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Byline: J.H.M. Schellens (1), B. Heinrich (2), M. Lehnert (3), M.E. Gore (4), S.B. Kaye (5), P. Dombernowsky (6), R. Paridaens (7), A.T. van Oosterom (7), J. Verweij (8), W.J. Loos (8), H. Calvert (9), N. Pavlidis (10), H. Cortes-Funes (11), J. Wanders (12), M. Roelvink (12), C. Sessa (13), K. Selinger (14), P.S. Wissel (14), T. Gamucci (15), A.R. Hanauske (7) Keywords: lurtotecan (GI147211); population analysis; pharmacokinetics; pharmacodynamics; NONMEM; Bayesian algorithm; phase II; topoisomerase I Abstract: 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. Author Affiliation: (1) The Netherlands Cancer Institute, Amsterdam, The Netherlands (2) Klinikum rechts der Isar, Munchen, Germany (3) Klinik C fur Innere Medizin, Kantonsspital St. Gallen, St. Gallen, Switzerland (4) CRC Center for Cancer Therapeutics, The Inst. of Cancer Research, Belmont, Surrey, UK (5) Dept. Med. Oncol, Beatson Oncology Center, Glasgow, UK (6) University Hospital Copenhagen, Herlev, Denmark (7) University Hospital Gasthuisberg, Catholic University, Leuven, Belgium (8) Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, The Netherlands (9) Div. Oncology, Newcastle General Hospital, Newcastle-upon-Tyne, UK (10) University of Ioannina, Greece (11) Dept. Med. Oncol, Hospital Universitario ``12 de Octubre'', Madrid, Spain (12) EORTC-New Drug Development Office, Amsterdam, The Netherlands (13) Ospedale San Giovanni, Bellinzona, Switzerland (14) GlaxoWellcome Inc, Research Triangle Park, NC, USA (15) Istituto Regina Elena, Rome, Italy Article History: Registration Date: 10/10/2004

Purpose: Gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) result in unbalanced STAT signaling and cause immune dysregulation and immunodeficiency. The latter is often characterized by the susceptibility to recurrent Candida infections, resulting in the clinical picture of chronic mucocutaneous candidiasis (CMC). This study aims to assess the frequency of GOF STAT1 mutations in a large international cohort of CMC patients., Methods: STAT1 was sequenced in genomic DNA from 57 CMC patients and 35 healthy family members. The functional relevance of nine different STAT1 variants was shown by flow cytometric analysis of STAT1 phosphorylation in patients' peripheral blood cells (PBMC) after stimulation with interferon (IFN)-α, IFN-γ or interleukin-27 respectively. Extended clinical data sets were collected and summarized for 26 patients., Results: Heterozygous mutations within STAT1 were identified in 35 of 57 CMC patients (61%). Out of 39 familial cases from 11 families, 26 patients (67%) from 9 families and out of 18 sporadic cases, 9 patients (50%) were shown to have heterozygous mutations within STAT1. Thirteen distinct STAT1 mutations are reported in this paper. Eight of these mutations are known to cause CMC (p.M202V, p.A267V, p.R274W, p.R274Q, p.T385M, p.K388E, p.N397D, and p.F404Y). However, five STAT1 variants (p.F172L, p.Y287D, p.P293S, p.T385K and p.S466R) have not been reported before in CMC patients., Conclusion: STAT1 mutations are frequently observed in patients suffering from CMC. Thus, sequence analysis of STAT1 in CMC patients is advised. Measurement of IFN- or IL-induced STAT1 phosphorylation in PBMC provides a fast and reliable diagnostic tool and should be carried out in addition to genetic testing.

Background: Several cancer therapies can prolong cardiac repolarization. This study assessed the potential of eribulin to affect cardiac repolarization in patients with advanced solid tumors., Methods: In this Phase I, open-label, single-arm study, patients received eribulin mesylate (1.4 mg/m(2); Days 1 and 8 of a 21-day cycle). The primary objective was to assess the effect of eribulin on the QTcF pre- and post-infusion; QTcF and QTcNi were compared for ability to remove heart-rate dependence of the QT interval. Relationship between concentration of eribulin and ΔQTc was explored using linear mixed-effects analysis. Secondary objectives explored pharmacokinetics, safety, and tolerability., Results: Twenty-six patients were enrolled. QTcNi was more effective than QTcF in correcting for heart-rate dependency of the QT interval. On Day 1, mean ΔQTcNi were ~0 at all timepoints. An apparent time-dependent increase in ΔQTc was observed: on Day 8, changes from baseline were larger and more variable, without clear relation to plasma levels of eribulin. Day 8 predose ΔQTcNi was 5 ms, post-infusion mean values ranged from 2 to 9 ms (largest mean ΔQTcNi at 6 h). No new or unexpected toxicities were reported., Conclusion: Eribulin demonstrated an acceptable safety profile and a minor prolongation of QTc not expected to be of clinical concern in oncology patients.

Purpose To study the influence of repeated oral administration of ketoconazole, a potent CYP3A4 inhibitor, on the plasma pharmacokinetics of eribulin mesylate administered by single-dose intravenous infusion. Eribulin mesylate is a non-taxane microtubule dynamics inhibitor that is currently under development in phase I-III trials for the treatment of solid tumors. Experimental design A randomized, open-label, two treatments, two sequences, crossover phase I study was performed in patients with advanced solid tumors. Treatments were given on day 1 and day 15 and consisted of 1.4 mg/m(2) eribulin mesylate alone or 0.7 mg/m(2) eribulin mesylate plus 200 mg ketoconazole on the day of eribulin mesylate administration and the following day. Pharmacokinetic sampling for determination of eribulin plasma concentration was performed up to 144 h following administration of eribulin mesylate. Also safety and anti-tumor activity were determined. Results Pharmacokinetic sampling and analysis was completed in ten patients. Statistical analysis of dose-normalized log-transformed AUC0-∞ and Cmax indicated that single-dose exposure of eribulin was not statistically different when co-administered with ketoconazole (ratio of geometric least square means: 0.95 (90%CI: 0.80-1.12) and 0.97 (90%CI: 0.83-1.12), respectively) in patients with solid tumors. Ketoconazole had no effect on eribulin clearance and elimination half-life. The most frequently reported treatment related adverse events were fatigue and nausea, each reported in 8/12 patients. Seven patients (58.3 %) achieved stable disease as best overall response. Conclusions The results indicate that eribulin mesylate can be safely co-administered with ketoconazole. Drug-drug interactions are not expected with other CYP3A4 inhibitors.

In cancer chemotherapy neutropenia is a common dose-limiting toxicity. An ability to predict the neutropenic effects of cytotoxic agents based on proposed trial designs and models conditioned on previous studies would be valuable. The aim of this study was to evaluate the ability of a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for myelosuppression to predict the neutropenia observed in Phase I clinical studies, based on parameter estimates obtained from prior trials. Pharmacokinetic and neutropenia data from 5 clinical trials for diflomotecan and from 4 clinical trials for indisulam were used. Data were analyzed and simulations were performed using the population approach with NONMEM VI. Parameter sets were estimated under the following scenarios: (a) data from each trial independently, (b) pooled data from all clinical trials and (c) pooled data from trials performed before the tested trial. Model performance in each of the scenarios was evaluated by means of predictive (visual and numerical) checks. The semi-mechanistic PK/PD model for neutropenia showed adequate predictive ability for both anti-cancer agents. For diflomotecan, similar predictions were obtained for the three scenarios. For indisulam predictions were better when based on data from the specific study, however when the model parameters were conditioned on data from trials performed prior to a specific study, similar predictions of the drug related-neutropenia profiles and descriptors were obtained as when all data were used. This work provides further indication that modeling and simulation tools can be applied in the early stages of drug development to optimize future trials.

Hypertension and proteinuria are commonly observed side-effects for anti-angiogenic drugs targeting the VEGF pathway. In most cases, hypertension can be controlled by prescription of anti-hypertensive (AH) therapy, while proteinuria often requires dose reductions or dose delays. We aimed to construct a pharmacokinetic-pharmacodynamic (PK-PD) model for hypertension and proteinuria following treatment with the experimental VEGF-inhibitor E7080, which would allow optimization of treatment, by assessing the influence of anti-hypertensive medication and dose reduction or dose delays in treating and avoiding toxicity. Data was collected from a phase I study of E7080 (n = 67), an inhibitor of multiple tyrosine kinases, among which VEGF. Blood pressure and urinalysis data were recorded weekly. Modeling was performed in NONMEM, and direct and indirect response PK-PD models were evaluated. A previously developed PK model was used. An indirect response PK-PD model described the increase in BP best, while the probability of developing proteinuria toxicity in response to exposure to E7080, was best described by a Markov transition model. This model may guide clinical interventions and provide treatment recommendations for E7080, and may serve as a template model for other drugs in this class.

The aim of this study was to assess the population pharmacokinetics (PopPK) of the novel oral anti-cancer agent E7820. Both a non-linear mixed effects modeling analysis and a non-compartmental analysis (NCA) were performed and results were compared. Data were obtained from a phase I dose escalation study in patients with malignant solid tumors or lymphomas. E7820 was administered daily for 28 days, followed by a washout period of 7 days prior to the start of subsequent cycles. A one compartment model with linear elimination from the central compartment was shown to give adequate fit, while absorption was described using a turnover model. Final population parameter estimates of basic PK parameters obtained with the PopPK method were (RSE): clearance, 6.24 L/h (7.1%), volume of distribution, 66.0 L (8.5%), mean transit time to the absorption compartment, 0.638 h (6.5%). The intake of food prior to dose administration slowed absorption (2.8-fold, RSE 13%) and increased relative bioavailability of E7820 by 36% (RSE 14%), although the effect on C (max) and AUC was not significant. Comparison with the NCA approach showed approximately equal PK parameter estimates and food effect measures, although specific advantages of PopPK included efficiency in use of data and more appropriate assessment of variability.

Background: DE-310 is composed of the topoisomerase-I-inhibitor DX-8951 (exatecan) and a biodegradable macromolecular carrier, which are covalently linked by a peptidyl spacer. In pre-clinical studies, high levels and prolonged retention of conjugated DX-8951 (carrier-bound DX-8951) have been observed in tumor tissues following DE-310 administration. This phenomenon is explained as the enhanced permeability and retention (EPR) effect. DX-8951 and G-DX-8951 (glycyl-DX-8951) exerting anti-tumor activity in vivo are released from DE-310 by enzymatic cleavage of the spacer., Methods: To quantify the concentration of conjugated DX-8951, DX-8951 and G-DX-8951 in human tissues, six patients with different solid tumor types received 6.0 mg/m(2) of DE-310 (as equivalent of DX-8951) as a single three-hour infusion administered 7 days (+/-2 days) prior to scheduled tumor resection. Drug concentrations were then determined in the resected tissues. To evaluate the plasma PK of DE-310, plasma samples were taken up to 42 days post dosing., Results: There were no severe side effects of the DE-310 infusion. Concentrations of conjugated DX-8951, DX-8951 and G-DX-8951 were in general similar in tumor and relevant normal tissue samples and preferential accumulation of DE-310, DX-8951 and G-DX-8951 in human tumor tissues was not observed., Conclusions: These data indicate that there is distribution of DE-310 into tissue and that DX-8951 and G-DX-8951 are released slowly over an extended period from DE-310 providing prolonged exposure similar to a continuous infusion. However, the similarity in the concentrations in tumor and relevant normal tissues does not support the EPR concept in the studied human cancers.

Indisulam (N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide, GOAL, E7070) is a novel anti-cancer drug currently in phase II clinical development for the treatment of solid tumors. Phase I dose-escalation studies were conducted comparing four treatment schedules. Neutropenia and thrombocytopenia were dose limiting in all schedules. The aim of this study was to describe the extent and the time course of the hematological toxicity and its possible schedule dependency using a semi-physiological model. Data from 142 patients were analyzed using NONMEM. The semi-physiological model comprised a progenitor blood cell compartment, linked to the central circulation compartment, through 3 transition compartments representing the maturation chain in the bone marrow. Plasma concentrations of the drug were assumed to reduce the proliferation rate in the progenitor compartment according to a linear function. A feedback mechanism was included in the model representing the rebound effect of endogenous growth factors. The model was validated using a posterior predictive check. The model adequately described the extent and time course of neutropenia and thrombocytopenia. The mean transition time (MTT, i.e. maturation time in bone marrow) of neutrophils was increased by 47% in patients who received indisulam as a weekly dose administered for four out of every six weeks. For platelets, MTT was increased by 33% in patients who received this schedule and also in patients who received a continuous 120-h infusion. The validation procedure indicated that the model adequately predicts the nadir value of neutrophils and platelets and the time to reach this nadir. A semi-physiological model was successfully applied to describe the time course and extent of the neutropenia and thrombocytopenia after indisulam administration for four treatment schedules.

Background: Sabarubicin (MEN-10755) is a third generation anthracycline, with a remarkable antitumor activity in human tumor xenografts, including doxorubicin-resistant tumors. Phase I studies have shown that myelosuppression is the main toxicity of sabarubicin, while its cumulative cardiotoxicity is mild., Methods: The aim of the study was to evaluate the activity and safety profile of sabarubicin in patients with locally advanced or metastatic ovarian cancer failing 1st line platinum and/or taxane based chemotherapy, and relapsing earlier than 6 months after the last chemotherapy. Eligible patients received sabarubicin at the dose of 80 mg/m2 (dose level 0) every 3 weeks over 30 minutes. Dose was to be escalated to 90 mg/m2 (dose level +1) after the 1st cycle in case of grade 0-1 toxicity, while it was to be reduced to 60 mg/m2 (dose level -1) in case of toxicity. Response was assessed every 2 courses according to WHO criteria. Toxicity was graded according to Common Toxicity Criteria version 2.0. Gehan's design was used for sample size determination., Results: Nineteen patients were enrolled and received 65 courses. One patient had a confirmed partial response, 9 patients had stable disease, 5 patients had disease progression, 3 patients were not evaluable for response, while one patient had an early progressive disease. The duration of response was 88 days. Mean time to disease progression was 125 days (range 56-188). Median survival was 62 days (range 36-202). Hematologic toxicity was moderate, since grade 3-4 neutropenia was observed in 25 out of 52 courses at 80 mg/m2, and grade 4 neutropenia occurred in one out of 12 courses at 90 mg/m2. Other grade 3-4 toxicities were: fatigue (five cases), nausea (two cases), stomatitis, general health deterioration, anorexia, vomiting, abdominal pain, hyponatremia (one case each). Cardiac toxicity was observed in the study; in fact, left ventricular ejection fraction (LVEF) fell below 50% in 2 patients, and 3 patients had a >15% decrease of LVEF from baseline, but there were no signs/symptoms of congestive heart failure., Conclusions: Sabarubicin showed limited activity in patients with resistant ovarian cancer. However, the observed data on disease stabilization, together with the drug's overall manageable toxicity profile, may prompt to its further investigation in advanced ovarian cancer.

Objective: S-1 is an oral anticancer agent combining tegafur (FT), a prodrug of 5-fluorouracil (5-FU), with potassium oxonate (oteracil) and gimeracil (CDHP) respectively to mitigate gastrointestinal toxicity and increase the half-life of 5-FU. This article presents a population pharmacokinetic analysis of these four compounds in Western cancer patients. The second objective was to compare the pharmacokinetics of S-1 in Western and Japanese patients., Methods: A single dose (25-45 mg/m2) of S-1 was administered to 60 patients. In each patient, 6 concentrations of FT, 5-FU, oteracil and CDHP were measured over 24 hr. Using NONMEM, oteracil and CDHP were analyzed separately, and the individual estimates of CDHP parameters were included in the joint analysis of FT and 5-FU. We used validation techniques to assess differences between the two populations, and finally we compared the exposures in Western and Japanese patients using simulations., Results: A compartmental model describing the PK of the 4 compounds was developed. The influence of CDHP on the elimination of 5-FU was well described by an enzymatic inhibition model. The model provided a good fit for all compounds. The pharmacokinetics for 5-FU and oteracil were similar between Western and Japanese patients, but apparent differences in exposure to 5-FU resulted from different total doses due to different body sizes.