Phase 2 Study of Trastuzumab Deruxtecan in the Neoadjuvant Treatment, or Trastuzumab Deruxtecan Plus Capecitabine Plus Durvalumab(MEDI4736) in the Preoperative and Postoperative Adjuvant Treatment for Patients With HER2 Positive Gastric and Gastroesophageal Junction Adenocarcinoma

Phase 2 Study of Trastuzumab Deruxtecan in the Neoadjuvant Treatment, or Trastuzumab Deruxtecan Plus Capecitabine Plus Durvalumab(MEDI4736) in the Preoperative and Postoperative Adjuvant Treatment for Patients With HER2 Positive Gastric and Gastroesophageal Junction Adenocarcinoma

This study is an open-label, single-arm, multicenter, Phase 2 study to evaluate the efficacy and safety of neoadjuvant chemotherapy with T-DXd monotherapy in patients with HER2-positive gastric cancer.

In the combination cohort, the efficacy and safety of neoadjuvant chemotherapy combined with T-DXd, capecitabine, and durvalumab are evaluated.

This study is an open-label, single-arm, multicenter, phase 2 clinical trial. Eligible patients are with previously untreated gastric and gastroesophageal junction adenocarcinoma as defined by cT2-4 and/or cN+ without evidence of metastatic disease. Study treatment in this study is neoadjuvant treatment with the investigational drug, T-DXd alone, followed by surgery. T-DXd will be administered at a dose of 6.4 mg/kg (decimal) by intravenous infusion every 21 days (3 weeks) for 3 cycles as the neoadjuvant treatment followed by surgery.

In the combination cohort, the efficacy and safety of neoadjuvant chemotherapy combined with T-DXd, capecitabine, and durvalumab are evaluated.

T-DXd 5.4 mg/kg and Durvalumab 1500 mg were infused intravenously once 3 weeks, and Capecitabine 750 mg/m2 was administered orally twice daily for 14 days with a 7-day rest period. T-DXd, Capecitabine, and Durvalumab were repeated 3 cycles preoperatively and 3 cycles postoperatively, followed by 10 cycles of Durvalumab monotherapy every 4 weeks.

Monotherapy will be analyzed in the following 2 analysis sets.

• Patients with HER2 overexpression (IHC3+ or IHC2+ and ISH-positive [FISH or DISH]) in the primary lesion or metastasis (primary analysis part)
• Patients with low expression of HER2 (IHC1+ or IHC2+ and negative for ISH [FISH or DISH]) and HER2-ECD > 11.6 ng/mL in the primary lesion or metastasis (exploratory part)

The combination cohort will be analyzed in the following analysis sets.

- Patients with HER2 overexpression (IHC3+ or IHC2+ and ISH-positive [FISH or DISH]) in the primary lesion or metastasis with gastric adenocarcinoma or GEJ adenocarcinoma

Inclusion Criteria:

1. Histologically confirmed adenocarcinoma of the gastric or gastroesophageal junction.

2. Has HER2 overexpression (IHC3+, or IHC2+ and ISH positive [FISH or DISH]). (HER2 Low expression: IHC1+, or IHC2+ and ISH-negative [FISH or DISH] with HER2-ECD > 11.6 ng/mL in the exploratory cohort).

3. Have previously untreated gastric and gastroesophageal junction adenocarcinoma and cT2-4 and/or cN+M0.according to the UICC TNM classification (8th edition),

4. Age ≥ 20 years as the day of informed consent.

5. Has an ECOG performance status (PS) of 0 or 1.

6. Has a left ventricular ejection fraction (LVEF) ≥ 50% by either echocardiogram (ECHO) or multigated collecting acquisition (MUGA) scan within 28 days before enrollment (acceptable on the same day of the week).

7. Has a corrected QT interval (QTc) ≦ 470 ms in females, or QTc ≦ 450 ms in males based on a 12-lead ECG screening within 28 days before enrollment (allowed on the same day of the week). [Fridericia's correction is recommended]

8. Satisfies all of the following requirements within 14 days before enrollment (allowed on the same day of the week).

   • Absolute neutrophil count ≧1500 / mm3 [except for assessment ≦ 14 days after administration of Granules colony-stimulating factors (G-CSF)]

   • Hemoglobin ≧ 8.0 g/dL (except for those measured within 7 days after whole blood transfusion or packed red blood cells)

   • Platelet count ≧100000 per mm3 (excluding measurements within 7 days after platelet transfusion).

   • Total bilirubin ≦1.5 mg/dL (patients with gilbert's syndrome will be allowed if they have < 3.0 mg/dL).

   • AST(GOT)≦100 IU/L

   • ALT(GPT)≦100 IU/L

   • Serum albumin ≧ 2.5 g/dL

   • Calculated creatinine clearance (Cockcroft-Gault ＊) or the actual value ≧ 30 mL/min

     ＊ Cockcroft-Gault equation: creatinine clearance= (140 - age) × body weight (kg) / (72 × Serum creatinine) (* 0.85 x the value obtained for females).

   • PT(INR)< 1.8

   • aPTT < 60 seconds

9. Has a treatment-free period from the end of pre-treatment to before enrollment (allowed on the same day of the week), defined as:

   i. Surgery with general anesthesia : ≧ 4 weeks ii. Radiotherapy: ≧ 4 weeks (including palliative stereotactic body radiation therapy to the chest; palliative stereotactic body radiation therapy to other than the chest ≧ 2 weeks; abdominal vertebral bodies should be included in the abdomen).

   iii. Chloroquine and hydroxychloroquine : ≧ 15 days

10. Has a prior radiotherapy or surgical AE recovered of ≦ Grade 1 or ≦ baseline on CTCAE v5.0. However, this shall not apply to events where the symptoms are stable even if they are grade 2 or higher.

11. Female of childbearing potential have a negative pregnancy test within 7 days before enrollment (allowed on the same day of the week). Male and Female of childbearing potential agree to contraception for a period (4 months for male and 7 months for Female) from informed consent to the last dose of study drug (see 4.3 "Pregnancy and contraception").

12. Written informed consent of participation in the study has been obtained from the patient.

Exclusion Criteria:

1. Has a medical history of myocardial infarction or congestive heart failure (New York Heart Association Classes II-IV) within 6 months before enrollment, corresponding to the value diagnosed as myocardial infarction as defined by the *validated test within 28 days before enrollment (allowed on the same day), unstable angina, or any serious arrhythmia requiring treatment.

   • tested in local institutions **: Enrollment is allowed with value exceeds ULN if myocardial infarction can be excluded.

2. Active other cancers [Synchronous other cancers and metachronous other cancers within 3 years prior to enrollment, but carcinoma in situ or other lesions corresponding to mucosal carcinoma that are considered curable with local treatment will not be included in active other cancers.]

3. Has serious (hospitalized) complications (intestinal palsy, intestinal obstruction, pulmonary fibrosis, diabetes mellitus that is difficult to control, heart failure, myocardial infarction, unstable angina, renal failure, liver failure, psychiatric disorders, cerebrovascular disorders, etc.).

4. Has history of gastrointestinal perforation and/or gastrointestinal fistula within 6 months before enrollment.

5. Has any of the following infections:

   • HBs antigen positive
   • HBs antibody or HBc antibody and HBV-DNA positive
   • Active hepatitis C (eg, if HCV RNA is detected qualitatively) Patients who are HBsAg positive but who have achieved HBV DNA level < 1.3 log IU/mL (2.1 log copies/mL) after treatment with antiviral drugs such as NAs, are eligible for the study.

6. HIV infection

7. Lung diseases defined as:

   • Has a history of non-infectious interstitial lung disease or pneumonitis that required treatment, has interstitial lung disease or pneumonitis, or these lung diseases cannot be ruled out by radiographic examination before enrollment.
   • Severe pulmonary disease (eg, pulmonary embolism within 3 months prior to enrollment, serious bronchial asthma, severe COPD, restrictive pulmonary disease, or pleural effusion).

   Lung-related autoimmune or connective tissue or inflammatory diseases (eg, rheumatoid arthritis, Sjögren's syndrome, or sarcoidosis) with clinically severe pulmonary risks.

   • Has history of pneumonectomy.

8. Has history of concomitant autoimmune disease or chronic or recurrent autoimmune disease.

9. Administration of systemic corticosteroids (except prophylactic administration for diagnostic tests or allergic reactions, and temporary use for the purpose of reducing edema associated with radiotherapy) or immunosuppressants is required, or has received these treatments within 14 days before enrollment in the study.

10. Has unhealed wounds, ulcers, or fractures.

11. If patients are a pregnancy or breastfeeding patient.

12. Has documented severe hypersensitivity to study drug active ingredients or additives.

13. Has history/complications of severe hypersensitivity reactions to other monoclonal antibodies.

14. has uncontrolled acute systemic infection that requires Infusion intravenous antibiotic, antiviral, or antifungal drug.

15. Unwilling or unable to follow study protocol or any of the instructions by the physician.

16. The investigator or subinvestigator considered it ineligible for the study.