Carboplatin dosage: prospective evaluation of a simple formula based on renal function.

A dosage formula has been derived from a retrospective analysis of carboplatin pharmacokinetics in 18 patients with pretreatment glomerular filtration rates (GFR) in the range of 33 to 136 mL/min. Carboplatin plasma clearance was linearly related to GFR (r = 0.85, P less than .00001) and rearrangements of the equation describing the correlation gave the dosage formula dose (mg) = target area under the free carboplatin plasma concentration versus time curve (AUC) x (1.2 x GFR + 20). In a prospective clinical and pharmacokinetic study the formula was used to determine the dose required to treat 31 patients (GFR range, 33 to 135 mL/min) with 40 courses of carboplatin. The target AUC was escalated from 3 to 8 mg carboplatin/mL/min. Over this AUC range the formula accurately predicted the observed AUC (observed/predicted ratio 1.24 +/- 0.11, r = 0.886) and using these additional data, the formula was refined. Dose (mg) = target AUC x (GFR + 25) is now the recommended formula. AUC values of 4 to 6 and 6 to 8 mg/mL. min gave rise to manageable hematological toxicity in previously treated and untreated patients, respectively, and hence target AUC values of 5 and 7 mg/mL min are recommended for single-agent carboplatin in these patient groups. Pharmacokinetic modeling demonstrated that the formula was reasonably accurate regardless of whether a one- or two-compartment model most accurately described carboplatin pharmacokinetics, assuming that body size did not influence nonrenal clearance. The validity of this assumption was demonstrated in 13 patients where no correlation between surface area and nonrenal clearance was found (r = .31, P = .30). Therefore, the formula provides a simple and consistent method of determining carboplatin dose in adults. Since the measure of carboplatin exposure in the formula is AUC, and not toxicity, it will not be influenced by previous or concurrent myelosuppressive therapy or supportive measures. The formula is therefore applicable to combination and high-dose studies as well as conventional single-agent therapy, although the target AUC for carboplatin will need to be redefined for combination chemotherapy.

Do high tuition fees make a difference? Characteristics of applicants to UK medical and dental schools before and after the introduction of high tuition fees in 2012.

Aim To compare trends in the volume, socio-demography and academic experience of UK applicants and entrants to medicine and dentistry in the UK with university in general, before and after the major increase in university fees in England in 2012.Methods Descriptive trend analyses of University and College Admissions Services (UCAS) data for focused (preferred subject was medicine or dentistry) and accepted applicants, 2010-14, compared with university in general in relation to socio-demography (age, sex, ethnicity, POLAR 2, region) and academic experience (school type). POLAR2 data provide an indication of the likelihood of young people in the area participating in further or higher education.Results In 2012 the volume of applicants to medicine and dentistry fell by 2.4% and 7.8% respectively, compared with 6.6% for university overall. Medical applications remained buoyant and by 2014 had risen by 10.2% from 2010 to 23,365. While dental applications fell in both 2012 and 2013, they had increased by 15.6% to 3,410 in 2014, above 2010 levels. Females formed the majority of applicants, and admissions, with the proportion gaining admission to dentistry in 2014 reaching an all-time high (64%), exceeding medicine (56%), and university in general (56%). Mature admissions to dentistry were at their highest in 2010 (29%) falling to 21% in 2014, compared with 22-24% in medicine. Black and minority ethnic group admissions to university, although rising (24% in 2014), are still less than for medicine (34%) and dentistry (48%). In 2013, just over half of the students admitted to dentistry were from BME groups (51%) for dentistry. Among UK applicants <19 years, over 60% of applicants, and 70% of accepted applicants, to medicine and dentistry are from the top two POLAR2 quintiles representing areas of high participation in education; however, in 2014 there was a notable increase in the proportion of applications from the lower two quintiles to dentistry (19%) and medicine (20%), with a very modest increase in those gaining admission over 2012 (14% of both; cf 10% and 12% respectively).Discussion The findings suggest that the short-term impact of the 2012 rise in fees had a greater influence on the volume and nature of applicants to dentistry than medicine, and that both programmes are gaining in popularity, despite high fees and reduced places. Dentistry remains particularly attractive to Asians, and females, the latter forming an increasing majority of students. While there is some recovery, social inequalities exist and present a challenge for widening participation in the professions.

Validated questionnaires on intimacy in patients who have had cancer.

Problems with intimacy in patients with cancer of the head and neck may not be recognised. Our aim was to review published papers on patient-reported outcomes that record concerns about intimacy, sex, and function, to help develop a tool for use in head and neck cancer. We specifically looked for instruments with evidence of validation in patients with cancer, which could be used to identify problems with intimacy and sexuality. After evaluating 2563 papers, we identified 20 that satisfied our inclusion criteria, and these have been presented in a tabulated form. This review has shown the need to develop a questionnaire on intimacy that is specific to patients with cancer of the head and neck. It is an important issue that must be addressed by clinical and research teams, and will be done most effectively if it is linked to specific interventions.

Design and conduct of early clinical studies of two or more targeted anticancer therapies: recommendations from the task force on Methodology for the Development of Innovative Cancer Therapies.

The Methodology for the Development of Innovative Cancer Therapies (MDICT) task force considered aspects of the design and conduct of early (phase I and II) studies of combinations of molecular targeted agents during their 2012 meeting. The task force defined necessary non-clinical data, such as evidence of additive or synergistic effects in multiple molecularly credentialed and validated models, and appropriate pharmacodynamic marker development. A robust hypothesis was considered critical while non-clinical pharmacokinetic studies were also considered valuable. Clinical trials should include clear objectives that will prove or disprove the hypothesis. Predictive biomarkers/classifiers should be explored in phase I studies, rather than used to select patients. Trial design should be efficient and flexible rather than based on a strict progression from phase I to II to III; researchers could consider phase I studies with an expansion cohort, Phase I/II designs or phase II studies with a safety run in. Pharmacokinetics are recommended when interactions or overlapping toxicity is expected. Pharmacodynamic evaluations should be considered especially in a subset of patients closest to the recommended dose; an attempt should be made to validate surrogate tissues to enable inclusion for all patients. Schedule and or dose should be formally explored for e.g. with a randomised or an adaptive design. Data and knowledge sharing was strongly recommended, including the creation of formal or informal consortia of laboratories with individual expertise in pathway or target based models, collaboration between companies to ensure that agents which are 'best in class' are combined, and the development of databases which will be able to inform the development of future recommendations/guidelines.

Reducing the incidence of TRALI in the UK: the results of screening for donor leucocyte antibodies and the development of national guidelines.

BACKGROUND AND OBJECTIVES: Transfusion-related acute lung injury (TRALI) is associated with the passive transfusion of leucocyte antibodies in blood products. Blood Transfusion Services have adopted a number of different strategies for reducing the incidence of TRALI, but, while these have been successful, TRALI has not been completely eliminated. Many Transfusion Services have introduced leucocyte antibody screening of donors to further reduce TRALI. This report describes the results of donor leucocyte antibody screening within NHS Blood and Transplant and the guidelines that have been developed for Transfusion Services within the United Kingdom (UK) to reduce the incidence of TRALI. MATERIALS AND METHODS: Blood samples from newly recruited female apheresis donors were tested for human leucocyte antigens (HLA) class I and class II antibodies and granulocyte-specific antibodies. RESULTS: A total of 1157 female donors were evaluated. Three hundred and fifteen (27·23%) donors had HLA class I or II antibodies and were returned to red cell component donation. Fifty-seven (6·77%) of the remaining 842 donors were found to have granulocyte-specific antibodies of which 11 (1·31%) had HNA-specific antibodies. A total of 818 donors (70·70%) were accepted for platelet apheresis, 336 donors (29·04%) were returned to red cell component donation, and three donors with HNA-3a antibodies (0·26%) were deferred from therapeutic donation. CONCLUSIONS: Female donors with leucocyte antibodies were identified in a stratified screening programme. Donors with antibodies were either directed to red cell donation or deferred. This process, combined with other measures that have already been introduced, is anticipated to further reduce the incidence of TRALI.

Nucleoside transport inhibitors: structure-activity relationships for pyrimido[5,4-d]pyrimidine derivatives that potentiate pemetrexed cytotoxicity in the presence of α1-acid glycoprotein.

Membrane transport of nucleosides or nucleobases is mediated by transporters including the equilibrative nucleoside transporters (ENTs), and resistance to antitumor antimetabolite drugs may arise via salvage of exogenous purine or pyrimidine nucleosides or nucleobases by ENT transporters. The therapeutic utility of dipyridamole (3), a potent ENT inhibitor, is compromised by binding to the serum protein α(1)-acid glycoprotein (AGP). Derivatives and prodrugs of the ENT inhibitor 4,8-bis[(3,4-dimethoxybenzyl)amino]-2,6-bis[(2-hydroxypropyl)amino]pyrimido[5,4-d]pyrimidine (6, NU3108) are described, with improved in vivo pharmacokinetic properties and reduced AGP binding relative to dipyridamole. The mono- and diglycine carbamate derivatives were at least as potent as 6 and showed no reduction in potency by AGP. In a [(3)H]thymidine incorporation assay, employing COR-L23 cells, the diastereoisomers of 6 (IC(50) = 26 nM) exhibited activity comparable with 3 (IC(50) = 15 nM). The monophenyl carbamate and mono-4-methoxyphenyl carbamate exhibited the best ENT-inhibitory activity in the COR-L23 assay (IC(50) = 8 and 4 nM, respectively). All of the new prodrugs were also highly effective at reversing thymidine/hypoxanthine rescue from pemetrexed cytotoxicity in the COR-L23 cell line.

The role of folate receptor alpha (FRalpha) in the response of malignant pleural mesothelioma to pemetrexed-containing chemotherapy.

BACKGROUND: The standard treatment of choice for malignant pleural mesothelioma is chemotherapy with pemetrexed and platinum, but the clinical outcome is poor. This study investigates the response to pemetrexed in a panel of eight mesothelioma cell lines and the clinical outcome for patients treated with pemetrexed in relation to folate receptor alpha (FRalpha). METHODS: Cell lines were treated with pemetrexed to determine the concentration that reduced growth to 50% (GI(50)). FRalpha expression was determined by western blotting and that of FRalpha, reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT) by real-time quantitative RT-PCR. Immunohistochemistry for FRalpha was carried out on 62 paraffin-embedded samples of mesothelioma from patients who were subsequently treated with pemetrexed. RESULTS: A wide range of GI(50) values was obtained for the cell lines, H2452 cells being the most sensitive (GI(50) 22 nM) and RS5 cells having a GI(50) value greater than 10 microM. No FRalpha protein was detected in any cell line, and there was no relationship between sensitivity and expression of folate transporters. FRalpha was detected in 39% of tumour samples, generally in a small percentage of cells. There was no correlation between the presence of FRalpha and the outcome of pemetrexed treatment, and no significant difference between histological subtypes. CONCLUSION: Response to treatment with pemetrexed does not depend on the presence of FRalpha.

No evidence of transmission of bacteria between reptiles and a CF patient--a case report of a young adult CF patient and reptiles.

A microbiological study was undertaken to assess the risk of infection to a CF patient from a collection of pet reptiles, particularly atypical mycobacteria. This study helped to verify that the reptiles under the care of the CF patient did not harbour bacterial organisms that would normally be pathogenic to CF patients. However, the chronic carriage of Pseudomonas aeruginosa and other pathogens in the CF patient may constitute a greater risk of infection to the animals being handled. Therefore, we recommend stringent infection control precautions by CF patients and their pets, particularly adherence to hand washing and disinfection, when handling the animals, their litter or when working with their immediate environment, to potentially minimize the spread of bacterial and other pathogens from animal to human and vice versa. Detailed risk assessments therefore need to be undertaken by clinicians and veterinarians to detail working models that protect both animals and patients from pathogens originating from the other.

Investigations into the lack of consensus in the reporting of HLA antibody specificities in the UK.

AIMS: Lack of consensus in HLA antibody reporting in proficiency schemes has previously been attributed to a number of differing factors. This study was set up to eliminate the majority of these factors by reducing analysis to a pure data handling exercise. METHODS: Anonymised raw data files for LABScreen Single Antigen class I and II and related patient information were provided to seven participating centres. The centres reported back the HLA antibody specificities according to their single antigen bead reporting policy. Details of the reporting policy of each centre were retrospectively requested by questionnaire. RESULTS: The number of HLA antibody specificities reported by the different centres varied widely. Software analysis called more HLA antibody specificities than any of the centres. None of the centres matched consensus for reported HLA class I specificities on any of the datasets, and no two centres reported the exact same HLA class I antibody profile; consensus was reached by one centre for HLA class II antibody specificities reported from two of the datasets. Retrospective review found data handling practice between centres to vary widely. CONCLUSIONS: Lack of agreement exists between UK centres in regard to HLA antibody specificity analysis. The fact that the required analysis was limited to interrogation of supplied data files makes the observation more concerning. The root cause of this variation is differences in data handling practice between the participating centres.

Phase 0 clinical trials: recommendations from the Task Force on Methodology for the Development of Innovative Cancer Therapies.

The Methodology for the Development of Innovative Cancer Therapies (MDICT) task force has been established as an expert forum to develop practical guidance on the development of innovative anticancer agents, in particular targeted agents. The task force recently addressed the utility, design and application of Phase 0 clinical trials in anticancer drug development. It was concluded that the role of non-therapeutic Phase 0 trials is controversial for several reasons, including the lack of clinical benefit for participating patients. However, it was recognised that Phase 0 trials provide an opportunity to generate essential human pharmacokinetic and pharmacodynamic data earlier in the drug development process, which could be a major advantage in the design and decision making concerning further clinical development of an agent. Construction of a 'decision chart' was highly recommended to assist investigators and sponsors in determining whether an agent is suitable for evaluation in a Phase 0 trial.

The development of phase I cancer trial methodologies: the use of pharmacokinetic and pharmacodynamic end points sets the scene for phase 0 cancer clinical trials.

Although the concept of a phase 0 trial is a relatively new one, there has been a slowly increasing trend toward basing early clinical trial designs on pharmacokinetic and pharmacodynamic end points that has been developing over many years. This article will review the early cancer trial methodologies and the various techniques that have been used to refine them. Several illustrative examples will be presented showing their relevance to trial designs using pharmacodynamic end points and targeted agents. Some criteria for characterizing suitable phase 0 end points are suggested. Four trial designs that are essentially developed for cytotoxic agents using the maximal tolerated dose as an end point are described. Although these trials were not designed with the use of more sophisticated pharmacodynamic end points (such as the measurement of the effect of a targeted agent on its target), they have been developed to optimize the speed with which a dose needed to achieve a particular effect can be determined and are, to this extent, relevant to the design of studies with pharmacodynamic end points.

Expression of gonadotrophin releasing hormone receptor I is a favorable prognostic factor in epithelial ovarian cancer.

The majority of epithelial ovarian cancers originate in the ovarian surface epithelium. The ovarian surface epithelium is a hormonally responsive tissue, and hormones are thought to play a key role in the development of this type of cancer. Gonadotrophin releasing hormone II is one of 2 isoforms which are thought to act through gonadotrophin releasing hormone receptor I, and gonadotrophin releasing hormone II has been shown to cause growth inhibition of cultured ovarian surface epithelium. The aim of this study was to investigate the expression levels and prognostic significance of gonadotrophin releasing hormone II and the gonadotrophin releasing hormone receptor I in epithelial ovarian cancer. Gonadotrophin releasing hormone II and gonadotrophin releasing hormone receptor I messenger RNA expression was examined in 23 cancers and 7 normal ovarian surface epithelium samples by quantitative real time polymerase chain reaction. An ovarian cancer tissue microarray containing 139 cases was constructed and immunohistochemical analysis of gonadotrophin releasing hormone II and gonadotrophin releasing hormone receptor I protein expression was performed and correlated with clinical outcome data. Gonadotrophin releasing hormone II messenger RNA expression was lower in cancer samples compared to normal ovarian surface epithelium samples (P < .05). Gonadotrophin releasing hormone II protein expression correlated with histologic subtype (25% serous versus 45% nonserous, P < .05) but not with overall survival. Gonadotrophin releasing hormone receptor I messenger RNA expression was highest in serous tumors when compared to non serous (P < .05) and normal tissue (P < .001). Expression of the gonadotrophin releasing hormone receptor I protein was also found to correlate with patient survival (P < .05). We have demonstrated gonadotrophin releasing hormone II and its receptor, gonadotrophin releasing hormone receptor I, are present in clinical ovarian samples, and that gonadotrophin releasing hormone receptor I protein expression is a favorable prognostic factor, suggesting these proteins play an important role in the development of epithelial ovarian cancer.

Design and conduct of phase II studies of targeted anticancer therapy: recommendations from the task force on methodology for the development of innovative cancer therapies (MDICT).

The Methodology for the Development of Innovative Cancer Therapies (MDICT) task force considered aspects of the design and conduct of phase II studies for molecular targeted agents during their 2007 meeting. The task force recommended that multinomial endpoints and designs should be considered for phase II studies of targeted agents, that both single arm as well as randomised designs remain appropriate in certain settings, and that further assessment of novel endpoints (tumour growth kinetic assessment, biomarker or functional imaging) and designs (randomised discontinuation or Bayesian adaptive design) be encouraged. The MDICT cautioned on the use of small randomised trials which have a number of statistical pitfalls and dangers and strongly encouraged the complete reporting, including negative trials, in the scientific literature.

Endpoints and other considerations in phase I studies of targeted anticancer therapy: recommendations from the task force on Methodology for the Development of Innovative Cancer Therapies (MDICT).

Oncology drug development has seen a paradigm shift in the past decade from traditional cytotoxic agents to molecular targeted therapies. Given the different mechanisms and toxicities of these agents, drug development methodology may also require novel approaches. To address emerging issues in oncology drug development the 'Methodology for the Development of Innovative Cancer Therapies' (MDICT) task force was established to provide a forum for academic leaders involved in cancer drug development to discuss methodological issues inherent to the study of targeted anticancer therapy. At the inaugural MDICT meeting in 2006, discussion focused on the most appropriate primary endpoints for first-in-man phase I studies of targeted anticancer agents and organisational issues of such studies. This report summarises the scientific reviews and discussions as well as the recommendations regarding phase I trial design formulated by the MDICT task force.

Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441.

DNA double-strand breaks (DSB) are the most cytotoxic lesions induced by ionizing radiation and topoisomerase II poisons, such as etoposide and doxorubicin. A major pathway for the repair of DSB is nonhomologous end joining, which requires DNA-dependent protein kinase (DNA-PK) activity. We investigated the therapeutic use of a potent, specific DNA-PK inhibitor (NU7441) in models of human cancer. We measured chemosensitization by NU7441 of topoisomerase II poisons and radiosensitization in cells deficient and proficient in DNA-PK(CS) (V3 and V3-YAC) and p53 wild type (LoVo) and p53 mutant (SW620) human colon cancer cell lines by clonogenic survival assay. Effects of NU7441 on DSB repair and cell cycle arrest were measured by gammaH2AX foci and flow cytometry. Tissue distribution of NU7441 and potentiation of etoposide activity were determined in mice bearing SW620 tumors. NU7441 increased the cytotoxicity of ionizing radiation and etoposide in SW620, LoVo, and V3-YAC cells but not in V3 cells, confirming that potentiation was due to DNA-PK inhibition. NU7441 substantially retarded the repair of ionizing radiation-induced and etoposide-induced DSB. NU7441 appreciably increased G(2)-M accumulation induced by ionizing radiation, etoposide, and doxorubicin in both SW620 and LoVo cells. In mice bearing SW620 xenografts, NU7441 concentrations in the tumor necessary for chemopotentiation in vitro were maintained for at least 4 hours at nontoxic doses. NU7441 increased etoposide-induced tumor growth delay 2-fold without exacerbating etoposide toxicity to unacceptable levels. In conclusion, NU7441 shows sufficient proof of principle through in vitro and in vivo chemosensitization and radiosensitization to justify further development of DNA-PK inhibitors for clinical use.

A phase I and pharmacokinetic study of paclitaxel poliglumex (XYOTAX), investigating both 3-weekly and 2-weekly schedules.

PURPOSE: To determine the safety, maximum tolerated dose, pharmacokinetics, and toxicities associated with administration of paclitaxel poliglumex (PPX, XYOTAX, Cell Therapeutics, Inc., Bresso, Italy) given on either 3-weekly or 2-weekly schedule. EXPERIMENTAL DESIGN: Nineteen patients were investigated on the 3-weekly phase Ia study and 11 patients on the 2-weekly phase Ib study. Dose escalation starting with 100% increments and one patient per dose level was modulated in accordance with the observed toxicities. Conjugated and unconjugated paclitaxel were measured in plasma. RESULTS: Dose-limiting toxicity of neutropenia was encountered at 266 mg/m(2) (paclitaxel equivalents) in phase Ia and the maximum tolerated dose was 233 mg/m(2). Neuropathy was dose-limiting in phase Ib with a maximum tolerated dose of 177 mg/m(2). Pharmacokinetic investigations indicated a prolonged half-life of >100 hours for conjugated taxanes. Plasma concentrations of unconjugated paclitaxel were similar to those following administration of an equivalent dose of Taxol. Two partial responses were observed, one in a patient with mesothelioma at 177 mg/m(2) in phase Ia and one in a patient with gastric carcinoma at 175 mg/m(2) in phase Ib. CONCLUSION: PPX is a water-soluble paclitaxel-polymer conjugate with a prolonged half-life and limited volume of distribution. Dose-limiting toxicities were neutropenia and neuropathy. PPX showed activity in this patient population.

Temozolomide pharmacodynamics in patients with metastatic melanoma: dna damage and activity of repair enzymes O6-alkylguanine alkyltransferase and poly(ADP-ribose) polymerase-1.

PURPOSE: Temozolomide, a DNA methylating agent used to treat melanoma, induces DNA damage, which is repaired by O6-alkylguanine alkyltransferase (ATase) and poly(ADP-ribose) polymerase-1 (PARP-1)-dependent base excision repair. The current study was done to define the effect of temozolomide on DNA integrity and relevant repair enzymes as a prelude to a phase I trial of the combination of temozolomide with a PARP inhibitor. EXPERIMENTAL DESIGN: Temozolomide (200 mg/m2 oral administration) was given to 12 patients with metastatic malignant melanoma. Peripheral blood lymphocytes (PBL) were analyzed for PARP activity, DNA single-strand breakage, ATase levels, and DNA methylation. PARP activity was also measured in tumor biopsies from 9 of 12 patients and in PBLs from healthy volunteers. RESULTS: Temozolomide pharmacokinetics were consistent with previous reports. Temozolomide therapy caused a substantial and sustained elevation of N7-methylguanine levels, a modest and sustained reduction in ATase activity, and a modest and transient increase in DNA strand breaks and PARP activity in PBLs. PARP-1 activity in tumor homogenates was variable (828 +/- 599 pmol PAR monomer/mg protein) and was not consistently affected by temozolomide treatment. CONCLUSIONS: The effect of temozolomide reported here are consistent with those documented in previous studies with temozolomide and similar drug, dacarbazine, demonstrating that a representative patient population was investigated. Furthermore, PARP activity was not inhibited by temozolomide treatment and this newly validated pharmacodynamic assay is therefore suitable for use in a proof-of-principle phase I trial a PARP-1 inhibitor in combination with temozolomide.

Phase I study of temozolomide plus paclitaxel in patients with advanced malignant melanoma and associated in vitro investigations.

The purpose of this study was to determine activity of temozolomide combined with paclitaxel or epothilone B in vitro, and to investigate the combination of temozolomide with paclitaxel in a Phase I clinical trial. Melanoma cell lines A375P and DX3 were treated with temozolomide and either paclitaxel or epothilone B. Combination indices were determined to assess the degree of synergism. In a clinical study, 21 patients with malignant melanoma were treated with increasing doses of temozolomide (orally, days 1-5), in combination with a fixed dose of paclitaxel (i.v. infusion day 1), followed by dose escalation of the latter drug. Cycles of treatment were repeated every 3 weeks. Pharmacokinetics of both agents were determined on day 1, with temozolomide pharmacokinetics also assessed on day 5. All three compounds were active against the melanoma cell lines, with epothilone B being the most potent. There was a strong degree of synergism between temozolomide and either paclitaxel or epothilone B. In the clinical study, no pharmacokinetic interaction was observed between temozolomide and paclitaxel. Dose escalation of both drugs to clinically active doses was possible, with no dose-limiting toxicities observed at 200 mg m(-2) day(-1) temozolomide and 225 mg m(-2) day(-1) paclitaxel. There were two partial responses out of 15 evaluable patients. One patient remains alive and symptom-free at 4 years after treatment. Temozolomide and paclitaxel may be administered safely at clinically effective doses. Further evaluation of these combinations in melanoma is warranted.

Randomized trial of two intravenous schedules of the topoisomerase I inhibitor liposomal lurtotecan in women with relapsed epithelial ovarian cancer: a trial of the national cancer institute of Canada clinical trials group.

PURPOSE: Liposomal lurtotecan (OSI-211) is a liposomal formulation of the water-soluble topoisomerase I inhibitor lurtotecan (GI147211), which demonstrated superior levels of activity compared with topotecan in preclinical models. We studied two schedules of OSI-211 in a randomized design in relapsed ovarian cancer to identify the more promising of the two schedules for further study. PATIENTS AND METHODS: Eligible patients had measurable epithelial ovarian, fallopian, or primary peritoneal cancer that was recurrent after one or two prior regimens of chemotherapy. Patients were randomly assigned to receive either arm A (OSI-211 1.8 mg/m(2)/d administered by 30-minute intravenous infusion on days 1, 2, and 3 every 3 weeks) or arm B (OSI-211 2.4 mg/m(2)/d administered by 30-minute intravenous infusion on days 1 and 8 every 3 weeks). The primary outcome measure was objective response, which was confirmed by independent radiologic review, and a pick the winner statistical design was used to identify the schedule most likely to be superior. RESULTS: Eighty-one patients were randomized between October 2000 and September 2001. The hematologic toxic effects were greater on arm A than on arm B (grade 4 neutropenia, 51% v 22%, respectively), as was febrile neutropenia (26% v 2.4%, respectively). Of the 80 eligible patients, eight patients (10%) had objective responses; six responders (15.4%; 95% CI, 6% to 30%) were in arm A and two responders (4.9%; 95% CI, 1% to 17%) were in arm B. CONCLUSION: The OSI-211 daily for 3 days intravenous schedule met the statistical criteria to be declared the winner in terms of objective response. This schedule was also associated with more myelosuppression than the schedule of OSI-211 administered in arm B.

Isoindolinone-based inhibitors of the MDM2-p53 protein-protein interaction.

A series of 2-N-alkyl-3-aryl-3-alkoxyisoindolinones has been synthesised and evaluated as inhibitors of the MDM2-p53 interaction. The most potent compound, 3-(4-chlorophenyl)-3-(4-hydroxy-3,5-dimethoxybenzyloxy)-2-propyl-2,3-dihydroisoindol-1-one (NU8231), exhibited an IC50 of 5.3 +/- 0.9 microM in an ELISA assay, and induced p53-dependent gene transcription in a dose-dependent manner, in the SJSA human sarcoma cell line.