A Study of IMU-131 (HER-Vaxx) in Combination With Chemotherapy or Pembrolizumab in Patients With Metastatic HER2/Neu Over-Expressing Gastric Cancer (nextHERIZON)

Inclusion Criteria:

1. Age ≥ 18 years with confirmed diagnosis of advanced or metastatic HER2/neu overexpressing gastric or GEJ adenocarcinoma;
2. Progressed on or after trastuzumab therapy;
3. Eastern Cooperative Oncology Group (ECOG) performance status 0-1;
4. Life expectancy of a minimum of 3 months;
5. At least one measurable lesion as defined by RECIST 1.1 criteria and assessed by the local investigator;
6. HER2/neu overexpression assessed using post-progression fresh or archival tissue, or post-progression pathology report;
7. Adequate left ventricular ejection function at baseline, defined as left ventricular ejection fraction (LVEF) \> 50% by echocardiogram or Multi Gated Acquisition (MUGA) scan;
8. Adequate hematologic, liver and renal function;
9. A female patient of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 120 days after the last dose of assigned treatment.

Exclusion Criteria:

1. Previous malignant disease (other than primary malignancy) within the last 5 years, except basal or squamous cell carcinoma of the skin or cervical carcinoma in situ;
2. Concurrent active malignancy except for adequately controlled limited basal cell carcinoma of the skin;
3. Systemic chemotherapy or major surgery within 28 days before starting study treatment and recovered from all adverse events ≤ Grade 1 or baseline with possible exceptions for neuropathy and endocrine-related AEs;
4. Received prior radiotherapy within 2 weeks of start of study treatment and recovered from all radiation-related toxicities and not require corticosteroids; or history of radiation pneumonitis.
5. Previous treatment with trastuzumab-deruxtecan or any other anti-HER2 therapy (except trastuzumab);
6. Clinically significant cardiovascular disease, or other diseases that in the Investigator's opinion may influence the patient's tolerance to study treatment;
7. Pleural effusion or ascites requiring more than weekly drainage;
8. Prior organ transplantation, including allogenic stem-cell transplantation;
9. Chronic immunosuppressive therapy within 7 days prior the first dose of study drug;
10. Active, known, or suspected autoimmune disease;
11. History of (non-infectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease;
12. Positivity for human immunodeficiency virus (HIV) (HIV 1/2 antibodies) or active hepatitis B (HBsAg reactive) or active hepatitis C (HCV ribonucleic acid \[RNA\] qualitative) infection;
13. Current participation or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment;
14. Any vaccination within 30 days prior to starting study treatment;
15. Pregnant or lactating females;
16. Arm 2 only: Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent;
17. Arm 2 only: Has received prior therapy with an ICI or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137) and was discontinued from treatment due to a grade 3 or higher adverse event.