Proof-of-concept Study of Ibrutinib in c-MYC and HER2 Amplified Oesophagogastric Carcinoma (iMYC)

Inclusion Criteria:

• Provision of signed and dated, written informed consent prior to any study specific procedures.
• Female or male aged 18 years or older.
• Histologically proven metastatic or locally advanced inoperable squamous or adeno carcinoma of the oesophagus,stomach or oesophago-gastric junction.
• Documented progression after at least 1 prior line of chemotherapy for advanced disease. For HER2 positive tumours documented progression after at least 1 line of chemotherapy with or without HER2 directed therapy.
• c-MYC or HER2 gene amplification as defined in trial protocol
• Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study. If female patients are taking hormonal contraceptives to prevent pregnancy then this should be combined with a barrier method of contraception. Men must agree to not donate sperm during and after the study. For both males and females restrictions apply for 3 month after the last dose of study drug. See protocol for highly effective methods of birth control.
• Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [b-hCG]) or urine pregnancy test at screening. Women who are pregnant or breastfeeding are ineligible for this study.
• Mandatory provision of archival or fresh tumour biopsy for confirmation of c-MYC or HER2 gene amplification.
• World Health Organisation (ECOG) performance status 0-2, minimum life expectancy of 12 weeks from proposed first dose date, no deterioration within 2 weeks of screening and first dose.
• Adequate organ and haematological function as evidenced by the following laboratory values within 14 days before enrolment:

absolute neutrophil count (ANC) ≥1,500/mm3μL platelets ≥100,000/mm3μL (independent of transfusion support) alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x upper limit of normal (ULN) total bilirubin ≤1.5 x ULN unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin serum creatinine ≤2 x ULN or estimated creatinine clearance (CCr) ≥30 mL/min/1.73m2

-At least one measurable target lesion, as per RECIST criteria 1.1

Exclusion Criteria:

• Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
• Concurrent treatment within 4 weeks of study entry with any other chemotherapy, anticancer immunotherapy or experimental therapy
• No available histology for c-MYC or HER-2 amplification testing
• Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification
• Patients with ECG abnormalities considered by the investigator to be clinically significant, or repeated baseline prolongation of the rate-corrected QT interval (QTc)
• Any actively bleeding gastrooesophageal tumour
• History of stroke or intracranial haemorrhage within 6 months prior to enrolment
• Symptomatic brain metastases
• Known history of human immunodeficiency virus (HIV) or active Hepatitis C Virus or active Hepatitis B Virus infection or any uncontrolled active systemic infection requiring intravenous (IV) antibiotics.
• Ongoing anticoagulation with a vitamin K antagonist
• Requiring use of strong P450 (CYP) 3A4 inhibitors
• Major surgery within 4 weeks of enrolment
• Vaccinated with live, attenuated vaccines within 4 weeks of enrolment
• Any pre-existing medical condition of sufficient severity to prevent full compliance with the study