T-Dxd in Combination With Ramucirumab as HER2 Low Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma

This is a Phase Ib/II study to identify the RP2D of T-DXd combination with Ram and to assess the safety and clinical efficacy of this combined treatment in advanced gastric cancer. The study will be conducted in two parts: Phase Ib dose escalation study to determine the MTD and RP2D of T-DXd combination and Ram, and Phase II to further evaluate the safety and tolerability of T-DXd combinations with Ram at the RP2D and determine anti-tumor activity.

This is a Phase Ib/II study to identify the RP2D of T-DXd combination with Ram and to assess the safety and clinical efficacy of this combined treatment in advanced gastric cancer after first-line treatment. The study will be conducted in two parts: Phase Ib dose escalation study to determine the MTD and RP2D of T-DXd combination and Ram, and Phase II to further evaluate the safety and tolerability of T-DXd combinations with Ram at the RP2D and determine anti-tumor activity.

Eligibility Criteria:
Inclusion Criteria:

1. Able and willing to give written informed consent and has signed the appropriate weitten informed consent form(ICF) prior to performance of any trial activityes.
2. Eligible male and female subjects aged ≥19 years.
3. Histologically or cytologically proven metastatic or locally advanced HER2 low gastric or GEJ adenocarcinoma: The definition of HER2 low is 1+ by immunohistochemistry (IHC) or 2+ by IHC and without HER2 gene amplification (negative by in situ hybridization\[ISH\]).
4. Progressed after 1st line palliative treatment. Adjuvant chemotherapy will be counted as 1st line treatment if the cancer has recurred within 6 months of completion of adjuvant chemotherapy.
5. Has measurable or evaluable disease as determined by RECIST ver 1.1.
6. ECOG performance status of 0 -1 at trial entry.
7. Life expectancy ≥12 weeks as judged by the Investigator.
8. Has LVEF ≥ 50% by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before enrollment.
9. Adequate baseline organ function defined as:

   * Absolute neutrophil count ≥1500/mm3
   * Platelets ≥100,000/mm3
   * Hemoglobin ≥9.0 g/dL
   * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 × upper limit of normal (ULN) of the study site (or ≤5.0 × ULN in patients with liver metastases)
   * Total bilirubin ≤1.5 × ULN - Serum albumin ≥2.5 g/dL
   * Creatinine ≤1.5 × ULN or creatinine clearance (either measured value or estimated value using the Cockcroft-Gault equation) \>40ml/min - Urinary protein ≤1+ on dipsick or routine urinalysis - INR and PTT/aPTT ≤1.5 × ULN 10. Adequate treatment washout period before randomization/enrollment. - Major Surgery ≥ 4 weeks - Radiation Therapy including palliative stereotactic radiation therapy to chest ≥ 4 weeks
   * Anti-Cancer chemotherapy \[Immunotherapy (non-antibody based therapy)\] ≥ 3 weeks

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

12. Female patients of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception from the time of screening and must agree to continue using such precautions for 7 months after the last dose of IMP.

13. Non-sterilized male patients who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening to 4 months after the final dose of IMP. 14. Female subjects must not donate, or retrieve for their own use, ova from the time of enrollment and throughout the study treatment period, and for at least 7 months after the final study drug administration

Exclusion Criteria:

1. Anticancer treatment within 14 days before the start of trial treatment.
2. Major surgery within 28 days before the start of trial treatment.
3. Have received more than 2 prior lines of chemotherapy.
4. Grade ≥ 2 peripheral neuropathy.
5. Multiple primary malignancies within 3 years.
6. Participants with a medical history of myocardial infarction within 6 months before treatment, symptomatic CHF (New York Heart Association Class II to IV), unstable angina pectoris, clinically important cardiac arrhythmias, or a recent (\< 6 months) cardiovascular event, including myocardial infarction, unstable angina pectoris, and stroke.
7. Corrected QT interval (QTcF) prolongation to \> 470 msec (females) or \>450 msec (males) based on an average of the screening triplicate 12-lead ECG.
8. Gastrointestinal perforation or fistula or any Grade 3-4 bleeding within 3 months of first dose of protocol therapy; or any arterial thromboembolic event, significant gastro-intestinal bleeding or any significant venous thromboembolism within 3 months before treatment
9. History of (non-infectious) ILD / pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
10. Lung criteria: A. Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder. B. Any autoimmune, connective tissue or inflammatory disorders C. Prior pneumonectomy
11. Has known active CNS metastases and/or carcinomatous meningitis.
12. Has substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions that may, in the opinion of the investigator, interfere with the subject's participation in the clinical study or evaluation of the clinical study results.
13. Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms.
14. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
15. Active primary immunodeficiency, known uncontrolled active HIV infection or active hepatitis B or C infection, such as those with serologic evidence of viral infection within 28 days of Cycle 1 Day 1. 16. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. 17. Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of trastuzumab deruxtecan. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of IMP. 18. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline. 19. Known allergy or hypersensitivity to study treatment or any of the study drug excipients.

20. History of severe hypersensitivity reactions to other monoclonal antibodies.

21. Pregnant or breastfeeding female patients, or patients who are planning to become pregnant.

22. Otherwise inappropriate for this study in the investigator's or sub-investigator's opinion.

23. Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis.

24. Serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to first dose of protocol therapy.

25. The patient is receiving chronic antiplatelet therapy, including dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use (maximum dose 325 mg/day) is permitted.

26. The patient has uncontrolled or poorly-controlled hypertension (\>160 mmHg systolic or \> 100 mmHg diastolic for \>4 weeks) despite standard medical management.