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Mackay H.J.,Princess Margaret Phase II Consortium | Hirte H.,Princess Margaret Phase II Consortium | Colgan T.,Sunnybrook Regional Cancer Center | Covens A.,Princess Margaret Phase II Consortium | And 9 more authors.
European Journal of Cancer | Year: 2010

Aim: Micropapillary/borderline (LMP) ovarian tumours are rarely included in clinical trials and are intrinsically resistant to radiation and chemotherapy. Platinum resistant epithelial ovarian cancer (EOC) has a poor prognosis. The histone deacetylase inhibitor belinostat demonstrated antitumour activity in pre-clinical ovarian cancer models. Methods: A phase II study was performed to evaluate the activity of belinostat in two patient populations: women with metastatic or recurrent platinum resistant (progression within 6 months) EOC and LMP ovarian tumours, both groups had received no more than 3 prior lines of chemotherapy. Belinostat 1000 mg/m2/d was administered iv days 1-5 of a 21 d cycle. Peripheral blood mononuclear cells (PBMCs) and tumour biopsies, where possible, for correlative studies were obtained prior to and following treatment. Results: Eighteen patients with EOC and 14 patients with LMP tumours were enrolled on study. Belinostat was well tolerated with no grade four toxicity (179 cycles). Grade 3 toxicity consisted of thrombosis (3 patients), hypersensitivity (1) and elevated ALP (1). One patient with LMP tumour had a partial response (unconfirmed) and 10 had stable disease (SD), 3 were non-evaluable. Median progression-free survival (PFS) was 13.4 months (95% confidence interval (CI), 5.6 - not reached). Best response in patients with EOC was SD (nine patients) and median PFS was 2.3 months (95% CI, 1.2-5.7 months). An accumulation of acetylated histones H3 and H4 was noted in PBMCs and in tumour tissue. Conclusions: Belinostat is well tolerated in both patient groups and shows some activity in patients with micropapillary (LMP) disease. © 2010 Elsevier Ltd. Source


Tang P.A.,Princess Margaret Phase II Consortium | Cohen S.J.,Fox Chase Cancer Center | Kollmannsberger C.,Princess Margaret Phase II Consortium | Bjarnason G.,Princess Margaret Phase II Consortium | And 6 more authors.
Clinical Cancer Research | Year: 2012

Purpose: Aflibercept is a recombinant fusion protein of the VEGF receptor (VEGFR) 1 and VEGFR2 extracellular domains.Weassessed the safety and efficacy of aflibercept in patients with metastatic colorectal cancer (MCRC) who had received at least one prior palliative regimen. Experimental Design: Seventy-five patients were enrolled onto this two-stage phase II trial in two cohorts, bevacizumab naïve (n = 24) and prior bevacizumab (n = 51). Aflibercept was administered at 4 mg/kg i.v. in two-week cycles. The primary endpoint was a combination of objective response rate and 16-week progression-free survival (PFS). Results: In the bevacizumab-naïve cohort (n = 24), the best response was stable disease for 16 weeks or more in five of 24 patients. In the prior bevacizumab cohort (n = 50), one patient achieved a partial response and six patients had stable disease for 16 weeks or more. The median PFS in the bevacizumab-naïve and prior bevacizumab cohorts was two months [95% confidence interval (CI): 1.7-8.6 months] and 2.4 months (95% CI: 1.9-3.7 months), respectively. Median overall survival (OS) was 10.4 months (95% CI: 7.6-15.5) and 8.5 months (95% CI: 6.2-10.6), respectively. The most common grade 3 or higher treatment-related adverse events were hypertension, proteinuria, fatigue, and headache. Ten patients discontinued study treatment due to toxicity. Mean free to VEGF-bound aflibercept ratio was 1.82, suggesting that free aflibercept was present in sufficient amount to bind endogenous VEGF. Conclusion: Aflibercept showed limited single-agent activity in patients with pretreated MCRC with moderate toxicity. Further study of aflibercept with chemotherapy is ongoing. ©2012 AACR. Source

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