Liposomal iRInotecan, Carboplatin or oXaliplatin for Esophagogastric Cancer

Inclusion Criteria:

• Patients must provide written informed consent according to International Conferenceon Harmonization (ICH)/Guideline for Good Clinical practice (GCP), andnational/local regulations prior to any screening procedures.

• Male or female adult patients (> 18 years).

• Patients with histologically confirmed diagnosis of metastatic or irresectable humanepidermal growth (HER2) negative adenocarcinoma of the stomach or oesophagus;patients with HER2 positive disease are eligible when treatment with trastuzumab iscontraindicated. If histology cannot be obtained, cytology is acceptable to provemetastatic disease.

• Patients with metastatic or irresectable adenocarcinoma of the stomach or oesophagusnot pre-treated with chemotherapy or radiotherapy for irresectable or metastaticdisease. Palliative radiotherapy on the primary tumor or a metastatic lesion isallowed if other untreated lesions eligible for evaluation are present.

• Measurable disease as assessed by RECIST 1.1

• Eastern Cooperative Oncology Group (ECOG) (WHO) performance status 0-2

• Patient has adequate bone marrow and organ function as defined by the followinglaboratory values:

• Absolute Neutrophil Count (ANC) > 1.5 x 109 /L

• Hemoglobin (Hgb) > 5.6 mmol/L

• Platelets > 100 x 109 /L

• Serum total bilirubin within ≤ 1.5 x ULN (upper limit of normal); or total bilirubin < 3.0 x upper limit of normal (ULN) with direct bilirubin within normal range inpatients with well documented Gilbert's syndrome; biliary drainage is allowed forbiliary obstruction

• Serum creatinine < 1.5 x ULN or creatinine clearance >30 mL/min/1.73 m2

• Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) < 2.5x ULNwithin normal range or < 5.0 x ULN if liver metastases are present

• If a female patient is of child-bearing potential, as evidenced by regular menstrualperiods, she must have a negative serum pregnancy test, beta-human chorionicgonadotropin (β-hCG) documented 72 hours prior to the first administration of studydrug. If sexually active, the patient must agree to use contraception consideredadequate and appropriate by the Investigator during the period of administration ofstudy drug and after the end of treatment as recommended.

• Absence of any psychological, familial, sociological or geographical conditionpotentially hampering compliance with the study protocol and follow-up schedule;those conditions should be discussed with the patient before registration in thetrial.

Exclusion Criteria:

• Prior systemic treatment for metastatic or irresectable stomach or oesophagealcancer.

• Evidence of disease progression within six months after completion of adjuvant orneoadjuvant treatment (whichever is last) containing a fluoropyrimidine and/orplatinum compound and/or irinotecan; progression on neoadjuvant chemoradiation withcarboplatin area under the curve (AUC2) and paclitaxel 50 mg/m2 within this timeframe is allowed.

• All target lesions in a radiation field without documented disease progression. 11

• Patient has known brain metastases, unless previously treated and well-controlledfor at least 3 months (defined as clinically stable, no edema, no steroids andstable in 2 scans at least 4 weeks apart).

• Past or current malignancy other than entry diagnosis interfering with prognosis ofmetastatic esophagogastric cancer.

• Known uncontrollable hypersensitivity or contraindications to any of the componentsof liposomal irinotecan (Nal-IRI) other liposomal irinotecan formulations,irinotecan, fluoropyrimidines, leucovorin, oxaliplatin, carboplatin. Patients withprevious dose reductions or delays are eligible.

• Complete dihydropyrimidine dehydrogenase deficiency .

• Patient has active, uncontrolled bacterial, viral or fungal infection(s) requiringsystemic therapy.

• Patient has known past or active infection with human immunodeficiency virus (HIV),hepatitis B or hepatitis C.

• Signs of interstitial lung disease (ILD)

• Patient has any other concurrent severe and/or uncontrolled medical condition thatwould, in the investigator's judgment contraindicate patient participation in theclinical study.

• Use of other investigational drugs within 30 days of enrollment.

• Patient is enrolled in any other clinical protocol or investigational trial thatwill interfere with the primary endpoint.

• Patients who in the investigators' opinion may be unwilling, unable or unlikely tocomply with requirements of the study protocol.

• Current use or any use in last two weeks of strong cytochrome P4503A (CYP3A-enzyme),CYP2C8, and/or strong UDP glucuronosyltransferase (UGT1A) inhibitors/inhibitors

• Breast feeding, known pregnancy, positive serum pregnancy test or unwillingness touse a reliable method of birth control, during therapy and for 3 months followingthe last dose of study treatment.

• Treatment within 4 weeks with dihydropyrimidine dehydrogenase (DPD) inhibitors,including sorivudine or its chemically related analogues such as brivudine.

• Pre-existing motor or sensory neurotoxicity greater than WHO grade 1.