Multicentre phase I/II study of PI-88, a heparanase inhibitor in combination with docetaxel in patients with metastatic castrate-resistant prostate cancer

Background: Docetaxel (Taxotere) improve survival and prostate-specific antigen (PSA) response rates in patients with metastatic castrate-resistant prostate cancer (CRPC). We studied the combination of PI-88, an inhibitor of angiogenesis and heparanase activity, and docetaxel in chemotherapy-naive CRPC.

Patients and methods: We conducted a multicentre open-label phase I/II trial of PI-88 in combination with docetaxel. The primary end point was PSA response. Secondary end points included toxicity, radiologic response and overall survival. Doses of PI-88 were escalated to the maximum tolerated dose; whereas docetaxel was given at a fixed 75 mg/m2 dose every three weeks

Results: Twenty-one patients were enrolled in the dose-escalation component. A further 35 patients were randomly allocated to the study to evaluate the two schedules in phase II trial. The trial was stopped early by the Safety Data Review Board due to a higher-than-expected febrile neutropenia of 27%. In the pooled population, the PSA response (50% reduction) was 70%, median survival was 61 weeks (6–99 weeks) and 1-year survival was 71%.

Conclusions: The regimen of docetaxel and PI-88 is active in CRPC but associated with significant haematologic toxicity. Further evaluation of different scheduling and dosing of PI-88 and docetaxel may be warranted to optimise efficacy with a more manageable safety profile.

Effects of asenapine in bipolar I patients meeting proxy criteria for moderate-to-severe mixed major depressive episodes: a post hoc analysis

OBJECTIVE: Depression is the predominant psychosocial and suicide burden in bipolar disorder, yet there is a paucity of evidence-based treatments for bipolar depression. METHODS: This post hoc subgroup analysis of data pooled from two 3-week, randomized, placebo- and olanzapine-controlled trials (December 2004-April 2006, N = 489 and November 2004-April 2006, N = 488) examined a subgroup of patients meeting criteria for moderate-to-severe mixed major depressive episodes, defined using DSM-IV-TR criteria for mixed episodes (mania and major depression simultaneously) with a baseline Montgomery-Asberg Depression Rating Scale (MADRS) total score ≥ 20. RESULTS: Decreases in MADRS scores (least squares mean [SE]), the a priori primary outcome, were significantly greater in the asenapine group than in the placebo group from baseline to day 7 (-11.02 [1.82] vs -4.78 [1.89]; P = .0195), day 21 (-14.03 [2.01] vs -7.43 [2.09]; P = .0264), and endpoint (-10.71 [1.76] vs -5.19 [1.98]; P = .039). Decreases in MADRS scores with asenapine were significantly greater than with olanzapine from baseline to day 7 (-6.26 [1.47]; P = .0436). Decreases in Young Mania Rating Scale mean total score were greater with asenapine than with placebo or olanzapine at all time points assessed. A significantly greater reduction from baseline to day 21 in the Short Form-36 mental component summary score was observed with asenapine, but not olanzapine, compared with placebo (16.57 vs 5.97; P = .0093). Asenapine was generally well tolerated. CONCLUSIONS: These data provide support for the potential efficacy of asenapine in mixed major depressive episodes; however, these data cannot be linearly extrapolated to nonmixed major depression.