Daily Dosing Schedule Research Articles

Pharmacokinetic and pharmacodynamic modelling of marbofloxacin administered alone and in combination with tolfenamic acid in calves

In a four-period, cross-over study, the fluoroquinolone antibacterial drug marbofloxacin (MB) was administered to calves, alone and in combination with the nonsteroidal anti-inflammatory drug tolfenamic acid (TA). Both drugs were administered intramuscularly (IM) at doses of 2 mg/kg. A tissue cage model of inflammation, based on the actions of the mild irritant carrageenan, was used to evaluate the pharmacokinetics (PK) of MB and MB in combination with TA. MB mean values of area under concentration-time curve (AUC) were 15.1 μg·h/mL for serum, 12.1 μg·h/mL for inflamed tissue cage fluid (exudate) and 9.6 μg·h/mL for noninflamed tissue cage fluid (transudate). Values of C(max) were 1.84, 0.35 and 0.31 μg/mL, respectively, for serum, exudate and transudate. Mean residence time (MRT) of 23.6 h (exudate) and 22.6 h (transudate) also differed significantly from serum MRT (8.6 h). Co-administration of TA did not affect the PK profile of MB. The pharmacodynamics of MB was investigated using a bovine strain of Mannheimia haemolytica. Time-kill curves were established ex vivo on serum, exudate and transudate samples. Modelling the ex vivo serum time-kill data to the sigmoid E(max) equation provided AUC(24 h) /MIC values required for bacteriostatic (18.3 h) and bactericidal actions (92 h) of MB and for virtual eradication of the organism was 139 h. Corresponding values for MB + TA were 20.1, 69 and 106 h. These data were used to predict once daily dosage schedules for a bactericidal action, assuming a MIC(90) value of 0.24 μg/mL, a dose of 2.6 mg/kg for MB and 2.19 mg/kg for MB + TA were determined, which are similar to the currently recommended dose of 2.0 mg/kg.

Prognostic Factors Associated with Progression of Myelodysplastic Syndromes (MDS) to Acute Myeloid Leukemia (AML) In Patients (pts) Treated with Decitabine

AbstractAbstract 4956 Background:About 50% of pts with MDS ultimately progress to AML with no clear pattern in underlying parameters leading to progression. This analysis sought to identify predictive factors in pts with MDS that are associated with progression to AML after treatment with decitabine. Methods:In a combined analysis of MDS pts treated with either a 3- or 5-day dosing schedule of decitabine, pts were stratified on the basis of those who progressed to AML (P) versus those who did not (NP). CR rates by IWG2006 criteria for each of the baseline factors were compared by using the chi-square test. Factors that were significant in the univariate analysis (p<0.05) were included in a multivariate analysis. Logistic regression analysis was conducted for progression to AML. The following variables were identified as predictors of progression: study effect; age; secondary or de novo MDS; prior MDS treatment, including growth factor use only and prior chemotherapy; del 5Q or 7; time to diagnosis; baseline ANC (< 500, 500 – 1000, or >1000 U/L); baseline HGB, plt and BM blast count ≤20; FAB classification; ECOG status; and IPSS (low, int-1, int-2). A Cox proportional-hazards analysis was conducted for survival. Results:A combined analysis of prognostic factors for MDS was completed in 163 pts with a complete response to decitabine; 37 (22.6%) had progressed to AML and 126 (77.3%) had not. Baseline characteristics in pts that progressed had significantly less time since diagnosis (<3mos), more RAEB, RAEB-t and IPSS classification of Int-2 and high-risk, lower baseline HGB levels and fewer prior treatments. From the multivariate analysis, the following factors were selected as predictors of progression: No history of prior treatment, time from diagnosis of MDS <3 months, hemoglobin levels under 10 g/dL, and a 3-day schedule of decitabine (p=0.005, 95% CI 1.4, 6.8). Survival estimates were determined for Del 5q or 7, baseline HGB <10, plt <50 and the 3-day dosing schedule approached but did not achieve a significant effect (p=0.08). Conclusions:MDS pts with a deep anemia (HGB <10), thrombocytopenia (plts <50), and a cytogenetic risk profile that includes a del5 and/or 7 anomaly are at a statistically higher risk of transformation into AML and should be considered for additional treatment options.Multivariate Analysis and Odds Ratio EstimatesParameterEstimateErrorChi-quarePr > ChiSqPoint Estimate95% Wald Confidence LimitsIntercept−1.15530.221427.2218<.0001Prior Therapy0.10620.21130.25250.61531.2370.5402.831Diagnosis <3 mos0.29850.21791.87540.17091.8170.7734.269Baseline HGB <100.008470.21780.00150.96901.0170.4332.3883-day Dosing (0007)0.56720.20197.89150.00503.1101.4096.862Survival estimates by Cox modelStandard EstimateqErrorChi-SquarePr > ChiSqHazard RatioDel 5Q or 7−0.840160.2520311.11310.00090.432IPSS: INTERMEDIATE 1−0.194480.319130.37140.54230.823IPSS: INTERMEDIATE 20.034080.291800.01360.90701.035Baseline HGB <100.572190.245465.43400.01971.772Baseline PLT <500.505620.215485.50600.01901.658Prior Therapy−0.285370.212271.80730.17880.7523-day Dosing (0007)0.365080.215252.87660.08991.441 Disclosures:Borthakur: Eisai Inc.: Research Funding. Kantarjian: Novartis: Consultancy, Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding. Jabbour: Eisai Inc.: Editorial and statistical support, Honoraria.

Feasibility study of two schedules of sunitinib in combination with pemetrexed in patients with advanced solid tumors

Summary Background Sunitinib is an oral multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors, as well as of other receptor types. We have performed a feasibility study to investigate the safety of sunitinib in combination with pemetrexed for treatment of advanced refractory solid tumors. Methods Sunitinib was administered once daily on a continuous daily dosing (CDD) schedule (37.5 mg/day) or a 2-weeks-on, 1-week-off treatment schedule (50 mg/day, Schedule 2/1) in combination with pemetrexed at 500 mg/m2 on day 1 of repeated 21-day cycles. Results Twelve patients were enrolled in the study: six on the CDD schedule and six on Schedule 2/1. None of the treated patients experienced a dose-limiting toxicity. Toxicities were manageable and similar in type to those observed in monotherapy studies of sunitinib and pemetrexed. Pharmacokinetic analysis did not reveal any substantial drug–drug interaction. One patient with squamous cell lung cancer showed a partial response and five patients had stable disease. Conclusions Combination therapy with sunitinib administered on Schedule 2/1 (50 mg/day) or a CDD schedule (37.5 mg/day) together with standard-dose pemetrexed (500 mg/m2) was well tolerated in previously treated patients with advanced solid tumors.

A phase 1 study of BMS-275183, a novel oral analogue of paclitaxel given on a daily schedule to patients with advanced malignancies

BMS-275183 is an oral C-4 methyl carbonate analogue of paclitaxel that has the same mechanism of action, stabilization of tubulin polymerization. The present study was designed to: (i) assess the safety and tolerability of BMS-275183, and (ii) determine a suitable Phase II dose of BMS-275183 when given on a continuous daily schedule to patients with advanced solid tumor(s). This was a multi-institutional, open-label, Phase I, single-arm dose escalation study in which cohorts of eligible patients with advanced malignancies were treated with BMS-275183 orally on a continuous daily schedule. The starting dose level was 6 mg/m(2)/day administered once daily. Cohorts of 3 patients were treated at each dose level provided no dose-limiting toxicities (DLTs) were observed. Each cycle of treatment lasted 28 days. Twenty patients were enrolled in dose cohorts ranging from the initial dose level of 6 mg/m(2)/day to 18 mg/m(2)/day. Overall, the most frequent (>20% of patients) treatment-related adverse events (AEs) were nausea (40%), constipation (20%), diarrhea (20%), and fatigue (20%). There were 2 fatal events of neutropenic sepsis one each at the 15 mg/m(2)/day and 18 mg/m(2)/day dose level, respectively. There were no objective responses; 4 of 20 patients experienced stable disease. Pharmacokinetic data indicated no clear correlation between dose and exposure following daily oral administration of BMS-275183 doses between 6 and 18 mg/m(2). Substantial inter-patient variability was observed, and high drug exposure was associated with fatal neutropenic sepsis. BMS-275183 is a novel oral analogue of paclitaxel with high inter-patient variability in exposure. The lack of evidence of clinical benefit and the occurrence of two fatal events of neutropenic sepsis, coupled with high drug exposure, argues against further evaluation of BMS-275183 on a daily dosing schedule.

An exploratory study of sunitinib plus paclitaxel as first-line treatment for patients with advanced breast cancer

BackgroundSunitinib has shown single-agent activity in patients with previously treated metastatic breast cancer (MBC). We investigated the safety of the combination of sunitinib and paclitaxel in an exploratory study of patients with locally advanced or MBC. MethodsPatients received oral sunitinib 25 mg/day (with escalation to 37.5 mg/day as tolerated) on a continuous daily dosing schedule and paclitaxel 90 mg/m2 on days 1, 8, and 15 of each 28-day cycle. Study endpoints included safety (primary endpoint), pharmacokinetics, and antitumor activity. ResultsTwenty-two patients were enrolled. The most frequent adverse events (AEs) were fatigue/asthenia (77%), dysgeusia (68%), and diarrhea (64%). Grade 3 AEs included neutropenia (43%), fatigue/asthenia (27%), neuropathy (18%), and diarrhea (14%). No drug–drug interaction was observed on the basis of pharmacokinetic analysis. Of 18 patients with measurable disease at baseline, 7 (38.9%) achieved objective responses (including 2 complete and 5 partial responses). Clinical responses were observed in three of nine patients with triple-negative receptor status (estrogen receptor negative, progesterone receptor negative, and human epidermal growth factor receptor-2 negative). ConclusionsThese data indicate that sunitinib and paclitaxel in combination are well tolerated in patients with locally advanced or MBC. No drug–drug interaction was detected and there was preliminary evidence of antitumor activity.

Sunitinib in combination with gemcitabine plus cisplatin for advanced non-small cell lung cancer: A phase I dose-escalation study

Purpose To determine the maximum tolerated dose (MTD) of sunitinib plus gemcitabine/cisplatin for first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). Safety, pharmacokinetics, and antitumor activities were evaluated. Methods Patients ≥18 years with Eastern Cooperative Oncology Group performance status 0/1 and stage IIIB/IV NSCLC were included in this open-label, multicenter, dose-escalation phase I study. Treatment was administered in 3-week cycles: oral sunitinib 37.5 or 50 mg/day intermittently (Schedule 2/1: 2 weeks on treatment, 1 week off treatment) or 25 mg continuous daily dosing (CDD) schedule with intravenous infusions of gemcitabine (1000 or 1250 mg/m 2 days 1, 8) and cisplatin (80 mg/m 2 day 1). Results A total of 28 evaluable patients were assigned to four dose levels. Most adverse events (AEs) on the Schedule 2/1 MTD were mild to moderate. Dose delays due to myelosuppression occurred on both schedules, limiting treatment to a median of four cycles. Four of 18 evaluable patients (22%) on Schedule 2/1 and 1 of 6 patients (17%) on the CDD schedule had confirmed partial responses. Conclusions The MTD was identified as sunitinib 37.5 mg (Schedule 2/1), gemcitabine 1250 mg/m 2, and cisplatin 80 mg/m 2, with most AEs being mild to moderate. However, frequent dose delays due to myelosuppression occurred. There was evidence of antitumor activity with this combination.

Abstract B210: Shed MET (sMET), VEGFA, and sVEGFR2 are markers of foretinib treatment in metastatic gastric cancer patients

Abstract Foretinib (formerly GSK1363089) is a small molecule multikinase inhibitor which includes inhibition of MET and VEGFR2. The ongoing phase II study, MET111643, is evaluating the safety and efficacy of 2 dosing schedules (continuous daily dosing and intermittent 5 days on/9 days off dosing) of foretinib as a single agent in pts with metastatic GC. An additional component of the study is to collect patient plasma samples before and during treatment with foretinib, to explore the potential pharmacodynamic effect and/or the modulation by foretinib of MET and VEGFR2. Plasma samples were collected from 42 pts on the intermittent 5 days on/9 off foretinib schedule at baseline and prior to dosing on days 5, 15, 29, and 47. The plasma levels of sMET, HGF, sVEGFR2, and VEGFA were measured using the Meso Scale Discovery platform (MSD). These marker changes from baseline were analyzed at each time point using analysis of variance and their relationships with plasma concentrations of foretinib (PK) and clinical outcome (progression free survival [PFS] and RECIST response) were also examined. Statistically significant increases from baseline of sMET at days 5, 15, 29, and 47 (p&amp;lt;.0001, p =.0344, p=.0353, p&amp;lt;.0001 respectively), VEGFA at days 5 (p&amp;lt;.0001) and 47 (p&amp;lt;.0001), and HGF at day 47 (p&amp;lt;.0001) were observed. Statistically significant decreases of sVEGFR2 at days 5, 15, 29, and 47 (all p&amp;lt;.0001) were also observed. Plasma VEGFA levels at day 5, 15, 29 are weakly correlated with PK (p=.033, p=.0138, p=.0165, respectively). Plasma sMET levels and changes from baseline at day 47 showed significant correlation with baseline tumor SLD (sum of longest diameter, R=0.54, p=0.0042; R=0.40, p=0.0443 respectively). Plasma VEGFA levels and changes from baseline at day 47 showed significant correlation with baseline tumor SLD (R=0.55, 0.44, respectively, p&amp;lt;0.01) and SLD at 8 weeks (R=0.64, 0.61, respectively, p&amp;lt;0.01). No correlation was observed between these four markers and PFS/RECIST response. Changes in sMET, VEGFA, and sVEGFR2 levels were observed for both intermittent and daily dosing schedules in the gastric cancer study. Although SLD at 8 weeks did not change significantly from baseline in the GC study, plasma levels of sMET and VEGFA correlated positively with the week 8 magnitude of SLD. Hence plasma levels of sMET and VEGFA may reflect biological changes following foretinib treatment. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B210.

Corneal Neovascularization and Ocular Irritancy Responses in Dogs Following Topical Ocular Administration of an EP4-Prostaglandin E2 Agonist

Prostaglandin receptor agonists have intraocular pressure-lowering effects in humans and are of interest in the treatment of glaucoma. The prostanoid receptor agonist PF-04475270 is a potent and selective agonist of the prostaglandin E(2) receptor EP4. This paper characterizes the toxicity associated with topical ocular administration of PF-04475270 in beagles. Dogs were given PF-04475270 topically to the eye on a consecutive daily dosing schedule for one or four weeks followed by a one-or four-week reversal period, respectively. Clinical observations, ophthalmic, and laboratory parameters were recorded. Necropsies were conducted at the end of the dosing and recovery phases, and histologic examinations performed. Corneal neovascularization that was considered adverse was observed at doses of >or=1.0 microg/eye and was not reversed by the end of the recovery phase. Dogs dosed with >or=0.25 microg/eye developed a dose-related conjunctival hyperemia that persisted throughout the reversal period. Corneal neovascular cells stained positive with EP4 and the endothelial biomarker Factor VIII-vWF. Other histopathology findings observed at doses of >or=1.0 microg included single-cell necrosis and neutrophils in the cornea, inflammatory cell infiltrates in the iris/ciliary body, and iridal endothelial cell hypertrophy. A resolving acute to subacute inflammation in the iris/ciliary body was observed after the four-week recovery period.

Effectiveness and Tolerance of Azacitidine for Treating Patients with Chronic Myelomonocytic Leukemia in Community-Based Management.

Abstract 4855 IntroductionAzacitidine (AZA) was recently approved in Europe by the EMEA for the treatment of Chronic Myelomonocytic Leukemia (CMMoL). Traditionally, CMMoL has been considered as part of the myelodysplastic syndrome (MDS) according to the FAB (French-American-British) classification. Nowadays, according to the criteria proposed by the World Health Organization (WHO), it is included as a subgroup of diseases of mixed characteristics named as myelodysplastic/myeloproliferative diseases (MDS/MPD) separate from MDS. Recent discoveries in the molecular biology of CMMoL have provided new therapeutic agents to test. Treatment with AZA was approved by the EMEA on the basis of the AZA-001 phase III clinical trial. AZA is also approved for the treatment of the MDS. AZA was available in Spain under compassionate use before its regulatory approval (May 2009). We present the effectiveness and tolerance data for AZA clinical activity in patients with CMMoL included in the Spanish compassionate use registry. Material and MethodsWe present the preliminary clinical results taken from data from a longitudinal, multicenter Spanish patient registry, which retrospectively collected data from community-based hematology clinics on the disease course and management of patients with CMMoL treated in a compassionate use setting with AZA, in whom the dosing schedule administered was documented. AZA dosing was applied to the patients in two different dosing schedules in 28-day cycles: either days 1, 2, 3, 4 and 5 or days 1, 2, 3, 4, 5, 8 and 9. Choice of schedule was based on patient status. As of August 1, 2009, data from 10 patients with MDS diagnosed according to the WHO criteria had been collected. Response to treatment was assessed using the International Working Group (IWG 2006) criteria. Treatment toxicity was assessed using the NCI-CTCAE version 3.0 criteria. ResultsData collection comprised results from 8 male and 2 female, with a median age of 64 years (range 62-80). An intermediate-2/high IPSS risk was documented in 20% of the patients and a 0-1 ECOG status before treatment initiation was documented 80% of the patients. Patients received a median of 5 cycles of AZA (range 2-12). The most frequently used dose was 75 mg/m2 (90%). A 5-day dosing schedule was administered to 70% of the patients and a 5+2 day dosing schedule with 2 free days was administered to the remaining 30%. The most frequent administration route was subcutaneous injection (70%). According to the IWG 2006 response criteria, 20% of patients obtained a complete response, 20% achieved a complete bone marrow response, and, in a further 10%, hematological response was documented. The grade 3-4 adverse events, regardless of their relationship with the active treatment, were of hematological nature (neutropenia n=5, thrombocytopenia n=4, anemia n=1). Other grade 3-4 adverse events documented were rash (n=2), injection site reaction (n=1), hypotension (n=1) and constitutional symptoms (n=1). These rates do not differ from those obtained in the AZA-001 study. ConclusionsThese results demonstrate that AZA is effective for the treatment of patients with CMMoL in community-based management. Different dosing schedules are prescribed to patients with CMMoL treated with AZA in the community-based setting. Further analyses from this registry are awaited. DisclosuresNo relevant conflicts of interest to declare.

Phase I trial of temozolomide plus O6-benzylguanine 5-day regimen with recurrent malignant glioma

This phase I clinical trial conducted with patients who had recurrent or progressive malignant glioma (MG) was designed to determine the maximum tolerated dose (MTD) and toxicity of three different 5-day dosing regimens of temozolomide (TMZ) in combination with O(6)-benzylguanine (O(6)-BG). Both TMZ and O(6)-BG were administered on days 1-5 of a 28-day treatment cycle. A bolus infusion of O(6)-BG was administered at 120 mg/m(2) over 1 h on days 1, 3, and 5, along with a continuous infusion of O(6)-BG at 30 mg/m(2)/day. TMZ was administered at the end of the first bolus infusion of O(6)-BG and then every 24 h for 5 days during the continuous infusion of O(6)-BG. Patients were accrued to one of three 5-day dosing regimens of TMZ. Twenty-nine patients were enrolled into this study. The dose-limiting toxicities (DLTs) were grade 4 neutropenia, leukopenia, and thrombocytopenia. The MTD for TMZ for the three different 5-day dosing schedules was determined as follows: schedule 1, 200 mg/m(2) on day 1 and 50 mg/m(2)/day on days 2-5; schedule 2, 50 mg/m(2)/day on days 1-5; and schedule 3, 50 mg/m(2)/day on days 1-5 while receiving pegfilgrastim. Thus, the 5-day TMZ dosing schedule that maximized the total dose of TMZ when combined with O(6)-BG was schedule 1. This study provides the foundation for a phase II trial of O(6)-BG in combination with a 5-day dosing schedule of TMZ in TMZ-resistant MG.

Clinical experience with different dosing schedules of decitabine in patients with myelodysplastic syndromes (MDS)

7011 Background: Decitabine, a potent DNA hypomethylating agent, has demonstrated efficacy in MDS patients using two dosing regimens: 15 mg/m2 intravenous (IV) over 3 hours (hrs) every (q) 8 hrs for 3 days q 6 weeks (wks) and 20 mg/m2 IV over 1 hr once daily for 5 consecutive days q 4 wks. Methods: Results were reviewed from two randomized phase 3 studies comparing the 3-day dosing schedule of decitabine with supportive care, D-0007 and EORTC-06011, and two phase 2 studies with the 5-day dosing schedule, DACO-020 and ID03–0180. Data from each clinical trial supporting overall improvement, duration of improvement, time to AML or death, progression-free survival (PFS), and transfusion independence was assessed. Results: Patients had IPSS classification scores of intermediate-2 or high-risk (D-0007, 70%; EORTC-06011, 93%; ID03–0180, 66%; DACO-020, 46%) and de novo MDS (D-0007, 87%; EORTC-06011, 88%; ID03–0180, 70%; DACO-020, 89%). Comparable overall improvement (complete response [CR] + partial response [PR] + hematologic improvement [HI]), time to AML or death, and PFS was observed across all trials (Table). The duration of improvement ranged between 9.2 and 11.3 months. A trend was observed for improved outcomes with an increased number of decitabine treatment cycles. Conclusions: Overall improvement rates by IWG criteria exceeded 30% in all 4 studies. Higher overall improvement rates corresponded to increased median number of treatment cycles. Increasing the number of decitabine treatment cycles administered may provide additional benefit to MDS patients. [Table: see text] [Table: see text]

Effect of TKI258 on plasma biomarkers and pharmcokinetics in patients with advanced melanoma

9020 Background: TKI258 (dovitinib lactate), is a multi-tyrosine kinase inhibitor of VEGF receptors-1,2,3, FGF receptors-1, 2, 3, PDGFR-β, and c-KIT. A phase I study was conducted to determine the maximum tolerated dose (MTD), the biological activity and the preliminary efficacy of TKI258 in patients with advanced melanoma. A panel of plasma biomarkers of angiogenesis and soluble receptors were evaluated to determine the pharmacodynamic effect of TKI258. Methods: Patients were treated orally with 200, 300, 400 or 500 mg/day on a once daily continuous dose schedule. The MTD was defined at 400 mg/day. Plasma samples from 43 patients were collected. Plasma concentration of TKI258 was measured by LC/MS/MS. Plasma VEGF, placental growth factor (PLGF), basic FGF (bFGF), and soluble VEGFR1 and VEGFR2 (sVEGFR1 and 2), and c-Kit were measured by multiplex assays using the Meso-Scale Discovery platform. Plasma FGF23 was evaluated by ELISA as a pharmcodynamic marker of FGFR1 inhibition. Results: Following 400 mg or 500 mg continuous daily dosing, the mean plasma exposure (AUC24hr) was approximately 3000 ng/mL*h and 4100 ng/mL*h, respectively. No accumulation in TKI258 plasma exposure was observed at doses of 400mg or below, while accumulation up to 2.5-fold was observed on day 15 following the 500 mg daily dose. At the end of the first treatment cycle, mean plasma VEGF, PLGF and FGF23 levels increased over baseline by 100%, 198% and 68%, respectively, while mean plasma sVEGFR2 levels decreased by 15% in patients treated with 400 and 500 mg/day TKI258. Further analysis of correlations with pharmacokinetic and clinical parameters is ongoing. Conclusions: TKI258 therapy is associated with increases of plasma VEGF and PLGF as well as decreases of sVEGFR2 suggesting VEGFR inhibition. Induction of plasma FGF23 suggest that FGFR may be inhibited at doses of 400 mg/day and above. This panel of circulating proteins may have utility as pharmacodynamic biomarkers of TKI258 activity in patients with advanced melanoma. [Table: see text]

Assessment of two dosing schedules of GSK1363089 (GSK089), a dual MET/VEGFR2 inhibitor, in metastatic gastric cancer (GC): Interim results of a multicenter phase II study

4502 Background: GSK089 is an oral, small-molecule inhibitor of cMET and VEGFR2/KDR, and has potent antitumor activity in cMET-amplified cell lines and xenografts. cMET is reportedly amplified, overexpressed and/or activated in GC, making it an attractive therapeutic target. This phase II study examines the safety and efficacy of 2 dosing schedules of GSK089 as a single agent in patients (pts) with metastatic GC. Methods: Pts with distal esophagus, GE junction or stomach adenocarcinoma, 0–2 prior chemotherapy regimens, adequate organ function, measurable disease, and ECOG PS 0–2 are sequentially enrolled in 2 cohorts: 1) Intermittent 5 days on/9 off - GSK089 240 mg/d on D1–5 repeated every 14 days, and 2) Daily - 80 mg/d. Primary study endpoint (response) is assessed every 8 weeks. cMET amplification by FISH (≥2 copies of cMET per copy of chromosome 7) is not an entry criterion, but is determined on archival tissue for all pts. Pre- and on-treatment tumor biopsies in select pts and plasma samples in all pts are analyzed for GSK089 effects on direct and downstream drug targets. GSK089 pharmacokinetics (PK) are also evaluated. Results: As of 12/19/08, enrollment to the 5 on/9 off cohort is complete with 41 evaluable pts, and 14 evaluable pts have enrolled on the daily cohort. cMET amplification was seen in 3/43 (7%) pts tested; all 3 were in 5 on/9 off cohort. Best response of stable disease (SD), was noted in 6/41 (15%) pts in the 5 on/9 off cohort (none were cMET-amplified), with 2 pts SD &gt;6 months, 1 ongoing; and in 3/14 (21%) pts in the daily cohort. Among all-enrolled pts (48 pts in 5 on/9 off, 16 pts in daily cohort), LFT abnormalities (9%), fatigue (5%), and venous thromboembolism (3%) were the most common GSK089 related grade 3- 4 adverse events (AE). Only 1 possibly related grade 5 AE, death due to unknown cause, was noted. Conclusions: GSK089 is well tolerated on both dosing schedules. cMET amplification in metastatic GC is rare. Single agent GSK089 demonstrates minimal antitumor activity in a cMET-unselected gastric population on the 5 on/9 off schedule. Enrollment on the daily dosing schedule continues, now with mandatory pre- and on-treatment biopsies to better define cMET pathway and target inhibition with GSK089. No significant financial relationships to disclose.

Pharmacokinetic and pharmacodynamic modelling of marbofloxacin administered alone and in combination with tolfenamic acid in goats

In a four-period cross-over study, the fluoroquinolone antibacterial drug marbofloxacin (MB) was administered to goats intramuscularly (IM) at a dose rate of 2 mg/kg, both alone and in combination with the non-steroidal anti-inflammatory drug tolfenamic acid (TA), also administered IM at a dose rate of 2 mg/kg. Using a tissue cage model of inflammation, based on the irritant actions of carrageenan, the pharmacokinetics (PK) of MB and MB in combination with TA were determined. MB mean values of area under concentration-time curve (AUC) were similar for serum (5.60 microg h/mL), inflamed tissue cage fluid (exudate; 5.32 microg h/mL) and non-inflamed tissue cage fluid (transudate; 4.82 microg h/mL). Values of mean residence time (MRT) of MB in exudate (15.5 h) and transudate (15.8 h) differed significantly from serum MRT (4.23 h). Co-administration of TA did not affect the PK profile of MB. The pharmacodynamics of MB were investigated using a caprine strain of Mannheimia haemolytica. Integration of PK data with ex vivo bacterial time-kill curve data for serum, exudate and transudate provided AUC(24h)/minimum inhibitory concentration (MIC) ratios of 160, 133 and 121 h, respectively, for the strain of organism used. Modelling of the ex vivo time-kill data to the sigmoid E(max) equation provided AUC(24h)/MIC values required for bacteriostatic and bactericidal actions of MB and for virtual eradication of the organism of 27.6, 96.2 and 147.3 h, respectively. Corresponding values for MB+TA were 20.5, 66.5 and 103.0 h. These data were used to predict once daily dosage schedules of MB for subsequent clinical evaluation.

Pleural Effusion in Dasatinib-Treated Chronic Myeloid Leukemia Patients after Imatinib Failure

Dasatinib, as a 2nd generation tyrosine kinase inhibitor, is an effective Bcr-Abl kinase inhibitor for chronic myeloid leukemia (CML) with more than 300-fold and 20-fold potency than imatinib and nilotinib, respectively. Through a series of phase I and II clinical trials, dasatinib has demonstrated durable efficacy in CML patients with resistance, suboptimal response, or intolerance to imatinib. However, some adverse effects from dasatinib therapy have been reported in several studies. Among them, pleural effusion is one of the most common adverse effects, and was reported in 15 to 30% of patients.We investigated the development of pleural effusion from 64 Korean patients registered in a single center for a phase II study which was approved by the institutional review committee and carried out in accordance with the Declaration of Helsinki with informed consent provided from patients. All the patients are under dasatinib therapy after failure of imatinib treatment (22 patients with intolerance and 44 patients with resistance). Median age was 44 years old (range, 18 to 65) and median duration of dasatinib therapy was 29 months (range, 0.5 to 41). The patients were in different phases including 30 in chronic phase (CP) and 30 in accelerated phase (AP) when they started dasatinib treatment.We found that 23 patients (36%) experienced pleural effusion of any grade (grade 1/2 in 22, grade 3/4 in 1) at least one time. Among the 23 patients, 14 (61%) patients experienced recurrent pleural effusion, and two of them showed a change in grade from grade 1 to 2. The median time to the first occurrence of pleural effusion was 18 weeks (range, 1 to 132), developing within the first 6 months and 12 months of treatment in 13 patients (57%) and in 15 patient (65%), respectively, while the adverse effect occurred even after 28 months (2.3 years) of treatment in 3 patients (13%).Age, gender, previous interferon a treatment, duration of imatinib treatment, and duration of dasatinib treatment were not significantly different between patients without pleural effusion and patients developed pleural effusion. However, disease phase when dasatinib therapy started showed significant difference (P=0.002) in the development of pleural effusion. Patients in AP showed higher cumulative % of pleural effusion in comparison with those in CP (16/34, 47% vs. 7/30, 23%).Daily dose amount and dose schedule also gave an influence on occurrence of pleural effusion. We used 4 different categories in dose amount and dose schedule; 100 mg QD (n=3), 140 mg QD (n=32), 50 mg BID (n=7) and 70 mg BID (n=22). Frequency of pleural effusion was higher in the patients treated with BID schedule than in QD schedule (56% vs. 22%, P=0.005), and also higher in the patients treated with 140 mg per day than in 100 mg per day, but not significant (39% vs. 20%, P=0.23). Among 4 categories, 70 mg BID showed relatively higher % of pleural effusion (64%, 14/22, P=0.006).To see whether dose amount or dose schedule can influence on efficacy, we investigate cytogenetic responses from patients. Portion of complete cytogenetic response (CCyR) was not significantly different in 100 mg doge group and 140 mg dose group (67% vs. 64%). Time to achieving CCyR showed no significant difference (P=0.21) between 100 mg dose group (median 3 months, range; 2 to 17) and 140 mg dose group (median 6 month, range; 1 to 18). In addition, dose schedule did not make any significant difference in portion of achieving CCyR between QD group and BID group (60% vs. 59%).Based on the observed characteristics of pleural effusion and analysis of cytogenetic response in this study, lower dose (100 mg) administration by QD can be proposed for dasatinib therapy to reduce any possible occurrence of pleural effusion. [Display omitted]

Decitabine in Myelodysplastic Syndromes: Argentine Initial Multi-Institutional Clinical Experience

Epigenetic therapy with a hypomethylating agent is becoming the standard of care in some intermediate and high-risk myelodysplastic syndromes (MDS). The DNA-targeted hypomethylating agent, decitabine (DACOGEN, Janssen Cilag Farmaceutica S.A. and Eisai Inc.), has been approved for patients (pts) with intermediate-1 (INT-1), intermediate-2 (INT-2), and high-risk MDS in Argentina. An alternative regimen with decitabine 20 mg/m2 IV over 1 hour once daily for 5 consecutive days repeating every 4 weeks, permits its use in the outpatient clinic. Clinical and hematological response and safety were analyzed retrospectively for pts with all FAB subtypes of MDS who had received this dosing regimen at 17 centers in our country between July 2007 and June 2008. Inclusion criteria were: ≥18 years of age; de novo or secondary MDS; and International Prognosis Scoring System (IPSS) score ≥0.5. Exclusion criteria were: diagnosis of acute myeloid leukemia (AML) or other progressive malignant disease. Patients with prior therapy were not excluded. The primary endpoint was overall response, assessed by IWG 2006 criteria. Thirty-eight pts were enrolled: median age 67 years; 71% male and 29% female. The diagnosis was de novo MDS in 34 pts (89%) and secondary MDS in 4 (11%). The median time from diagnosis to first dose of decitabine was 7 months. Eastern Cooperative Oncology Group performance status scores were 0 (21%), 1 (47%), 2 (26%) and 3 (5%). IPSS scores were INT-1 (50%), INT-2 (8%), and high-risk (42%). Cytogenetic abnormalities were found in 37% of pts. FAB classification was: RA (21%), RARS (8%), RAEB (18%), RAEB-T (24%) and CMML (29%). A median of 3.5 cycles (range, 1–8) were given. Dosage had to be reduced in 7 pts (18%) due to comorbidity and cytopenias. Overall improvement rate in the intent-to-treat population was 45% (Table), including: 9% complete response (CR), 5% marrow complete response (mCR), 5% partial response (PR) and 26% hematological improvement (HI). Two pts (5%) had stable disease. Four pts (11%) were non-evaluable for response. Most pts had their first hematological response by cycle 2 and their best response by cycle 4. The mean ± SD time to best response was 2.7±3 months. No differences in clinical and hematological response were observed between pts with INT-2/High compared to INT-1 (8/19 and 9/19, respectively); red cell and platelet transfusion requirements resolved during the first 2 cycles in 13/16 and 7/8 pts, respectively. Overall improvement rates were similar in pts with more and less than 1 year since MDS diagnosis (9/18 and 8/20, respectively). Overall survival was 71% during the observational period (up to 11 months). The most frequent adverse events were neutropenia without fever (47%) and with fever (21%), especially during cycle 2, and thrombocytopenia (23%). This study showed prompt clinical activity for an alternative 5-day dosing schedule of decitabine in the outpatient setting and an overall improvement rate of 45%, with an initial response by cycle 2, the best response by cycle 4, and acceptable tolerability.<>Table. Response to 5-Day Decitabine Dosing ScheduleIWG 2006 CriteriaITT (N=38)Overall Improvement Rate (CR+mCR+PR+HI)17 (45%)CR (Complete Response)3 (9%)mCR (Marrow Complete Response)2 (5%)PR (Partial Response)2 (5%)HI (Hematological Improvement)10 (26%)SD (Stable Disease)2 (5%)Failure (Progressive Disease or Death)15 (39%)Non-Evaluable4 (11%)

Nonclinical Safety Evaluation of Sunitinib: A Potent Inhibitor of VEGF, PDGF, KIT, FLT3, and RET Receptors

Sunitinib malate (SUTENT) is a multitargeted receptor tyrosine kinase (RTK) inhibitor that is approved multinationally for the treatment of imatinib-resistant/-intolerant gastrointestinal stromal tumor and advanced renal cell carcinoma. This paper characterizes the organ toxicity of sunitinib in Sprague-Dawley rats and cynomolgus monkeys, and the reversibility of any treatment-induced effects. Rats and monkeys received sunitinib (0-15 and 0-20 mg/kg/day, respectively) orally on a consecutive daily dosing schedule for thirteen weeks or on an intermittent daily dosing schedule for up to nine months. Clinical observations and laboratory parameters were recorded. Necropsy was conducted following treatment/recovery periods, and histologic examinations were performed. In rats, sunitinib was generally tolerated at 0.3 and 1.5 mg/kg/day, and findings were reversible. In monkeys, the level at which there were no observed adverse effects was 1.5 mg/kg/day, and findings were similarly reversible (except for uterine/ovarian weight changes and skin pallor). Data suggest that inhibition of multiple RTK pathways may induce pharmacologic effects on organ systems in nonclinical species. Key pharmacologic effects of sunitinib included reversible inhibition of neovascularization into the epiphyseal growth plate, and impaired corpora lutea formation and uterine development during estrus. Similar observations have been noted with this class of RTK signaling inhibitors and are consistent with pharmacologic perturbations of physiologic/angiogenic processes associated with the intended molecular targets.

Phase 1 study of TAS-102 administered once daily on a 5-day-per-week schedule in patients with solid tumors

This study was designed to determine the safety and optimal dosing of TAS-102, a novel oral combination of alphaalphaalpha-trifluorothymidine (FTD) and an inhibitor of thymidine phoshorylase, in patients with solid tumors. Patients who met the eligibility criteria were treated with one of two different TAS-102 regimens: once per day on either days 1-5 and 8-12 every 4 weeks (schedule A) or days 1-5 every 3 weeks (schedule B). The primary objectives were the determination of the maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended phase II dose. Pharmacokinetic analysis was conducted during courses 1 and 2. Sixty-three patients received a total of 172 courses of therapy with the median number of courses delivered on both schedules being 2. DLTs were observed in three patients on schedule A, 70 mg/m(2)/day (1) and 110 mg/m(2)/day (2); and in five patients on schedule B, 120 mg/m(2)/day (1), 170 mg/m(2)/day (2), 180 mg/m(2)/day (2). Granulocytopenia was the DLT in seven of the eight cases. The most frequent toxicities were nausea, fatigue, granulocytopenia, anemia, diarrhea, and abdominal pain. Twelve patients, 6 on schedule A and 6 on schedule B, were treated at the recommended phase II dose, with good tolerance. No objective responses were seen in this heavily pretreated, 5-FU-refractory population. The pharmacokinetic parameters of FTD are a T (max) of 0.53 to 3.15 h, t (1/2) of 1.46 to 4.20 h, volume of distribution of 0.0526 to 0.483 l/kg, and clearance of 0.0194 to 0.197 1/h/kg. The recommended phase II doses for TAS-102 are 100 mg/m(2)/day on schedule A and 160 mg/m(2)/day on schedule B. Future development of TAS-102 should focus upon multiple daily dosing schedules.

Use of Netilmicin Once or Twice Daily in Preterm Newborns: Evaluation of Nephrotoxicity by Urinary α1-Microglobulin and Retinol Binding Protein

Since aminoglycoside efficacy is proportional to serum peak/MIC ratio and linked to post antibiotic effect, use of netilmicin once rather than twice a day has been proposed. On the other hand netilmicin might play a role in drug-induced nephrotoxicity, mainly on proximal tubule. Urinary retinol binding protein (RBP) and α1 microglobulin (α1m) are early and specific indicators of tubular damage and dysfunction.21 preterm neonates (GA < 37 weeks) were divided in two groups on the basis of netilmicin administration modality (1: once a day, 2: twice a day, both for 7 days, at 5 mg/kg/die) and differences in netilmicin tolerability were assessed by evaluation of α1m and RBP levels by immunonephelometric method. No significant differences were found between the two groups either considering levels at time 1 and at time 2, or considering the difference between time 1 and 2 (∆1/2). In our study once-daily dosing schedule shows similar low rates of nephrotoxicity, compared with multiple daily dosing schedule: this result may support the general adoption of once-daily dosing of netilmicin in clinical practice.

A multicenter phase II trial of the decitabine alternative 5-day dosing regimen: Analysis of efficacy in various subgroups of patients with myelodysplastic syndromes (MDS)

7032 Background: Decitabine is an efficient hypomethylating agent approved by the FDA for the treatment of MDS. In a Phase III trial that studied a 3-day dosing regimen, the overall improvement (IWG 2000: complete response [CR] + partial response [PR] + hematologic improvement [HI]) rate for decitabine was 30% versus 7% in the supportive care arm (Cancer 2006:106:1794); responses were seen in all International Prognostic Scoring System (IPSS) risk groups. A single center Phase II trial in patients (pts) with MDS, examining an alternative outpatient regimen of decitabine administered at 20 mg/m2 IV over 1 hour once daily for 5 days every 4 weeks, resulted in an overall improvement rate (IWG 2006: CR + marrow CR (mCR) + PR + HI) of 72% (Cancer 2007:109:265). The purpose of this trial was to examine the efficacy and safety of this alternative dosing regimen in a multicenter setting. Methods: This Phase II trial enrolled pts with all FAB classifications of MDS and IPSS scores ≥ 0.5 with an ECOG performance status of 0–2. An expert review of responses according to IWG 2006 criteria was performed. Results: Baseline patient characteristics: median age 72 yrs, 11% had secondary MDS, 27% with prior MDS disease-modifying therapy, and 29% had poor risk cytogenetics. The overall improvement rate was similar across IPSS risk groups (Intermediate-1 [n=52]: 50%; Intermediate-2 [n=23]: 61%; High Risk [n=23]: 43%). 82% of pts who experienced clinical improvement did so by cycle 2. The overall improvement rate was 51% for pts with de novo MDS, 45% for secondary MDS, and 44% for pts who received prior disease-modifying agents. The safety profile was consistent with previous studies. Conclusions: This multicenter trial examining the alternative 5-day decitabine dosing schedule compares favorably with that of the 3-day dosing regimen, provides validation and generalizability of the previously published single center trial and confirms that the alternative schedule is safe and effective in pts with MDS including those who have poor prognostic factors. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration MGI Pharma MGI Pharma MGI Pharma MGI Pharma MGI Pharma, Pharmion