A Phase II, Trial of Neoadjuvant Trastuzumab + Durvalumab + FLOT Targeted Immunochemotherapy

Inclusion Criteria:

• 1. The subject must provide written informed consent prior to any study-specific procedures after receiving adequate information regarding the study.

  2. The subject must be ≥19 years of age. 3. Body weight >30 kg. 4. Histologically documented adenocarcinoma of the stomach or gastroesophageal junction (GEJ) with available HER2 IHC results.

  5. Confirmed HER2-positive disease, defined as HER2 IHC 3+ or HER2 IHC 2+/SISH-positive.

  6. Locally advanced, resectable gastric or gastroesophageal junction cancer as determined by the investigator (e.g., cT2 or higher and/or node-positive disease), with no unequivocal distant organ metastasis and for whom perioperative treatment is considered indicated.

  7. ECOG performance status of 0-1, with no deterioration between screening and the first dose of study treatment.

  8. Left ventricular ejection fraction (LVEF) ≥50% as assessed by echocardiography (ECHO) within 28 days prior to treatment.

  9. Measurable target disease as assessed by the investigator according to modified RECIST version 1.1.

  10. Adequate organ, bone marrow, hepatic, and renal function within 28 days prior to treatment.

Note: No transfusion of red blood cells or platelets and no administration of G-CSF are permitted from 14 days prior to assessment of bone marrow function through C1D1.

• Hemoglobin ≥9.0 g/dL (≥8.0 g/dL for the gastric cancer indication)
• Platelet count ≥100 × 10⁹/L
• Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L
• Total bilirubin ≤1.5 × ULN, except in patients with documented Gilbert syndrome (unconjugated hyperbilirubinemia), for whom \<3 × ULN is acceptable
• AST (SGOT)/ALT (SGPT) ≤3.0 × ULN
• Serum albumin ≥2.5 g/dL
• Creatinine clearance (CrCL/Ccr) ≥30 mL/min, calculated using the Cockcroft-Gault formula with actual body weight
• INR, PT, or APTT ≤1.5 × ULN 11. Female subjects must use a highly effective method of contraception throughout the study and for 15 months after permanent discontinuation of the study drugs, including the agents used in neoadjuvant and postoperative adjuvant treatment. The overall contraception period has been aligned with the locally approved labeling for oxaliplatin, which recommends contraception for 15 months in women of childbearing potential. If the most recent local prescribing information for any study drug specifies a longer contraception period, that requirement will take precedence.

At screening, there must be evidence that the patient is not breastfeeding and is either not of childbearing potential or has a negative pregnancy test, as defined by at least one of the following:

• Postmenopausal status, defined as age ≥50 years and amenorrhea for at least 12 months after cessation of all exogenous hormonal therapy
• Documented irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy; tubal ligation alone is not sufficient
• Amenorrhea for 12 months with serum FSH, LH, and plasma estradiol levels within the institution's postmenopausal range Further details are provided in Appendix F (Definition and Acceptable Methods of Contraception for Women of Childbearing Potential).

Female subjects must not breastfeed and must not donate or retrieve ova from screening until 60 days after the last dose.

12. Male subjects who are sexually active with a female partner of childbearing potential and who have not undergone sterilization must use a condom with spermicide from screening until 12 months after the final dose of study treatment.

Complete heterosexual abstinence during the study and drug washout period is acceptable if this is consistent with the patient's usual and preferred lifestyle. Periodic abstinence, calendar/rhythm methods, and withdrawal are not acceptable methods of contraception.

Female partners of male subjects are strongly encouraged to use at least one highly effective method of contraception throughout this period.

Male subjects must also refrain from fathering a child and from cryopreserving or donating sperm from enrollment through the study period and for 12 months after the final dose of study treatment. If the latest local prescribing information for any study drug specifies a longer contraception period, that requirement will take precedence.

Exclusion Criteria:

Inclusion Criteria

1. The subject must provide written informed consent prior to any study-specific procedures after receiving adequate information regarding the study.
2. The subject must be ≥19 years of age.
3. Body weight >30 kg.
4. Histologically documented adenocarcinoma of the stomach or gastroesophageal junction (GEJ) with available HER2 IHC results.
5. Confirmed HER2-positive disease, defined as HER2 IHC 3+ or HER2 IHC 2+/SISH-positive.
6. Locally advanced, resectable gastric or gastroesophageal junction cancer as determined by the investigator (e.g., cT2 or higher and/or node-positive disease), with no unequivocal distant organ metastasis and for whom perioperative treatment is considered indicated.
7. ECOG performance status of 0-1, with no deterioration between screening and the first dose of study treatment.
8. Left ventricular ejection fraction (LVEF) ≥50% as assessed by echocardiography (ECHO) within 28 days prior to treatment.
9. Measurable target disease as assessed by the investigator according to modified RECIST version 1.1.

10. Adequate organ, bone marrow, hepatic, and renal function within 28 days prior to treatment.

    Note: No transfusion of red blood cells or platelets and no administration of G-CSF are permitted from 14 days prior to assessment of bone marrow function through C1D1.

    • Hemoglobin ≥9.0 g/dL (≥8.0 g/dL for the gastric cancer indication)
    • Platelet count ≥100 × 10⁹/L
    • Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L
    • Total bilirubin ≤1.5 × ULN, except in patients with documented Gilbert syndrome (unconjugated hyperbilirubinemia), for whom \<3 × ULN is acceptable
    • AST (SGOT)/ALT (SGPT) ≤3.0 × ULN
    • Serum albumin ≥2.5 g/dL
    • Creatinine clearance (CrCL/Ccr) ≥30 mL/min, calculated using the Cockcroft-Gault formula with actual body weight
    • INR, PT, or APTT ≤1.5 × ULN

11. Female subjects must use a highly effective method of contraception throughout the study and for 15 months after permanent discontinuation of the study drugs, including the agents used in neoadjuvant and postoperative adjuvant treatment. The overall contraception period has been aligned with the locally approved labeling for oxaliplatin, which recommends contraception for 15 months in women of childbearing potential. If the most recent local prescribing information for any study drug specifies a longer contraception period, that requirement will take precedence.

    At screening, there must be evidence that the patient is not breastfeeding and is either not of childbearing potential or has a negative pregnancy test, as defined by at least one of the following:

    • Postmenopausal status, defined as age ≥50 years and amenorrhea for at least 12 months after cessation of all exogenous hormonal therapy
    • Documented irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy; tubal ligation alone is not sufficient
    • Amenorrhea for 12 months with serum FSH, LH, and plasma estradiol levels within the institution's postmenopausal range Further details are provided in Appendix F (Definition and Acceptable Methods of Contraception for Women of Childbearing Potential).

    Female subjects must not breastfeed and must not donate or retrieve ova from screening until 60 days after the last dose.

12. Male subjects who are sexually active with a female partner of childbearing potential and who have not undergone sterilization must use a condom with spermicide from screening until 12 months after the final dose of study treatment.

Complete heterosexual abstinence during the study and drug washout period is acceptable if this is consistent with the patient's usual and preferred lifestyle. Periodic abstinence, calendar/rhythm methods, and withdrawal are not acceptable methods of contraception.

Female partners of male subjects are strongly encouraged to use at least one highly effective method of contraception throughout this period.

Male subjects must also refrain from fathering a child and from cryopreserving or donating sperm from enrollment through the study period and for 12 months after the final dose of study treatment. If the latest local prescribing information for any study drug specifies a longer contraception period, that requirement will take precedence.

Exclusion Criteria

1. Patients with unequivocal peritoneal metastasis, including malignant cells detected in peritoneal fluid, or with distant metastasis.
2. Known dihydropyrimidine dehydrogenase (DPD) deficiency. DPD deficiency must be assessed according to applicable local and/or institutional requirements.
3. Uncontrolled intercurrent illness, including but not limited to ongoing or active infection, uncontrolled hypertension, significant chronic gastrointestinal disease associated with diarrhea, or psychiatric illness/social circumstances that would limit study compliance, significantly increase the risk of adverse events, or impair the patient's ability to provide written informed consent.
4. Unresolved toxicity of Grade ≥2 according to CTCAE v5.0 from prior therapy, except for vitiligo, alopecia, endocrine disorders controlled with hormone replacement therapy, or asymptomatic laboratory abnormalities.
5. History of organ transplantation.

6. Active primary immunodeficiency, a history of active primary immunodeficiency, or active infectious disease.

   Active or previously documented autoimmune or inflammatory disorders at screening, including but not limited to:

   • inflammatory bowel disease (IBD; e.g., Crohn's disease, ulcerative colitis, or diverticulitis)
   • systemic lupus erythematosus (SLE)
   • sarcoidosis syndrome
   • tuberculosis
   • Wegener's syndrome
   • myasthenia gravis
   • Graves' disease
   • rheumatoid arthritis
   • hypophysitis
   • uveitis For studies involving known hepatotoxicity or other relevant risks, consideration should also be given to a history of organ transplantation requiring immunosuppressive therapy within the previous 2 years, glomerulonephritis, nephrotic syndrome, Fanconi syndrome, or renal tubular acidosis.

   Exceptions include:

   • Subjects with vitiligo, alopecia, hypothyroidism stable on hormone replacement therapy (e.g., following Hashimoto syndrome), psoriasis not requiring systemic treatment, or celiac disease controlled by diet alone
   • Subjects with no active disease within the previous 5 years may be eligible after consultation with the principal investigator
   • HBsAg carriers without active viral infection who are receiving entecavir prophylaxis may be eligible
7. History of interstitial lung disease (ILD)/pneumonitis requiring steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be excluded by screening imaging.

8. Active hepatitis B (HBsAg-positive) or active hepatitis C. Viral quantification is not mandatory for study eligibility. Patients with prior or resolved HBV or HCV infection may be eligible.

   Note: If HBsAg-negative, patients must have discontinued antiviral therapy for at least 6 months.

9. Subjects with prior or resolved HBV infection are eligible only if all of the following criteria are met:

   • anti-HBc positive (IgG or total Ig)
   • HBV DNA undetectable
   • no evidence of cirrhosis or fibrosis on prior imaging or biopsy
   • no concurrent or prior HCV infection
   • access to a local hepatitis B specialist during and after the study These subjects should be closely monitored for HBV reactivation. If the comparator treatment or combination study treatment carries a high risk of HBV reactivation and is incompatible with antiviral therapy, exclusion of all subjects with HBV infection should be considered.

10. Known positive test for human immunodeficiency virus (HIV; HIV-1/2 antibody-positive) or active tuberculosis infection based on clinical history, physical examination, radiographic findings, or local testing practice.

    Subjects with poorly controlled HIV infection are excluded. Well-controlled HIV infection requires all of the following:

    • undetectable viral RNA
    • CD4+ count ≥350 cells/μL
    • no history of AIDS-defining opportunistic infection within the previous 12 months
    • stable on the same antiretroviral regimen for at least 4 weeks, with no anticipated change in the number or type of antiretroviral agents If these criteria are met, monitoring of viral RNA load and CD4+ count is recommended. HIV testing may be performed if permitted by local regulations or the institutional IRB/IEC.

11. Patients meeting any of the following cardiac criteria:

    • Mean corrected QT interval using Fridericia's correction (QTcF ≥470 ms)
    • Any clinically significant abnormality in rhythm, conduction, or morphology on resting ECG, such as complete left bundle branch block, third-degree heart block, second-degree heart block, or PR interval >250 ms
    • Any factor increasing the risk of QT prolongation or arrhythmic events, including heart failure, uncorrectable chronic hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death before age 40 in a first-degree relative, or concomitant medications known to prolong the QT interval
    • Uncontrolled hypotension, defined as systolic BP \<90 mmHg and/or diastolic BP \<60 mmHg, or clinically relevant orthostatic hypotension including a ≥20 mmHg decrease in blood pressure
    • Atrial fibrillation with resting ventricular rate >100 bpm
    • Symptomatic heart failure (NYHA Class II-IV)
    • Symptomatic congestive heart failure (NYHA Class II-IV)
    • Known LVEF \<50%
    • Previous or current cardiomyopathy of any etiology
    • Previous or current acute myocardial infarction within the past 6 months
    • Severe valvular heart disease
    • Uncontrolled angina despite medical therapy (Canadian Cardiovascular Society Class II-IV)
    • Stroke or transient ischemic attack prior to screening
    • Acute coronary syndrome within 6 months prior to treatment initiation

12. Pregnant or breastfeeding women, or male or female subjects of childbearing potential who are unwilling to use effective contraception from screening until the specified period after the final dose of each study treatment, including trastuzumab, FLOT, durvalumab, and postoperative adjuvant XELOX:

    • 15 months for women of childbearing potential
    • 12 months for men These requirements are consistent with the inclusion criteria.
13. Known allergy or hypersensitivity to any study drug or any of its excipients.

14. Any of the following within 14 days prior to the first dose:

    • Current or prior significant chronic gastrointestinal disease associated with diarrhea, such as active inflammatory bowel disease
    • Active noninfectious skin disorder requiring systemic treatment, including rash, urticaria, dermatitis, ulceration, or psoriasis of any grade
    • Active or previously documented autoimmune or inflammatory disease requiring chronic treatment with steroids or other immunosuppressive therapy

    Exceptions include:

    • Intranasal, inhaled, topical corticosteroids, or local corticosteroid injections (e.g., intra-articular injection)
    • Systemic corticosteroids at physiologic doses not exceeding prednisone 10 mg/day or equivalent
    • Steroids used as premedication for hypersensitivity or infusion-related reactions

15. Receipt of a live attenuated vaccine within 30 days prior to the first dose of study intervention.

    Note: Subjects must not receive live vaccines while receiving study intervention and for 30 days after the final dose of study intervention.

16. Peripheral neuropathy of CTCAE Grade ≥2 at screening.
17. Patients with hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.