Developing ctDNA Guided Adjuvant Therapy for Gastrooesophageal Cancer

Inclusion Criteria:

• Pathologically documented adenocarcinoma of the stomach (clinical stage beforesurgery of AJCC I-III), gastroesophageal junction, or lower oesophagus (to includeType I Siewert only), with HER2 overexpression (IHC 3+ or IHC 2+/ISH+) based onlocal tissue testing results.

• ctDNA positive after surgery as per Signatera assay

• Capable of giving signed informed consent prior to any mandatory study specificprocedures, sampling, or analyses and which includes compliance with therequirements and restrictions listed in the ICF and in this protocol.

• Male and female participants must be at least 18 years of age at the time of signingthe ICF.

• Treated with neoadjuvant chemotherapy before surgery for at least six weeks.

• Surgical resection with clear margins (R0).

• Recovered from surgery in the opinion of the investigator.

• No previous treatment with trastuzumab or other HER2 directed therapy.

• No evidence of metastatic disease on post-surgical CT.

• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

• Has LVEF ≥ 50% by either echocardiogram (ECHO) or multigated acquisition (MUGA) scanwithin 28 days before treatment.

• Has adequate organ and bone marrow function within 14 days before treatmentallocation as below:

• Platelet count ≥ 100x109/L (Platelet transfusion is not allowed within 1 week priorto screening assessment, use of thrombopoietin receptor agonists is not allowedwithin 2 weeks prior to screening assessment)

• Haemoglobin ≥ 80 g/L. Participants requiring transfusions or growth factor supportto maintain haemoglobin ≥ 80 g/L are not eligible. (Red blood cell transfusions isnot allowed within 1 week prior to screening assessment)

• Absolute neutrophil count ≥ 1.5 x 109/L (granulocyte-colony stimulating factor [G-CSF] administration is not allowed within 1 week prior to screening assessment

• ALT/AST ≤ 3 x ULN

• Total bilirubin ≤ 1.5 x ULN or < 3 x ULN in the presence of documented Gilbert'sSyndrome (unconjugated hyperbilirubinemia)

• Serum albumin ≥ 3.0 g/dl

• Creatinine clearance ≥ 50 mL/min as calculated using the Cockcroft-Gault equation

• Adequate clotting function International Normalized Ratio (INR) or prothrombin timeand either partial thromboplastin or activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN.

• Reproduction:

• Evidence of post-menopausal status or negative serum pregnancy test for females ofchildbearing potential who are sexually active with a non-sterilised male partner.

• For women of childbearing potential, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be available at thescreening visit and urine beta-human chorionic gonadotropin (β-HCG) pregnancy testprior to each administration of IMP.

• Women of childbearing potential are defined as those who are not surgically sterile (i.e., underwent bilateral salpingectomy, bilateral oophorectomy, or completehysterectomy) or post-menopausal.

I. Women aged <50 years will be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the site.

II. Women aged ≥ 50 years will be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses >1 year ago.

• Female participants of childbearing potential who are sexually active with anon-sterilised male partner must use at least one highly effective method ofcontraception from the time of screening, and must agree to continue using suchprecautions for 7 months after the last dose of IMP. Not all methods ofcontraception are highly effective.

• Female participants must refrain from breastfeeding and must not donate (or retrievetheir own for use) ova, from the time of screening, throughout the study treatmentperiod, and for at least 7 months after the last dose of IMP.

• Complete heterosexual abstinence for the duration of the study and drug washoutperiod is an acceptable contraceptive method if it is in line with the patient'susual lifestyle (consideration must be made to the duration of the clinical trial);however, periodic or occasion abstinence, the rhythm method, and the withdrawalmethod are not acceptable methods of contraception.

• Non-sterilised male participants who are sexually active with a female partner ofchildbearing potential must use a condom with spermicide from screening to 4 monthsafter the final dose of IMP.

• It is strongly recommended for the female partners of a male participant to also useat least one highly effective method of contraception throughout this period. Inaddition, male participants should refrain from fathering a child or freezing ordonating sperm from screening, throughout the study treatment period, and for atleast 4 months after the last dose of IMP.

• Investigators should advise male participants on the conservation of sperm prior tostarting treatment because of the possibility of irreversible infertility/testiculardamage due to IMP administered in this study.

• Female subjects must not donate, or retrieve for their own use, ova from the time ofenrolment and throughout the study treatment period, and for at least 7 months afterthe final study drug administration. They should refrain from breastfeedingthroughout this time. Preservation of ova prior to enrolment in this study, can bediscussed with the patient if clinically appropriate to do so.

Exclusion Criteria:

• Uncontrolled intercurrent illness, including but not limited to, ongoing or activeinfection, or psychiatric illness/social situations that would limit compliance withstudy requirement, substantially increase risk of incurring AE's, or compromise theability of the participant to give written informed consent.

• Participants with a medical history of myocardial infarction within 6 months beforetreatment or symptomatic CHF (New York Heart Association Class II to IV), unstableangina pectoris, clinically important cardiac arrhythmias, or a recent (<6 months)cardiovascular event, including myocardial infarction, unstable angina pectoris, andstroke. Participants with troponin levels above ULN at screening (as defined by themanufacturer)m and without myocardial related symptoms, should have a cardiologicconsultation before enrolment to rule out myocardial infarction.

• Corrected QT interval (QTcF) prolongation to > 470 msec (females) or > 450 msec (males) based on average of the screening triplicate 12-lead ECG

• History of (non-infectious) ILD/pneumonitis, current ILD/pneumonitis, or wheresuspected ILD/pneumonitis cannot be ruled out by imaging at screening.

• Any of the following:

1. Lung-specific intercurrent clinically significant illnesses including, but notlimited to, any underlying pulmonary disorder (e.g., clinically significantpulmonary emboli within 3 months of treatment, severe asthma, severe chronicobstructive pulmonary disease, restrictive lung disease, clinically significantpleural effusion etc.)

2. Any autoimmune, connective tissue, or inflammatory disorders with pulmonaryinvolvement (e.g., rheumatoid arthritis, Sjogren's, sarcoidosis etc.), wherethere is documented, or a suspicion of, pulmonary involvement at the time ofscreening

3. Prior pneumonectomy (complete)

• Uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, orantifungals

• Multiple primary malignancies within the prior 3 years, except adequately resectednon-melanoma skin cancer, curatively treated in situ disease, or other solid tumourscuratively treated.

• A pleural effusion, ascites or pericardial effusion that requires drainage,peritoneal shunt.

• Unresolved toxicities from previous anticancer therapy, defined as toxicities (otherthan alopecia) not yet resolved to Grade ≤1 or baseline. The following exemptionwill apply; stable chronic G2 toxicity which in the opinion of the investigator isnot reasonably expected to be exacerbated by treatment with study drugs.

• Known allergy or hypersensitivity to T-DXd or any of the study drug components

• History of severe hypersensitivity reactions or other monoclonal antibodies

• Pregnant or breastfeeding female participants, or participants who are planning tobecome pregnant

• Involvement in the planning and/or conduct of the study

• Has substance abuse or any other medical conditions, that may, in the opinion of theinvestigator, interfere with the subjects participation in the clinical study orevaluation of the clinical study results

• Receipt of live, attenuated vaccine within 30 days prior to the first dose oftrastuzumab deruxtecan. Note: Patients, if enrolled, should not receive live vaccineduring the study and up to 30 days after the last dose of IMP

• Active primary immunodeficiency, known human immunodeficiency virus (HIV) infection,or active hepatitis B or C infection. Patients positive for hepatitis (HCV) antibodyare eligible only if polymerase chain reaction is negative for HCV RNA.

• Judgement by the Investigator that the participant should not participate in thestudy, if the participant is unlikely to comply with study procedures, restrictions,and requirements.