Tinzaparin for Primary Treatment and Extended Secondary Prophylaxis of Venous Thromboembolism in Patients With Cancer

The purpose of this study is to use long-term administration of a low molecular weight
heparin (tinzaparin) for primary treatment and secondary prophylaxis of venous
thromboembolism in patients with cancer. We will determine the efficacy (recurrent VTE) and
safety (major hemorrhage) of this approach. Secondarily, we will analyze the outcome of
patients in terms of survival and response to therapy versus matched controls. We will also
determine baseline levels of markers of hemostasis, fibrinolysis, and angiogenesis and will
follow changes with treatment as well as correlate levels of these plasma markers with
outcomes, including recurrent venous thromboembolism, major hemorrhage,and survival.

Inclusion Criteria:

- Diagnosis of active cancer

- Patients have documented or recurrent malignancy and must meet at least one of the
following criteria:

- Diagnosis or documented presence of cancer within 6 months, excluding squamous
cell or basal cell carcinoma of the skin OR

- Receive any therapy for cancer within the previous 6 months OR

- Currently receiving any treatment (surgery, radiation, chemotherapy, hormonal
therapy, biotherapy, palliative therapy, and/or combined modality therapy) for
cancer

- Documented first venous thromboembolic event

- Patients must meet at least one of the following criteria:

- Deep vein thrombosis of the lower extremity confirmed with duplex
ultrasonography, magnetic resonance imaging, or venogram OR

- Pulmonary embolism confirmed with high probability V/Q scan, CT angiogram, or
pulmonary angiogram

- ECOG performance status of 0, 1, or 2

- Signed written informed consent

- Age 18 years or greater

Exclusion Criteria:

- Body weight less than 40 kg

- Recurrent spontaneous fractures unrelated to the underlying active malignancy

- Administration of therapeutic doses of unfractionated or low molecular weight heparin
for more than 48 hours prior to registration Amendment 3 (05/26/2009) 11

- Need for long-term oral anticoagulant therapy (e.g., mechanical heart valves, atrial
fibrillation)

- Poor performance status with an ECOG score of 3 or 4

- Serious hemorrhage requiring hospitalization, transfusion, or surgical intervention
within 2 weeks of presentation

- Known acute (symptomatic or active bleeding) gastroduodenal ulcer

- Epidural/spinal puncture within the last 24 hours

- Neurosurgery within 1 week of registration or any previous history of intracranial
hemorrhage

- Septic endocarditis

- Overt pericardial effusion

- Current platelet count of less than 50 x 109/L

- Undergoing high dose chemotherapy for peripheral blood stem cell or bone marrow
transplantation, induction chemotherapy for acute leukemia, or has other conditions
associated with persistent thrombocytopenia of less than 100 109/L for a duration of
at least four consecutive weeks

- Familial bleeding diathesis

- Uncontrolled hypertension despite antihypertensive therapy

- Dependent upon renal dialysis or significant renal failure with a serum creatinine of
greater than three times the upper limit of normal

- Allergy to heparin (unfractionated or low molecular weight)

- Allergy to contrast medium

- Pregnant or of childbearing potential and not using adequate contraception

- Geographically inaccessible for follow-up

- Failure or inability to give informed consent