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Steele N.L.,Beatson West of Scotland Cancer Center | Steele N.L.,University of Glasgow | Plumb J.A.,University of Glasgow | Vidal L.,Royal Marsden Hospital | And 8 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2011

Purpose: The primary objective of this sub-study, undertaken as an extension to the previously reported phase-I study, was to explore the feasibility, tolerability and pharmacokinetics (PK) of belinostat when administered by the oral route. Preliminary pharmacodynamic (PD) studies were also performed to enable comparison of the biological effects of the oral and intravenous formulations. Patients and methods: Oral belinostat was administered in a range of doses and schedules (once, twice or thrice daily), on either day 1 or days 1-5, of the second or a subsequent treatment cycle in 15 patients who were included in the phase-I trial of intravenous belinostat. Serial blood samples were collected for PK and PD (histone acetylation) analyses, and the results compared with corresponding analyses following intravenous administration. Results: A total mean daily AUC of 2,767 ± 1,453 ng h/ml (8.7 ± 4.6 μM h) resulted from a dose of 1,000 mg/m2 once daily (qd). There was no clear evidence of drug accumulation on twice daily dosing (bid); however, a trend towards accumulation was apparent when belinostat was given three times daily (tid). Mean half-life (T1/2) of a single dose of 1,000 mg/m2 was 1.5 h (±0.3 h) and peak levels were reached in an average of 1.9 h (±0.3 h). The half-life was found to be independent of dose, but a trend towards increasing half-life following multiple dosing was observed. Histone H4 hyperacetylation in PBMCs estimated after oral dosing was comparable to that achieved after intravenous administration. Conclusions: High doses of oral belinostat, up to 1,000 mg/m2 bid for 5 consecutive days, have been tolerated in this small study. An oral formulation could lead to enhanced drug exposure and, more importantly, prolonged effects on the intended drug target. Future trials are required to establish the optimal dose and schedule of oral administration of belinostat. © 2010 Springer-Verlag.

O'Connor O.A.,Columbia University | Horwitz S.,Sloan Kettering Cancer Center | Masszi T.,St Istvan And St Laszlo Hospital | Van Hoof A.,General Hospital St Jan | And 13 more authors.
Journal of Clinical Oncology | Year: 2015

Purpose: Peripheral T-cell lymphomas (PTCLs) represent a diverse group of non-Hodgkin lymphomas with a poor prognosis and no accepted standard of care for patients with relapsed or refractory disease. This study evaluated the efficacy and tolerability of belinostat, a novel histone deacetylase inhibitor, as a single agent in relapsed or refractory PTCL. Patients and Methods: Patients with confirmed PTCL who experienced progression after ≥ one prior therapy received belinostat 1,000 mg/m2 as daily 30-minute infusions on days 1 to 5 every 21 days. Central assessment of response used International Working Group criteria. Primary end point was overall response rate. Secondary end points included duration of response (DoR) and progression-free and overall survival. Results: A total of 129 patients were enrolled, with a median of two prior systemic therapies. Overall response rate in the 120 evaluable patients was 25.8% (31 of 120), including 13 complete (10.8%) and 18 partial responses (15%). Median DoR by International Working Group criteria was 13.6 months, with the longest ongoing patient at ≥ 36 months. Median progression-free and overall survival were 1.6 and 7.9 months, respectively. Twelve of the enrolled patients underwent stem-cell transplantation after belinostat monotherapy. The most common grade 3 to 4 adverse events were anemia (10.8%), thrombocytopenia (7%), dyspnea (6.2%), and neutropenia (6.2%). Conclusion: Monotherapy with belinostat produced complete and durable responses with manageable toxicity in patients with relapsed or refractory PTCL across the major subtypes, irrespective of number or type of prior therapies. These results have led to US Food and Drug Administration approval of belinostat for this indication. © 2015 by American Society of Clinical Oncology.

Foss F.,Yale Cancer Center | Advani R.,Stanford University | Duvic M.,University of Texas M. D. Anderson Cancer Center | Hymes K.B.,New York University | And 15 more authors.
British Journal of Haematology | Year: 2015

Belinostat is a pan-histone deacetylase inhibitor with antitumour and anti-angiogenic properties. An open label, multicentre study was conducted in patients with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL) who failed ≥1 prior systemic therapy and were treated with belinostat (1000mg/m2 intravenously ×5d of a 21-d cycle). The primary endpoint was objective response rate (ORR). Patients with PTCL (n=24) had received a median of three prior systemic therapies (range 1-9) and 40% had stage IV disease. Patients with CTCL (n=29) had received a median of one prior skin-directed therapy (range 0-4) and four prior systemic therapies (range 1-9); 55% had stage IV disease. The ORRs were 25% (PTCL) and 14% (CTCL). Treatment-related adverse events occurred in 77% of patients; nausea (43%), vomiting (21%), infusion site pain (13%) and dizziness (11%) had the highest incidence. Treatment-related serious adverse events were Grade 5 ventricular fibrillation; Grade 4 thrombocytopenia; Grade 3 peripheral oedema, apraxia, paralytic ileus and pneumonitis; and Grade 2 jugular vein thrombosis. Belinostat monotherapy was well tolerated and efficacious in patients with recurrent/refractory PTCL and CTCL. This trial was registered at as NCT00274651. © 2014 John Wiley & Sons Ltd.

The present application discloses a compound of the formula (I) wherein Q is optionally substituted pyridyl; p is 0-6. Y is formulae (i), (ii) and (iii) where X is O, S and NCN, r is 1-12, R is Z-A, Z is a single bond, S(O)_(2), >PO, >CO, C(O)NH, and C(S)NH; and A is hydrogen, C_(1-12)-alkyl, C_(3-12)-cycloalkyl, [CH_(2)CH_(2)O]_(1-10)(C_(1-6)-alkyl), C_(1-12)-alkenyl, aryl, heterocyclyl, and heteroaryl; B is a single bond, NR^(N), S(O)_(2) and O; wherein R^(N )is selected from hydrogen, C_(1-12)-alkyl, C_(3-12)-cycloalkyl, [CH_(2)CH_(2)O]_(1-10)(C_(1-6)-alkyl), C_(1-12)-alkenyl, aryl, heterocyclyl, and heteroaryl; s is 0-6; and Cy is aryl, cycloalkyl, heterocyclyl, and heteroaryl. The compounds are useful for use as a medicament for the treatment of a disease or a condition caused by an elevated level of nicotinamide phosphoribosyltransferase (NAMPRT).

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