimental drug (exceptnon-interventional research)

• Evidence of clinically active spinal cord compression or brain metastases, definedas untreated and symptomatic, or requiring therapy with corticosteroids oranticonvulsants to control associated symptoms. Participants with clinicallyinactive or treated brain metastases who are asymptomatic (ie, without neurologicsigns or symptoms and do not require treatment with corticosteroids oranticonvulsants) may be included in the study. Participants must have a stableneurologic status for at least 2 weeks prior to Cycle 1 Day 1

• Inadequate washout period prior to Cycle 1 Day 1, defined as:

1. Whole brain radiation therapy within 14 days before treatment or stereotacticbrain radiation therapy, within 7 days before treatment

2. Any cytotoxic chemotherapy, investigational agents or other anticancer drug(s)from a previous cancer treatment regimen or clinical study, within 14 daysbefore treatment or 5 half-lives, whichever is longer

3. Immune checkpoint inhibitor therapy, within 21 days before treatment

4. Endocrine therapy within 21 days before treatment

5. Major surgery (excluding placement of vascular access), within 28 days beforetreatment

6. Radiotherapy treatment to more than 30% of the bone marrow or with a wide fieldof radiation, within 28 days before treatment or palliative radiation therapywithin 14 days before treatment

7. Chloroquine or hydroxychloroquine within 14 days before treatment.

8. Live virus vaccination, within 28 days before treatment

• Prior treatment with an anti-HER3 antibody and/or ADC containing an exatecanderivative that is a topoisomerase I inhibitor (eg, trastuzumab deruxtecan).

• Participants with grade ≥2 unresolved toxicities from previous anticancer therapy (other than alopecia), as defined by the NCI-CTCAE version 5.0

• Participant with a known hypersensitivity to either the drug substances or inactiveingredients in the drug product Participant with a history of severehypersensitivity reactions to other monoclonal antibodies Participant has anyprimary malignancy other than locally advanced or metastatic breast cancer within 3years 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:

1. Corrected QT interval higher than 470 ms for females and 450 ms for malesaccording to Fridericia's formula (QTcF) and assessed based on triplicate ECGs,approximately 1 minute apart

2. Left ventricular ejection fraction (LVEF) less than 50% by either ECHO orcardiac MRI

3. Resting systolic blood pressure higher than 140 mmHg or diastolic bloodpressure higher than 90 mmHg

4. Myocardial infarction within six months

5. NYHA Classes 2 to 4 within 28 days before treatment

6. Uncontrolled angina pectoris within six months.

7. Cardiac arrhythmia requiring antiarrhythmic treatment

• Participants with past or resolved hepatitis B virus (HBV) infection are eligibleif:

1. Hepatitis surface antigen (HBsAg) negative and hepatitis B core antibody (anti-HBc) positive; OR

2. HBsAg positive and HBV DNA viral load is documented to be equal or less than 2,000 IU/mL in the absence of anti-viral therapy and during the previous 12weeks prior to the viral load evaluation with normal transaminases (in theabsence of liver metastasis); OR

3. HBsAg positive and HBV DNA viral load is documented to be equal or less than 2,000 IU/mL in the absence of anti-viral therapy and during the previous 12weeks prior to the viral load evaluation with liver metastasis and abnormaltransaminases AST/ALT less than 3 ULN

Participants with a history of Hepatitis C infection will be eligible for enrollment only if the viral load according to local standards of detection, is documented to be below the level of detection in the absence of anti-viral therapy during the previous 12 weeks (ie, sustained viral response according to the local product label but no less than 12 weeks, whichever is longer)

• Female participant who is pregnant or breastfeeding or intends to become pregnantduring the study

• Participants with human immunodeficiency virus (HIV)

• Participants with any psychological, familial, sociological or geographicalcondition potentially hindering compliance with the study protocol procedures andfollow-up schedule Participants under guardianship or deprived of his liberty by ajudicial or administrative decision or incapable of giving its consent.

• Participation in another clinical trial evaluating an experimental drug (exceptnon-interventional research