Tinzaparin Is Effective and Safe for the Treatment and Extended Secondary Prophylaxis In Cancer Patients with Venous Thromboembolism.

Venous thromboembolism (VTE) is a major complication in cancer patients. The traditional treatment algorithm for VTE of UF or LMW heparin followed warfarin is associated with a higher risk of recurrent VTE and bleeding in cancer patients. A recent randomized trial has demonstrated that initial treatment and secondary prophylaxis with LMWH is associated with a lower VTE recurrence when compared to secondary prophylaxis with warfarin. We initiated a single arm Phase 2 IRB approved study to evaluate the efficacy and safety of once daily tinzaparin for the initial treatment and extended prophylaxis (6 months) of VTE in cancer patients. Included in this study was a prospective analysis of plasma biomarkers to assess whether any biomarkers could predict treatment failure or be predictive of patient survival.

Patients (pts)with objectively confirmed symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE) or unexpected PE detected on staging CT scans by the criteria of OConnell et al. (JCO 24:4928, 2006) were eligible for this study, if they had an ECOG score <2 and an estimated 6 month survival. After informed consent, treatment was initiated with tinzaparin 175 U/Kg for 6 months. Planned enrollment was 100 pts. Pts who completed the 6 month study could continue on treatment for an additional 6 months if clinically appropriate. All pts who received at least one injection of tinzaparin were evaluable for efficacy and safety. Study endpoints were objectively confirmed DVT, PE or major bleeding events. Serial blood samples were obtained prior to treatment, at 1 wk, 1 month, 3 months and 6 months. Biomarkers to be studied included D-dimer (D-D), Thrombin-antithrombin complex (TAT), interleukin 6 and 8 (Il-6, Il-8) and plasma tissue factor. Only pts in whom the pretreatment, I week and 1 month blood samples were collected were included in the biomarker analysis.

At time of this submission 91 pts were treated on study. Of 91 pts enrolled 39 (42.9%) have completed the 6 months and 5 (5.5%) remain on active treatment. Eight (8.8%) pts withdrew from study for hospice care and one pt was withdrawn due to poor compliance. Forty-two (46%) pts died before 6 months. Ten (11%) pts continued on treatment after 6 months and one pt transitioned to warfarin treatment. Treatment endpoints included 8 (8.8%) pts with recurrent VTE (5 DVT, 3 PE); 2 occurred within the first 4 wks on treatment and the 6 events before month 3. No recurrent VTE occurred after 12wks. Three pts (3%) had major bleeding events. There were no fatal thrombotic or bleeding events. All deaths were considered due to progressive cancer, although the possible fatal VTE in pts who died at home or in hospice could not be excluded. There were 76 (83.5%) pts were evaluable for the biomarker study. Biomarker data failed to show a correlation between the level of D-D, TAT or Il-6 and patient survival from the time of their thrombotic event. However, in pts who developed recurrent VTE after 1 month, the D-D level at month 1 was higher than the pretreatment in 4/6 (66.7%) patients compared to 8/70 (11.4%) pts with no recurrence in whom month 1 samples were obtained.

In this prospective study of tinzaparin for initial treatment and secondary prophylaxis of cancer-associated VTE, treatment appeared both safe and efficacious. Our recurrent VTE event rate of 8.8% compares favorably with the 8% recurrent VTE reported in the pts treated with dalteparin. The 3% of patients who had major bleeding events also compares favorably with the CLOT trial. Survival was difficult to predict at the time of enrollment since 46% failed to survive the 6 months. Biomarker data failed to predict survival, but patients who recurred after the first month were more likely to have month 1 D-D levels greater than pretreatment. The reason for the failure of tinzaparin treatment to effectively suppress thrombin generation in these patients remains unexplained.

Tagawa:Leo Pharmaceutical: Research Funding; Celgene: Research Funding. Liebman:Leo Pharmaceutical: Research Funding; Celgene: Research Funding.