Publications (22) View all
-
Article: Pharmacokinetic and pharmacodynamic properties of an oral formulation of the histone deacetylase inhibitor Belinostat (PXD101).
[show abstract] [hide abstract]
ABSTRACT: 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. 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. 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/m(2) 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 (T½) of a single dose of 1,000 mg/m(2) 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. High doses of oral belinostat, up to 1,000 mg/m(2) 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.Cancer Chemotherapy and Pharmacology 06/2011; 67(6):1273-9. · 2.83 Impact Factor -
Article: The insulin-like growth factor-I receptor inhibitor figitumumab (CP-751,871) in combination with docetaxel in patients with advanced solid tumours: results of a phase Ib dose-escalation, open-label study.
[show abstract] [hide abstract]
ABSTRACT: This phase Ib trial assessed safety, tolerability, and maximum tolerated dose (MTD) of figitumumab (CP-751,871), a fully human monoclonal antibody targeting the insulin-like growth factor type 1 receptor (IGF-IR), in combination with docetaxel. Patients with advanced solid tumours were treated with escalating dose levels of figitumumab plus 75 mg m(-2) docetaxel every 21 days. Safety, efficacy, pharmacokinetics (PKs), and biomarker responses were evaluated. In 46 patients, no dose-limiting toxicities were attributable to the treatment combination. Grade 3 and 4 toxicities included neutropaenia (n=28), febrile neutropaenia (n=11), fatigue (n=10), leukopaenia (n=7), diarrhoea (n=5), hyperglycaemia, lymphopaenia, cellulitis, DVT, and pain (all n=1). The MTD was not reached. Four partial responses were observed; 12 patients had disease stabilisation of > or =6 months. Pharmacokinetic and biomarker analyses showed a dose-dependent increase in plasma exposure, and complete sIGF-IR downregulation at doses of >or =3 mg kg(-1). Pharmacokinetics of docetaxel in combination was similar to when given alone. Out of 18 castration-resistant prostate cancer patients, 10 (56%) had > or =5 circulating tumour cells (CTCs) per 7.5 ml of blood at baseline: 6 out of 10 (60%) had a decline from > or =5 to <5 CTCs and 9 out of 10 (90%) had a > or =30% decline in CTCs after therapy. Figitumumab and docetaxel in combination are well tolerated. Further evaluation is warranted.British Journal of Cancer 07/2010; 103(3):332-9. · 5.04 Impact Factor -
Article: A phase I study of the safety and pharmacokinetics of the histone deacetylase inhibitor belinostat administered in combination with carboplatin and/or paclitaxel in patients with solid tumours.
[show abstract] [hide abstract]
ABSTRACT: This phase I study assessed the maximum tolerated dose, dose-limiting toxicity (DLT) and pharmacokinetics of belinostat with carboplatin and paclitaxel and the anti-tumour activity of the combination in solid tumours. Cohorts of three to six patients were treated with escalating doses of belinostat administered intravenously once daily, days 1-5 q21 days; on day 3, carboplatin (area under the curve (AUC) 5) and/or paclitaxel (175 mg m(-2)) were administered 2-3 h after the end of the belinostat infusion. In all 23 patients received 600-1000 mg m(-2) per day of belinostat with carboplatin and/or paclitaxel. No DLT was observed. The maximal administered dose of belinostat was 1000 mg m(-2) per day for days 1-5, with paclitaxel (175 mg m(-2)) and carboplatin AUC 5 administered on day 3. Grade III/IV adverse events were (n; %): leucopenia (5; 22%), neutropenia (7; 30%), thrombocytopenia (3; 13%) anaemia (1; 4%), peripheral sensory neuropathy (2; 9%), fatigue (1; 4%), vomiting (1; 4%) and myalgia (1; 4%). The pharmacokinetics of belinostat, paclitaxel and carboplatin were unaltered by the concurrent administration. There were two partial responses (one rectal cancer and one pancreatic cancer). A third patient (mixed mullerian tumour of ovarian origin) showed a complete CA-125 response. In addition, six patients showed a stable disease lasting > or =6 months. The combination was well tolerated, with no evidence of pharmacokinetic interaction. Further evaluation of anti-tumour activity is warranted.British Journal of Cancer 06/2010; 103(1):12-7. · 5.04 Impact Factor -
Article: Characterization of the adaptive and innate immune response to intravenous oncolytic reovirus (Dearing type 3) during a phase I clinical trial.
[show abstract] [hide abstract]
ABSTRACT: There is an emerging realization from animal models that the immune response may have both detrimental and beneficial therapeutic effects during cancer virotherapy. However, there is a dearth of clinical data on the immune response to viral agents in patients. During a recently completed phase I trial of intravenous reovirus type 3 Dearing (RT3D), heavily pretreated patients with advanced cancers received RT3D at doses escalating from 1 x 10(8) tissue culture infectious dose-50 (TCID(50)) on day 1 to 3 x 10(10) TCID(50) on 5 consecutive days of a 4 weekly cycle. A detailed analysis of the immune effects was conducted by collecting serial clinical samples for analysis of neutralizing anti-reoviral antibodies (NARA), peripheral blood mononuclear cells (PBMC) and cytokines. Significant increases in NARA were seen with peak endpoint titres >1/10 000 in all but one patient. The median fold increase was 250, with a range of 9-6437. PBMC subset analysis showed marked heterogeneity. At baseline, CD3+CD4+ T cells were reduced in most patients, but after RT3D therapy their numbers increased in 47.6% of patients. In contrast, most patients had high baseline CD3+CD8+ T-cell levels, with 33% showing incremental increases after therapy. In some patients, there was increased cytotoxic T-cell activation post-therapy, as shown by increased CD8+perforin/granzyme+ T-cell numbers. Most patients had high numbers of circulating CD3-CD56+ NK cells before therapy and in 28.6% this increased with treatment. Regulatory (CD3+CD4+CD25+) T cells were largely unaffected by the therapy. Combined Th1 and Th2 cytokine expression increased in 38% of patients. These data confirm that even heavily pretreated patients are capable of mounting dynamic immune responses during treatment with RT3D, although these responses are not clearly related to the administered virus dose. These data will provide the basis for future studies aiming to modulate the immune response during virotherapy.Gene therapy 07/2008; 15(12):911-20. · 4.75 Impact Factor -
Article: Combining radiation and cancer gene therapy: a potential marriage of physical and biological targeting?
[show abstract] [hide abstract]
ABSTRACT: The development and progression of cancer is marked by the acquisition of specific genetic hallmarks that endow tumour cells with a survival advantage over their normal tissue counterparts. In the process, tumours frequently develop resistance to radiotherapy and chemotherapy, and acquire the ability to evade the host immune response. Cancer gene therapy (CGT) represents an ideal therapeutic tool to target one or more of these underlying genetic abnormalities, and restore some form of order, to the otherwise autonomous and discordant microenvironment of the tumour. Most of the current research in CGT is aimed at its development as a novel form of targeted therapy that can be combined with other treatment modalities such as radiotherapy and chemotherapy. CGT may be integrated into radical chemoradiotherapy regimens, with the rationale of optimising the therapeutic index, through selective enhancement of radiosensitivity and cytotoxicity in tumour compared to normal tissues. CGT strategies have been developed that are aimed at enhancing the radiosensitivity of tissues by targeting angiogenesis, silencing abnormal cellular signalling, restoration of apoptosis, and promotion of immune detection and destruction of tumour cells. In addition, cytotoxic approaches such as virus directed enzyme prodrug therapy (VDEPT), genetic radionuclide therapy (GRANT) and oncolytic viral therapy have been combined with radiation to augment the cumulative tumour cell kill and overall therapeutic effect. In this article, we discuss various CGT strategies that have been investigated in combination with radiation. All the available preclinical and clinical evidence is reviewed with special emphasis on strategies that have already found their way into the clinic, or those with significant translational potential for the future.Current cancer drug targets 07/2007; 7(4):389-409. · 5.13 Impact Factor
