The Addition of Nab-paclitaxel (Abraxane) to First Line Treatment of Metastasized Oesophagogastric Carcinoma (ACTION)

Phase 1: To assess the safety and tolerability of Nab-paclitaxel added to oxaliplatin and capecitabine at their currently optimal doses.

Phase 2: To determine the anti-tumor activity of Nab-paclitaxel when co-administered with oxaliplatin and capecitabine in patients with irresectable or metastasized oesophagogastric cancer in terms of progression free survival.

Study design This is a single-center, open label, dose finding, phase I/II study.

Intervention In the phase I part of the study, the dose of nab-paclitaxel in combination of capecitabine and oxaliplatin will be escalated in fixed increments according to the dose escalation scheme outlined below

Dose level Nab-paclitaxel Capecitabine Oxaliplatin Minimum Day 1 and 8 14 days Day 1 and 8 number of patients -1 40 mg/m2 1000 mg/m2 65 mg/m2 -

• (starting) 60 mg/m2 1000 mg/m2 65 mg/m2 3
• 80 mg/ m2 1000 mg/m2 65 mg/m2 3
• 100 mg/ m2 1000 mg/m2 65 mg/m2 3
• 120 mg/ m2 1000 mg/m2 65 mg/m2 3

In the phase II part of the study the maximum tolerated dose from the phase I part of the study will be used in combination with fixed dosages of capecitabine and oxaliplatin; nab-paclitaxel day 1 and 8 according to the Maximum Tolerated Dose (MTD) of the phase 1 part of the study combined with capecitabine for 14 days at 1000mg/m2 twice daily and oxaliplatin day 1 and 8 65mg/m2.

Inclusion criteria

• Patients must provide written informed consent according to ICH/GCP, and national/local regulations prior to any screening procedures.
• Patients with histologically confirmed diagnosis of metastatic or irresectable carcinoma of the stomach or oesophagus
• Patients with metastatic or irresectable carcinoma of the stomach or oesophagus not pre-treated with chemotherapy or radiotherapy for irresectable or metastatic disease.
• Measurable disease as assessed by RECIST 1.1
• ECOG (WHO) performance status 0-2
• Patient has adequate bone marrow and organ function
• If a female patient is of child-bearing potential: negative serum pregnancy test, If sexually active, the patient must agree to use contraception.
• Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial

Exclusion criteria

• Prior systemic treatment for metastatic or irresectable stomach or oesophageal cancer.
• Evidence of disease progression within 3 months after completion of adjuvant or neoadjuvant treatment containing capecitabine and/or oxaliplatin.
• History of hypersensitivity to nab-paclitaxel, capecitabine or oxaliplatin.
• All target lesions in a radiation field without documented disease progression.
• WHO 2-4
• Use of other investigational drugs within 30 days of enrollment.
• Patient has known brain metastases, unless previously treated and well-controlled for at least 3 months (defined as clinically stable, no oedema, no steroids and stable in 2 scans at least 4 weeks apart).
• History of malignancy in the last 5 years. Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible. Patients with other malignancies are eligible if they were cured by surgery alone or surgery plus radiotherapy and have been continuously disease-free for at least 5 years.
• Patients who are not willing to avoid consumption of Seville oranges, grapefruit or grapefruit juice grapefruit hybrids, pomelos and exotic citrus fruits during the entire study.
• Patient is currently being treated with drugs known to be strong inhibitors or inducers of CYP3A4 or CYP2C8, which cannot be discontinued or switched to a different medication 7 days prior to starting study treatment and for the duration of the study.
• Patient has active, uncontrolled bacterial, viral or fungal infection(s) requiring systemic therapy.
• Patient has known historical or active infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C.
• Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment contraindicate patient participation in the clinical study (e.g. hematological, cardiovascular, lung disease etc)
• Patient is enrolled in any other clinical protocol or investigational trial with the same primary endpoint.
• Patients who in the investigators' opinion may be unwilling, unable or unlikely to comply with requirements of the study protocol.