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Purpose: The aim of this study was to determine the plasma pharmacokinetics of eribulin mesylate in patients with solid tumors with mild and moderate hepatic impairment. Patients and methods: A phase I, pharmacokinetic study was performed in patients with advanced solid tumors and normal hepatic function or Child-Pugh A (mild) or Child-Pugh B (moderate) hepatic impairment. Treatments were given on day 1 and 8 of a 21-day cycle and consisted of 1.4, 1.1 and 0.7 mg/m eribulin mesylate, for normal hepatic function, Child-Pugh A and B hepatic impairment, respectively. Also safety and anti-tumor activity were determined. Results: Hepatic impairment increased exposure to eribulin. In patients with Child-Pugh A ( N = 7) and Child-Pugh B ( N = 5), mean dose-normalized AUC was 1.75-fold (90 % confidence intervals (CI): 1.16-2.65) and 2.48-fold (90 % CI: 1.57-3.92) increased, respectively, compared with patients who have normal function ( N = 6). The most frequently reported treatment-related events were alopecia (12/18) and fatigue (7/18) and these were observed across all groups. Nine patients (50 %) had stable disease as best response. Conclusions: A reduced dose of 1.1 and 0.7 mg/m of eribulin mesylate is recommended for patients with Child-Pugh A or B hepatic impairment, respectively. [ABSTRACT FROM AUTHOR]

Background:The objectives of this phase I study were to assess the safety and tolerability of E7080 in patients with advanced, refractory solid tumours; to determine the maximum tolerated dose (MTD) and pharmacokinetics profile of E7080; and to explore preliminary evidence of its anti-tumour efficacy.Methods:E7080 was administered orally in escalating doses on a once-daily continuous schedule in 28-day cycles to eligible patients. Samples for pharmacokinetic analyses were collected on days 1, 8, 15 and 22 of cycle 1 and day 1 of cycle 2. Anti-tumour efficacy was assessed every two cycles.Results:Eighty-two patients received E7080 in dose cohorts from 0.2 to 32 mg. Dose-limiting toxicities were grade 3 proteinuria (two patients) at 32 mg, and the MTD was defined as 25 mg. The most frequently observed cumulative toxicities (all grades) were hypertension (40% of patients), diarrhoea (45%), nausea (37%), stomatitis (32%) and vomiting (23%). Seven patients (9%) had a partial response and 38 patients (46%) had stable disease as best response. E7080 has dose-linear kinetics with no drug accumulation after 4 weeks' administration.Conclusion:E7080 is well tolerated at doses up to 25 mg per day. Encouraging anti-tumour efficacy was observed in patients with melanoma and renal cell carcinoma. [ABSTRACT FROM AUTHOR]

E7820 is an orally active inhibitor of α-integrin mRNA expression, currently tested in phases I and II. We aimed to evaluate what levels of inhibition of integrin expression are needed to achieve tumor stasis in mice, and to compare this to the level of inhibition achieved in humans. Tumor growth inhibition was measured in mice bearing a pancreatic KP-1 tumor, dosed at 12.5-200 mg/kg over 21 days. In the phase I study, E7820 was administered daily for 28 days over a range of 0-200 mg, followed by a 7-day washout period. PK-PD models were developed in NONMEM. α-Integrin expression measured on platelets, corresponding to tumor stasis at t = 21 in 50% and 90% of the mice ( I, I) were calculated. It was evaluated if these levels of inhibition could be achieved in patients at tolerable doses. One hundred nineteen α-Integrin measurements and 210 tumor size measurements were available from mice. The relationship between PK and α-integrin expression was modeled using an indirect-effect model, subsequently linked to an exponential tumor growth model. I and I were 14.7% (RSE 7%) and 17.9% (RSE 8%). Four hundred sixty two α-integrin measurements were available from 29 patients. Using the schedule of 100 mg qd (MTD), α-integrin expression was inhibited more strongly than the I and I in greater than 95% and greater than 50% of patients, respectively. Moderate inhibition of α-integrin expression corresponded to tumor stasis in mice, and similar levels could be reached in patients with the dose level of 100 mg qd. [ABSTRACT FROM AUTHOR]

This dose escalation study was designed to determine the recommended dose of the multi-targeted cell cycle inhibitor indisulam in combination with capecitabine in patients with solid tumours and to evaluate the pharmacokinetics of the combination. Thirty-five patients were treated with indisulam on day 1 of each 21-day cycle. Capecitabine was administered two times daily (BID) on days 1–14. Plasma concentrations of indisulam, capecitabine and its three metabolites were determined for pharmacokinetic analysis. The main dose-limiting toxicity was myelosuppression. Hand/foot syndrome and stomatitis were the major non-haematological toxicities. The recommended dose was initially established at indisulam 700 mg m−2 and capecitabine 1250 mg m−2 BID. However, during cycle 2 the recommended dose was poorly tolerated in three patients. A dose of indisulam 500 mg m−2 and capecitabine 1250 mg m−2 BID proved to be safe at cycle 1 and 2 in nine additional patients. Indisulam pharmacokinetics during cycle 1 were consistent with pharmacokinetic data from phase I mono-therapy studies. However, exposure to indisulam was remarkably increased at cycle 2 due to a drug–drug interaction between capecitabine and indisulam. Partial response was confirmed in two patients, one with colon carcinoma and the other with pancreatic carcinoma. Seventeen patients had stable disease. Indisulam (700 mg m−2) in combination with capecitabine (1250 mg m−2 BID) was well tolerated during the first cycle. A dose of indisulam 500 mg m−2 and capecitabine 1250 mg m−2 BID was considered safe in multiple treatment cycles. The higher incidence of toxicities observed during cycle 2 can be explained by a time-dependent pharmacokinetic drug–drug interaction.British Journal of Cancer (2008) 98, 1320–1326. doi:10.1038/sj.bjc.6604300 www.bjcancer.com Published online 15 April 2008 [ABSTRACT FROM AUTHOR]

Indisulam (E7070) is an anticancer agent that is currently being evaluated in phase II clinical studies. A significant reduction in glutathione synthetase and glutathione reductase transcripts by indisulam provided a molecular basis for its combination with platinum agents. Indisulam demonstrated high anti-tumour activity in various preclinical cancer models. The objectives of this study were (1) to determine the recommended dose of indisulam in combination with carboplatin in patients with solid tumours and (2) to evaluate the pharmacokinetics of the combination. Patients with solid tumours were treated with indisulam in combination with carboplatin. Indisulam (350, 500, or 600 mg m−2) was given as a 1-hour intravenous infusion on day 1 and carboplatin (5 or 6 mg min ml−1) as an intravenous infusion over 30 min on day 2 of a three-weekly cycle. Sixteen patients received study treatment and were eligible. Thrombocytopenia was the major dose limiting toxicity followed by neutropenia. Both drugs contributed to the myelosuppressive effect of the combination. Indisulam 500 mg m−2 in combination with carboplatin 6 mg min ml−1 was identified not to cause dose limiting toxicity, but a delay of re-treatment by 1 week was required regularly to allow recovery from myelosuppression. The recommended dose and schedule for an envisaged phase II study in patients with non-small cell lung cancer is indisulam 500 mg m−2 in combination with carboplatin 6 mg min ml−1 repeated four-weekly. Patients who do not experience severe thrombocytopenia at cycle 1 will be permitted to receive an escalated dose of indisulam of 600 mg m−2 from cycle 2 onwards.British Journal of Cancer (2007) 96, 559–566. doi:10.1038/sj.bjc.6603606 www.bjcancer.com Published online 6 February 2007 [ABSTRACT FROM AUTHOR]

Aim. MEN-10755 is a novel anthracycline analogue that has shown an improved therapeutic efficacy over doxorubicin in animal models, especially in gynaecological and lung cancers and is currently under clinical development for the treatment of solid tumours. The aim of the project was to develop an optimal sampling strategy for MEN-10755 to provide an efficient basis for future pharmacokinetic/pharmacodynamic investigations. Methods. Data from 24 patients who participated in a phase I clinical pharmacokinetic study of MEN-10755 administered as a short i.v. infusion were included. Individual pharmacokinetic values were calculated by fitting the plasma concentration data to a two-compartment model using nonlinear least-squared regression (KINFIT, Ed 3.5). Population pharmacokinetic analysis was carried out using (a) the traditional standard two-stage method (STS) based on all data (KINFIT-ALL), (b) the iterative two-stage Bayesian (IT2B) population modelling algorithm (KINPOP), and (c) the STS method using KINFIT and using four optimally timed plasma concentrations (KINFIT-OSS4). Determinant (D) optimal sampling strategy (OSS) was used to evaluate the four most information-rich sampling times. The pharmacokinetic parameters Vc (l), kel (h-1), k12 (h-1) and k21 (h-1) calculated using KINPOP served as a model for calculation of four D-optimal sampling times. D-optimal sampling data sets were analysed using KINFIT-OSS4 and compared with the population model obtained by the traditional standard two-stage approach for all data sets (KINFIT-ALL). Results. The optimal sampling times were: the end of the infusion, and 1.5 h, 3.8 h and 24 h after the start of the infusion. The four-point D-optimal sampling design determined in this study gave individual parameter estimates close to the basic standard estimates using the full data set. Conclusion. Because accurate estimates of pharmacokinetic parameters were achieved, the four-point D-optimal sampling design may be very useful in future studies with MEN-10755. [ABSTRACT FROM AUTHOR]

S-1 is an oral formulation of ftorafur (FT), oxonic acid and 5-chloro-2,4-dihydroxypyridine (CDHP) at a molar ratio of 1:0.4:1. FT is a 5-fluorouracil (5-FU) prodrug, CDHP is a dihydropyrimidine dehydrogenase (DPD) inhibitor and oxonic acid is an inhibitor of 5-FU phosphoribosylation in the gastrointestinal mucosa and was included to prevent gastrointestinal toxicity. We determined the pharmacokinetics of S-1 in 28 patients at doses of 25, 35, 40 and 45 mg/m2. The plasma Cmax values of FT, 5-FU, oxonic acid and CDHP increased dose-dependently and after 1–2 h were in the ranges 5.8–13 μM, 0.4–2.4 μM, 0.026–1.337 μM, and 1.1–3.6 μM, respectively. Uracil levels, indicative of DPD inhibition, also increased dose-dependently from basal levels of 0.03–0.25 μM to 3.6–9.4 μM after 2–4 h, and 0.09–0.9 μM was still present after 24 h. The pharmacokinetics of CDHP and uracil were linear over the dose range. The areas under the plasma concentration curves (AUC) for CDHP and uracil were in the ranges 418–1735 and 2281–8627 μmol·min/l, respectively. The t1/2 values were in the ranges 213–692 and 216–354 min, respectively. Cumulative urinary excretion of FT was predominantly as 5-FU and was 2.2–11.9%; the urinary excretion of both fluoro-β-alanine and uracil was generally maximal between 6 and 18 h. During 28-day courses with twice-daily S-1 administration, 5-FU and uracil generally increased. Before each intake of S-1, 5-FU varied between 0.5 and 1 μM and uracil was in the micromolar range (up to 7 μM), indicating that effective DPD inhibition was maintained during the course. In a biopsy of an esophageal adenocarcinoma metastasis that had regressed, thymidylate synthase, the target of 5-FU, was inhibited 50%, but increased four- to tenfold after relapse in subsequent biopsies. In conclusion, oral S-1 administration resulted in prolonged exposure to micromolar 5-FU concentrations due to DPD inhibition, and the decrease in uracil levels after 6 h followed the pattern of CDHP and indicates reversible DPD inhibition. [ABSTRACT FROM AUTHOR]

Cancer of the colon and rectum is one of the most frequent malignancies both in the US and Europe. Standard palliative therapy is based on 5-fluorouracil/folinic acid combinations, with or without oxaliplatin or irinotecan, given intravenously. Oral medication has the advantage of greater patient convenience and acceptance and potential cost savings. S-1 is a new oral fluorinated pyrimidine derivative. In a nonrandomized phase II study, patients with advanced/metastatic colorectal cancer were treated with S-1 at 40 mg m-2 b.i.d. for 28 consecutive days, repeated every 5 weeks, but by amendment the dose was reduced to 35 mg m-2 during the study because of a higher than expected number of severe adverse drug reactions. In total 47 patients with colorectal cancer were included. In the 37 evaluable patients there were nine partial responses (24%), 17 stable diseases (46%) and 11 patients had progressive disease (30%). Diarrhoea occurred frequently and was often severe: in the 40 and 35 mg m-2 group, respectively, 38 and 35% of the patients experienced grade 3-4 diarrhoea. The other toxicities were limited and manageable. S-1 is active in advanced colorectal cancer, but in order to establish a safer dose the drug should be subject to further investigations. [ABSTRACT FROM AUTHOR]

Population pharmacokinetic-dynamic analysiswas prospectively integrated in a broadphase II program of lurtotecan (GI147211),a novel camptothecin derived topoisomeraseI inhibitor, to determine the populationpharmacokinetic profile in a largerpopulation, to estimate individualpharmacokinetic parameters and toinvestigate relationships with clinicaloutcome. A sparse sampling method wasapplied during course one, which involvedtwo sampling time-points. A Bayesianalgorithm was used to estimate individualpharmacokinetic parameters, in particulartotal plasma clearance (CL) and volume ofdistribution. In total, samples werecollected of 109 (63%) of 173 patients.Pharmacokinetic-dynamic evaluation could becarried out successfully in 85 (78%) ofthe sampled patients. CL of lurtotecanshowed substantial variability (mean 87± 28 L/h) and was of the same magnitudeas in the phase I studies where fullpharmacokinetic curves were used. Residualvariability in the population estimate ofCL was 9.9%. No significant relationshipswere observed between exposure parametersand toxicity nor likelihood of tumorresponse, however the latter relationshipmay well have been obscured by theheterogeneity of the studied population.Prospective implementation of large scalepopulation pharmacokinetic-dynamic analysisis feasible and important to establishwhether interpatient variability in drugexposure is a major determinant of toxicityor activity. [ABSTRACT FROM AUTHOR]

The doxorubicin analogue MEN-10755 has been identified as a compound with promising antitumour activity based on structure-activity studies of a new series of anthracycline disaccharides. The high antitumour activity of MEN-10755 in human tumour xenografts, including doxorubicin-resistant xenografts, and its unique pharmacological and biological properties made this novel disaccharide analogue an interesting candidate for clinical evaluation. Two pharmacokinetic phase I studies with different dosing schedules were performed in adults with solid refractory malignancies. The pharmacokinetics of MEN-10755 were studied after a 15-min i.v. infusion given once every 3 weeks or once every week for 3 weeks followed by 1 week rest. Plasma and urine levels of MEN-10755 were measured by HPLC with fluorescent detection. It was possible to combine the pharmacokinetic results of the two studies because there was no accumulation of MEN-10755 before the next infusion of MEN-10755 in the weekly study with 1 week rest. The administered dose levels on day 1 in this study were all in the lower range from the 3-weekly study. The postinfusion plasma kinetics of MEN-10755 were best described by a triexponential model. The plasma peak levels (Cmax) of MEN-10755 showed a linear relationship with the administered dose. Peak plasma MEN-10755 levels ranged between 474 and 21,587 µg/l. The mean elimination half-life (T1/2γ) was 20.7±9.0 h. The AUC0–∞ was proportional to the administered dose. The mean plasma clearance of MEN-10755 was 6.0±2.2 l/h per m2 with a mean volume of distribution (Vss) of 95.6±43.4 l/m2. The mean renal excretion of unchanged drug within 24 h was 4.3±1.8%. Compared to epirubicin and doxorubicin, the pharmacokinetics of MEN-10755 were characterized by an approximately twofold shorter terminal half-life, a much lower total plasma clearance and a much smaller volume of distribution. [ABSTRACT FROM AUTHOR]

Purpose: EO9 is a new synthetic bioreductive alkylating indoloquinone, with preferential activity against solid tumors and higher antitumor activity under anaereobic conditions compared with aerobic conditions. In preclinical models EO9 demonstrated no major organ toxicity. The aim of the present phase I study was to determine the toxicities and the maximal tolerated dose (MTD) of EO9 administered as a 5-min i.v. infusion weekly to patients with solid cancers. Methods: Twenty-eight patients entered the study. The dose was escalated from 2.7 mg/m2 according to a Fibonacci-like schedule. Results and conclusion: The dose-limiting toxicity was proteinuria. No other major toxicities were detected and in particular there was no significant increase in serum creatinine. This was in contrast to findings in a previous phase I trial using EO9 in a 3-weekly schedule, where a number of patients experienced severely decreased kidney function. The MTD in the present study was 15.0 mg/m2 weekly and the recommended dose for phase II studies was 12.0 mg/m2 weekly. Compared with 3-weekly EO9, the dose intensity could be increased from 22 mg/m2 to 36 mg/m2 with the weekly administration. Phase II studies have been performed by the EORTC Early Clinical Study Group in advanced breast, gastric, colorectal, pancreatic, and non-small-cell lung cancer. [ABSTRACT FROM AUTHOR]

Carzelesin is a cyclopropylpyrroloindole analogue which acts as a DNA-sequence-specific alkylating agent. In this phase I study, Carzelesin was given as a 4-weekly 10 min IV infusion to 51 patients with advanced solid tumours. Patients received a median of two courses (range 1-5) at one of nine dose levels: 24, 48, 96, 130, 150, 170, 210, 250 and 300 μg m[SUP-2]. According to NCI-CTC criteria, non-haematological toxicities (grade 1/2) included fever, nausea and vomiting, mucositis and anorexia, none of which was clearly dose related. The dose-limiting toxicity was haematological and consisted mainly of neutropenia and to a lesser extent thrombocytopenia. From the dose level 150 μg m[SUP-2], the haematological toxicity (particularly thrombocytopenia) was delayed in onset, prolonged and cumulative in some patients. In several courses, double WBC nadirs occurred. The maximum tolerated dose for a single course was 300 μg m[SUP-2]. From the dose level 170 μg m[SUP-2], the intended dose intensity could not be delivered to most patients receiving > 2 courses owing to cumulative haematological toxicity. The dose level with the best dose intensity for multiple courses was 150 μg m[SUP-2]. The pharmacokinetics of Carzelesin and its metabolites (U-76,073; U-76,074) have been established in 31 patients during the first course of treatment using a HPLC method. Carzelesin exhibited linear pharmacokinetics. The concentration of U-76,074 (active metabolite) extended above the lower limit of quantitation (1 ng ml[SUP-1]) for short periods of time and only at the higher dose levels. There was no relationship between neutropenia and the AUC of the prodrug Carzelesin, but the presence of detectable plasma levels of the active metabolite U-76,074 was usually associated with a substantial decrease in ANC values. [ABSTRACT FROM AUTHOR]

The antitumor activity of zeniplatin, a third-generation, water-soluble platinum compound that has shown broad preclinical antitumor activity and no significant nephrotoxicity in phase I trials, was tested in patients with advanced malignant melanoma and advanced renal cancer. Patients who had not previously been treated, except with local limb perfusion and immunotherapy, were given zeniplatin as bolus injections at 125 mg/m2 every 3 weeks. The main hematological toxicity was leukopenia (7/30 patients, WHO grade > or = 3) and the main nonhematological toxicity was nausea and vomiting (21/30 patients, WHO grade > or = 2). Serious nephrotoxicity was observed early in the renal cancer study and, later, also in the melanoma study. Hyperhydration did not prevent the nephrotoxicity, and the studies were stopped after 6 renal cancer patients and 24 malignant melanoma patients had been included. Zeniplatin gave objective responses in 3 of the 21 evaluable malignant melanoma patients [2 complete responses (CRs) in patients with lymph-node metastases lasted 5 and 14 months, respectively; 1 partial response (PR) in a patient with lymph-node and liver metastases lasted 6 months]. In the renal cancer study, only four patients were evaluable for response and none responded. The results show that zeniplatin has some activity (14%) in patients with advanced malignant melanoma, but no conclusion can be drawn regarding the activity of zeniplatin in renal cancer as the number of patients was too low. The main toxicities were leukopenia and nausea and vomiting. Unexpected and serious nephrotoxicity was observed, and for this reason the studies were terminated before the planned number of patients had been included. A possible explanation for the nephrotoxicity may be drug interactions, but no firm conclusion can yet be drawn. [ABSTRACT FROM AUTHOR]