Feasibility Study of Short Term Fondaparinux (Arixtra) in Chemotherapy-Pretreated Ovarian Carcinoma Patients at High Risk of Progression

Feasibility Study of Short Term Fondaparinux (Arixtra) in Chemotherapy-Pretreated Ovarian Carcinoma Patients at High Risk of Progression

07-742 Phase I/ Feasibility Study of Short Term Fondaparinux (Arixtra) in Chemotherapy-Pretreated Ovarian Carcinoma Patients at High Risk of Progression

The purpose of this study is to assess feasibility and safety of using once daily Fondaparinux Sodium (ARIXTRA®) in patients with ovarian cancer who are in 'clinical remission' (no clinical evidence of disease) after chemotherapy but at high risk of ovarian cancer recurrence.

Rationale: A large body of work supports the association of abnormal coagulation (blood clot formation) and malignancy. A coagulation enzyme thrombin is able to 1) enhance cancer cell adhesion to platelets and endothelial cells 2) stimulate tumor cell growth, 3) increase metastasis and 4) stimulate tumor angiogenesis. Thrombin inhibition has anti-metastatic and anti-tumor activity in mouse models. Recent meta-analysis of 4 major randomized clinical trials that have evaluated the effect of anticoagulants on overall survival in cancer patients comparing low molecular weight heparin (LMWH) to placebo demonstrates a 13% risk reduction in mortality at 1 year and 10% risk reduction at 2 years, which is statistically significant and independent of the potential confounding effect of anticoagulation in the prevention of venous thromboembolic disease. Fondaparinux sodium (ARIXTRA® ) is a highly effective newer anticoagulant that is a fully synthetic pentasaccharide. Arixtra binds to antithrombin III and subsequently inhibits Factor Xa and hence thrombin generation. Arixtra has an excellent safety profile in clinical trials of over 10,000 patients. When compared to LMWHs, ARIXTRA® has a potential pharmacokinetic advantage based on its longer half-life of 16-17 hours. Hypothesis: The hypothesis to be tested is whether the completion of 8 weeks of ARIXTRA® in patients with ovarian cancer who are in 'clinical remission' (no clinical evidence of disease) after chemotherapy but at high risk of ovarian cancer recurrence is feasible and safe and if the inhibition of thrombin generation by ARIXTRA® in ovarian cancer will result in decrease ovarian cancer recurrence. A concise description of the methodology: The trial will be a prospective open-label cohort feasibility study of giving 2 months of ARIXTRA® in patients at high risk of recurrence of ovarian cancer. The planned accrual is 15 patients. Patients will be treated with a fixed dose of ARIXTRA® 2.5 mg by subcutaneous injection once daily. Treatment will continue for 2 months or until disease recurrence or grade 3 adverse events or patient refusal. In addition, all patients will be followed for survival and recurrence.

Arixtra 2.5 mg by subcutaneous injection once daily for 8 weeks or until disease recurrence or grade 3, 4 adverse events.

Estimate the proportion of patients who complete an eight week course of once daily administration of fondaparinux (Arixtra).

Inclusion Criteria: Patients 18 years of age and ≤75 years of age Biopsy-proven ovarian, tubal or primary peritoneal epithelial adenocarcinomas; Performance status 0,1 (ECOG) ( table 2) Patients at high risk of clinical relapse: first remission stage III/IV who were suboptimally debulked (residual disease >1 cm) Patients of any stage who have recurred and are in second chemotherapy induced remission. Clinical remission defined as: absence of symptoms that may be related to disease imaging without abnormalities greater then or equal to 1 cm suspicious for disease (no ascites) CA 125 obtained x 1 and <35 units/ml. Adequate end organ function, defined as the following: Total bilirubin < 1.5 x ULN SGOT and SGPT < 2.5 x UNL Creatinine < 1.5 x ULN ANC > 1.5 x 109/L Platelets > 100 x 109/L Weight ≥ 50 kg Exclusion Criteria: Patients with performance status ECOG =2,3,4 Patients who are on warfarin or prior therapeutic anticoagulation Patient has another primary malignancy that has required active intervention within 5 years, with the exception of basal cell skin cancer or a cervical carcinoma in situ. Patient has a severe and/or uncontrolled medical disease (i.e., uncontrolled diabetes, chronic renal disease, or active uncontrolled infection). Patient who had a major surgery within 2 weeks prior to study entry Patients with the following lab abnormalities: WBC <3000 absolute neutrophil count < 1,500 hemoglobin <10 g/dL platelet < 100,000 creatinine clearance <30 cc/min serum ALT, AST, or total bilirubin >1.5X the upper limit of normal Patients with known bleeding disorder