Overall Survival of Inoperable Gastric/GastroOesophageal Cancer Subjects on Treating With LMWH + Chemotherapy(CT) vs Standard CT

Randomized, Phase III-b, Multi-centre, Open-label, Parallel Study of Enoxaparin (Low Molecular Weight Heparin) Given Concomitantly With Chemotherapy vs Chemotherapy Alone in Patients With Inoperable Gastric and Gastro-oesophageal Cancer

Due to evidence available both in terms of efficacy and safety of low molecular weight heparin, its use for the prevention of thromboembolic disease in cancer patients undergoing surgical intervention, and its extended use in higher doses for the prevention of recurrent thromboembolism in cancer patients with established thrombosis, with a view that the potential benefits for survival in cancer patients from low molecular weight heparin therapy comes because of a biological activity, the dose of 1mg/Kg (50% of the full treatment dose) for a period of 6 months coincident with 6 cycles of chemotherapy, has been chosen for this study.

In the GASTRANOX study, patients will have inoperable (locally advanced) or metastatic newly diagnosed gastric or gastro oesophageal cancer. These patients carry a definite thrombosis risk. Patients will be scheduled to have at least 6 months of palliative chemotherapy. During this period symptomatic thromboembolism will be common but currently no routine prophylaxis is provided.

The dose of Enoxaparin to be evaluated in this study is 1mg/kg. This represents half of the full treatment dose. For an average weight individual this will represent between 60 and 70 mg a day of Enoxaparin. The prophylactic dose for high-risk surgical patients in the United States is 60mg total daily dosing of Enoxaparin per day. This high-risk dose has been shown to be safe and effective in preventing thromboembolic disease in high-risk populations such as those undergoing major elective orthopaedic surgery. An alternative for high-risk dose is 40mg given once a day. This dose is also effective and safe. Thus the dose to be provided in the GASTRANOX study is not markedly different from the high-risk doses already in routine clinical practice either in North America (30mg twice a day - 60mg total daily dosing) or 40mg once a day in Europe. It is also half of the full treatment dose which has been shown to be effective and safe in the treatment of venous thromboembolism.

Since cancer patients are recognised to have bleeding risk it was felt inappropriate to provide the full treatment dose of Enoxaparin. Thus half the full treatment doses provided. On the other hand the biological effect of low molecular weight heparins in cancer suggests that higher doses be given to enhance the potential survival benefit.

The study is intended to evaluate the safety and efficacy of the study drug compared to best normal practice. The standard methodology for such a comparison is to conduct a randomized, comparative study.

Multi-centre: It is anticipated that a single centre will be unable to recruit sufficient subjects, in 1 year, to conduct the assessment and therefore multiple centres will be recruited to conduct the study.

Open Label: All patients will receive standard care at their site. It would not be feasible to expect placebo parenteral administration for six months. All VTE events will be adjudicated. Mortality is an objective end-point.

Standard treatment control: subjects will be treated according to best practice with half also receiving the study treatment.

Parallel-group: due to the nature of the condition this is the only practical design.

Inclusion Criteria:

• Signed written informed consent
• Male or Female of age 18-75 years
• Histologically confirmed gastric or gastro-oesophageal carcinoma.
• Adenocarcinoma of the stomach stage III or IV considered inoperable at presentation.
• ECOG performance status ≤ 1
• Criteria for chemotherapy fulfilled (haematological, hepatic, renal).
• Ability to receive daily injection (self-injection or by patient relative).
• Urine-Pregnancy test negative.
• Consent to the use of Contraceptive for women of child bearing age group

Exclusion Criteria:

• History of previous malignancy within the previous 5 years (except curatively treated carcinoma in situ of the uterine cervix, or basal cell carcinoma of the skin), or concomitant malignancy.
• Prior treatment with chemotherapy or radiotherapy if relapse less than 6 months
• Non-epithelial gastric tumours, borderline tumours.
• Medically unstable patients, including but not limited to those with active infection, acute hepatitis, gastrointestinal bleeding, uncontrolled cardiac arrhythmias, interstitial lung disease, inflammatory bowel disease, uncontrolled angina, uncontrolled hypercalcaemia, uncompensated congestive heart failure, uncontrolled diabetes, persistent renal failure, dementia, seizures, superior vena cava syndrome.
• Persistent renal failure (persistent value of the calculated creatinine clearance < 30 mL/min defined as a documented value < 30 mL/min on at least 2 occasions ≥ 3 days prior entry into the study).
• Prosthetic heart valves.
• Any evidence of active bleeding disorder or risk of bleeding identified on fibroscopy done as a routine investigation before the consent for the trial. Fibroscopy is not mandatory to be done for the trial
• Current, objectively-verified DVT, PE or other clinically significant thrombosis.
• Documented previous episode of heparin-induced thrombocytopenia and/or thrombosis (HIT, HAT, or HITTS).
• Contraindications to anticoagulation
• Coagulopathies (acquired or inherited)
• Prior history of cerebral hemorrhage or neurosurgery within the previous month
• Bacterial endocarditis
• Uncontrolled arterial hypertension (systolic BP:200 mmHg or diastolic BP:110 mmHg) at 2 successive readings
• Haemostatic abnormalities: circulating anticoagulant, baseline platelet count <50 000/mm3, activated partial thromboplastin time (aPTT) value 1.5 x the upper limit of normal, or International Normalized Ratio (INR) >1.5. The laboratory test valid would be no earlier than 14 days for this criterion.
• Indication for thrombolytic therapy
• Any long-term anticoagulant therapy for medical condition.
• Immunocompromised subjects, such as subjects with known HIV and those who have either had an AIDS-defining condition (e.g. Kaposi's sarcoma, Pneumocystitis carinii pneumonia) or have CD4 + T-lymphocyte count < 200 /mm3.
• Known hypersensitivity to heparin, or LMWH, or pork derived products.
• Body weight >100 kg.
• Pregnant or lactating women.
• Women of childbearing potential not protected by effective contraceptive method of birth control and/or who are unwilling to be tested for pregnancy (pregnancy status should be checked by serum or urine pregnancy testing prior to exposure to the investigational product
• Participation in another clinical trial (study medications / study devices) within the previous 30 days. (Surgical trials are allowed).
• Psychiatric disorders of altered mentation that would preclude understanding of the informed consent process.
• Psychological, familial, sociological, or geographical conditions, which do not permit treatment and/or medical follow-up required to comply with the study protocol.