Search

BRAFV600E alterations are prevalent across multiple tumors. Here we present final efficacy and safety results of a phase 2 basket trial of dabrafenib (BRAF kinase inhibitor) plus trametinib (MEK inhibitor) in eight cohorts of patients with BRAFV600E-mutated advanced rare cancers: anaplastic thyroid carcinoma (n = 36), biliary tract cancer (n = 43), gastrointestinal stromal tumor (n = 1), adenocarcinoma of the small intestine (n = 3), low-grade glioma (n = 13), high-grade glioma (n = 45), hairy cell leukemia (n = 55) and multiple myeloma (n = 19). The primary endpoint of investigator-assessed overall response rate in these cohorts was 56%, 53%, 0%, 67%, 54%, 33%, 89% and 50%, respectively. Secondary endpoints were median duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Median DoR was 14.4 months, 8.9 months, not reached, 7.7 months, not reached, 31.2 months, not reached and 11.1 months, respectively. Median PFS was 6.7 months, 9.0 months, not reached, not evaluable, 9.5 months, 5.5 months, not evaluable and 6.3 months, respectively. Median OS was 14.5 months, 13.5 months, not reached, 21.8 months, not evaluable, 17.6 months, not evaluable and 33.9 months, respectively. The most frequent (≥20% of patients) treatment-related adverse events were pyrexia (40.8%), fatigue (25.7%), chills (25.7%), nausea (23.8%) and rash (20.4%). The encouraging tumor-agnostic activity of dabrafenib plus trametinib suggests that this could be a promising treatment approach for some patients with BRAFV600E-mutated advanced rare cancers. ClinicalTrials.gov registration: NCT02034110.

BackgroundThe phase I first-in-human study ENGAGE-1 evaluated the humanized IgG1 OX40 agonistic monoclonal antibody GSK3174998 alone (Part 1 (P1)) or in combination with pembrolizumab (Part 2 (P2)) in patients with advanced solid tumors.MethodsGSK3174998 (0.003–10 mg/kg) ± pembrolizumab (200 mg) was administered intravenously every 3 weeks using a continuous reassessment method for dose escalation. Primary objectives were safety and tolerability; secondary objectives included pharmacokinetics, immunogenicity, pharmacodynamics, and clinical activity.Results138 patients were enrolled (45 (P1) and 96 (P2, including 3 crossovers)). Treatment-related adverse events occurred in 51% (P1) and 64% (P2) of patients, fatigue being the most common (11% and 24%, respectively). No dose-toxicity relationship was observed, and maximum-tolerated dose was not reached. Dose-limiting toxicities (P2) included Grade 3 (G3) pleural effusion and G1 myocarditis with G3 increased troponin. GSK3174998 ≥0.3 mg/kg demonstrated pharmacokinetic linearity and >80% receptor occupancy on circulating T cells; 0.3 mg/kg was selected for further evaluation. Limited clinical activity was observed for GSK3174998 (P1: disease control rate (DCR) ≥24 weeks 9%) and was not greater than that expected for pembrolizumab alone (P2: overall response rate 8%, DCR ≥24 weeks 28%). Multiplexed immunofluorescence data from paired biopsies suggested that increased infiltration of natural killer (NK)/natural killer T (NKT) cells and decreased regulatory T cells (Tregs) in the tumor microenvironment may contribute to clinical responses: CD16+CD56–CD134+ NK /NKT cells and CD3+CD4+FOXP3+CD134+ Tregs exhibited the largest magnitude of change on treatment, whereas CD3+CD8+granzyme B+PD-1+CD134+ cytotoxic T cells were the least variable. Tumor gene expression profiling revealed an upregulation of inflammatory responses, T-cell proliferation, and NK cell function on treatment with some inflammatory cytokines upregulated in peripheral blood. However, target engagement, evidenced by pharmacologic activity in peripheral blood and tumor tissue, did not correlate with clinical efficacy. The low number of responses precluded identifying a robust biomarker signature predictive of response.ConclusionsGSK3174998±pembrolizumab was well tolerated over the dose range tested and demonstrated target engagement. Limited clinical activity does not support further development of GSK3174998±pembrolizumab in advanced cancers.Trial registration numberNCT02528357.

Background Despite the clinical efficacy of enzalutamide monotherapy in patients with advanced prostate cancer, therapeutic resistance and disease progression are inevitable. We proposed a study to evaluate NLG207, a nanoparticle-drug conjugate (NDC) of the potent topoisomerase I inhibitor camptothecin, in combination with enzalutamide, in patients with metastatic castration-resistant prostate cancer (mCRPC) following progression on enzalutamide. Methods This was a single-arm, optimal two-stage, phase II study to evaluate the efficacy of NLG207 in combination with enzalutamide in patients with mCRPC who received prior enzalutamide. A lead-in dose escalation evaluated the recommended phase 2 dose of NLG207 in combination with enzalutamide. Patients received NLG207 via IV infusion every 2 weeks and enzalutamide 160 mg orally once daily. Results Between March 2019 and June 2021, four patients were accrued to the lead-in dose escalation. Two of the four patients were evaluable and both experienced DLTs at the NLG207 12 mg/m2 dose level; one DLT was related to a dose delay for noninfective cystitis and myelosuppression, the other a grade 3 noninfective cystitis. Further evaluation of NLG207 in combination with enzalutamide was halted and the study was ultimately terminated. PSA declines from baseline were observed in two patients. Conclusion NLG207 12 mg/m2 in combination with enzalutamide was not well tolerated in patients with mCRPC following several lines of the standard of care therapy. ClinicalTrials.gov Identifier NCT03531827.

Introduction Oral formulations of docetaxel have successfully been developed as an alternative for intravenous administration. Co-administration with the enzyme inhibitor ritonavir boosts the docetaxel plasma exposure. In dose-escalation trials, the maximum tolerated doses for two different dosing regimens were established and dose-limiting toxicities (DLTs) were recorded. The aim of current analysis was to develop a pharmacokinetic (PK)-toxicodynamic (TOX) model to quantify the relationship between docetaxel plasma exposure and DLTs. Methods A total of 85 patients was included in the current analysis, 18 patients showed a DLT in the four-week observation period. A PK-TOX model was developed and simulations based on the PK-TOX model were performed. Results The final PK-TOX model was characterized by an effect compartment representing the toxic effect of docetaxel, which was linked to the probability of developing a DLT. Simulations of once-weekly, once-daily 60 mg and once-weekly, twice-daily 30 mg followed by 20 mg of oral docetaxel suggested that 14% and 34% of patients, respectively, would have a probability25% to develop a DLT in a four-week period. Conclusions A PK-TOX model was successfully developed. This model can be used to evaluate the probability of developing a DLT following treatment with oral docetaxel and ritonavir in different dosing regimens.

Fluoropyrimidines are frequently used anti-cancer drugs. It is known that patients with reduced activity of dihydropyrimidine dehydrogenase (DPD), the key metabolic enzyme in fluoropyrimidine inactivation, are at increased risk of developing severe fluoropyrimidine-related toxicity. Upfront screening for DPD deficiency and dose reduction in patients with partial DPD deficiency is recommended and improves patient safety. For patients with complete DPD deficiency, fluoropyrimidine-treatment has generally been discouraged. During routine pretreatment screening, we identified a 59-year-old patient with a sigmoid adenocarcinoma who proved to have a complete DPD deficiency. Genetic analyses showed that this complete absence of DPD activity was likely to be caused by a novel DPYD genotype, consisting of a combination of amplification of exons 17 and 18 of DPYD and heterozygosity for DPYD*2A. Despite absence of DPD activity, the patient was treated with capecitabine-based chemotherapy, but capecitabine dose was drastically reduced to 150 mg once every 5 days (0.8% of original dose). Pharmacokinetic analyses showed that the area under the concentration-time curve (AUC) and half-life of 5-fluorouracil were respectively tenfold and fourfold higher than control values of patients receiving capecitabine 850 mg/m2. When extrapolating from the dosing schedule of once every 5 days to twice daily, the AUC of 5-fluorouracil was comparable to controls. Treatment was tolerated well for eight cycles by the patient without occurrence of capecitabine-related toxicity. This case report demonstrates that a more comprehensive genotyping and phenotyping approach, combined with pharmacokinetically-guided dose administration, enables save fluoropyrimidine-treatment with adequate drug exposure in completely DPD deficient patients.

Carriers of the genetic DPYD*2A variant, resulting in dihydropyrimidine dehydrogenase deficiency, are at significantly increased risk of developing severe fluoropyrimidine-associated toxicity. Upfront DPYD*2A genotype-based dose reductions improve patient safety, but uncertainty exists whether this has a negative impact on treatment effectiveness. Therefore, our study investigated effectiveness and safety of DPYD*2A genotype-guided dosing. A cohort of 40 prospectively identified heterozygous DPYD*2A carriers, treated with a ~50% reduced fluoropyrimidine dose, was identified. For effectiveness analysis, a matched pair-analysis was performed in which for each DPYD*2A carrier a matched DPYD*2A wild-type patient was identified. Overall survival and progression-free survival were compared between the matched groups. The frequency of severe (grade ≥ 3) treatment-related toxicity was compared to 1] a cohort of 1606 wild-type patients treated with full dose and 2] a cohort of historical controls derived from literature, i.e. 86 DPYD*2A variant carriers who received a full fluoropyrimidine dose. For 37 out of 40 DPYD*2A carriers, a matched control could be identified. Compared to matched controls, reduced doses did not negatively affect overall survival (median 27 months versus 24 months, p = 0.47) nor progression-free survival (median 14 months versus 10 months, p = 0.54). Risk of severe fluoropyrimidine-related toxicity in DPYD*2A carriers treated with reduced dose was 18%, comparable to wild-type patients (23%, p = 0.57) and significantly lower than the risk of 77% in DPYD*2A carriers treated with full dose (p0.001). Our study is the first to show that DPYD*2A genotype-guided dosing appears to have no negative effect on effectiveness of fluoropyrimidine-based chemotherapy, while resulting in significantly improved patient safety.

AIM: Pharmacokinetics of small molecule kinase inhibitors (KIs) used in cancer treatment may alter with increasing age, but results are conflicting. This study aims to compare exposure to KIs between older and younger patients (≥70 and

Transporters such as ABCB1 and ABCG2 limit the exposure of several anticancer drugs to the brain, leading to suboptimal treatment in the central nervous system. The purpose of this study was to investigate the effects of the ABCB1 and ABCG2 inhibitor elacridar on brain uptake using

Preclinical evidence suggests that concomitant BRAF and EGFR inhibition leads to sustained suppression of MAPK signaling and suppressed tumor growth in BRAF V600E colorectal cancer (CRC) models. Patients with refractory BRAF V600–mutant metastatic CRC (mCRC) were treated with a selective RAF kinase inhibitor (encorafenib) plus a monoclonal antibody targeting EGFR (cetuximab), with (n = 28) or without (n = 26) a PI3K-alpha inhibitor (alpelisib). The primary objective was to determine the maximum tolerated dose (MTD) or a recommended phase 2 dose. Dose-limiting toxicities were reported in three patients receiving dual- and two patients receiving triple-treatment. The MTD was not reached for either group and the Phase 2 doses were selected as 200 mg encorafenib (both groups) and 300 mg alpelisib. Combinations of cetuximab and encorafenib show promising clinical activity and tolerability in patients with BRAF-mutant mCRC; confirmed overall response rates of 19% and 18% were observed, and median progression-free survival was 3.7 and 4.2 months, for the dual- and triple-therapy groups, respectively.

Omacetaxine mepesuccinate (hereafter referred to as omacetaxine) is a protein translation inhibitor approved by the US Food and Drug Administration for adult patients with chronic myeloid leukemia with resistance and/or intolerance to two or more tyrosine kinase inhibitors. The objective was to investigate the metabolite profile of omacetaxine in plasma, urine and faeces samples collected up to 72 h after a single 1.25-mg/m

Pharmacokinetic monitoring is increasingly becoming an important part of clinical care of tyrosine kinase inhibitor treatment. Vemurafenib is an oral tyrosine kinase inhibitor that inhibits mutated serine/threonine protein kinase B-Raf (BRAF) and is approved for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. The aim of this study was to establish the relationship between dried blood spot (DBS) and plasma concentrations of vemurafenib to enable the use of DBS sampling, which is a minimally invasive form of sample collection. In total, 43 paired plasma and DBS samples (in duplicate) were obtained from 8 melanoma patients on vemurafenib therapy and were analyzed using high-performance liquid chromatography-tandem mass spectrometry. Plasma concentrations were predicted from the DBS concentrations using 2 methods: (1) individual hematocrit correction and blood cell-to-plasma partitioning and (2) the calculated slope explaining the relationship between DBS and plasma concentrations (without individual hematocrit correction). Vemurafenib DBS concentrations and plasma concentrations showed a strong correlation (r = 0.964), and the relationship could be described by ([vemurafenib]plasma = [vemurafenib]DBS /0.64). The predicted plasma concentrations were within ±20% of the analyzed plasma concentrations in 97% and 100% of the samples for the methods with and without hematocrit correction, respectively. In conclusion, DBS concentrations and plasma concentrations of vemurafenib are highly correlated. Plasma concentrations can be predicted from DBS concentration using the blood cell-to-plasma partition and the average hematocrit value of this cohort (0.40 L/L). DBS sampling for pharmacokinetic monitoring of vemurafenib treatment can be used in clinical practice.

Learning Objectives After completing this course, the reader will be able to: Evaluate the clinical use of bevacizumab, both for cancer and for non-oncologic diseases, and discuss approved and investigational combination chemotherapies that include bevacizumab.Describe the pharmacology of bevacizumab and its mechanism of action in order to predict degrees of patient response. CME This article is available for continuing medical education credit at CME.TheOncologist.com.

This article provides a brief summary of the use of methylnaltrexone for opioid-induced constipation in patients with advanced illness receiving palliative care when the response to laxatives is insufficient.

Learning Objectives After completing this course, the reader will be able to: Identify the current indications for imatinib.Describe the pharmacokinetics of imatinib.Discuss the mechanisms involved in imatinib resistance. Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com

Learning Objectives After completing this course, the reader will be able to: Identify the main toxicity profile associated with capecitabine therapy.Identify the main clinical indications for capecitabine therapy.Identify the populations at risk for severe toxicity from capecitabine therapy. CME Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com

The objective of this study was to determine whether genotyping of MIR27A polymorphisms rs895819AG and rs11671784CT can be used to improve the predictive value of DPYD variants to identify patients at risk of severe fluoropyrimidine-associated toxicity (FP-toxicity). Patients treated previously in a prospective study with fluoropyrimidine-based chemotherapy were genotyped for rs895819 and rs11671784, and DPYD c.2846AT, c.1679TG, c.1129-5923CG and c.1601GA. The predictive value of MIR27A variants for early-onset grade ≥3 FP-toxicity, alone or in combination with DPYD variants, was tested in multivariable logistic regression models. Random-effects meta-analysis was performed, including previously published data. A total of 1,592 patients were included. Allele frequencies of rs895819 and rs11671784 were 0.331 and 0.020, respectively. In DPYD wild-type patients, MIR27A variants did not affect risk of FP-toxicity (OR 1.3 for ≥1 variant MIR27A allele vs. none, 95% CI: 0.87-1.82, p = 0.228). In contrast, in patients carrying DPYD variants, the presence of ≥1 rs895819 variant allele was associated with increased risk of FP-toxicity (OR 4.9, 95% CI: 1.24-19.7, p = 0.023). Rs11671784 was not associated with FP-toxicity (OR 2.9, 95% CI: 0.47-18.0, p = 0.253). Patients carrying a DPYD variant and rs895819 were at increased risk of FP-toxicity compared to patients wild type for rs895819 and DPYD (OR 2.4, 95% CI: 1.27-4.37, p = 0.007), while patients with a DPYD variant but without a MIR27A variant were not (OR 0.3 95% CI: 0.06-1.17, p = 0.081). In meta-analysis, rs895819 remained significantly associated with FP-toxicity in DPYD variant allele carriers, OR 5.4 (95% CI: 1.83-15.7, p = 0.002). This study demonstrates the clinical validity of combined MIR27A/DPYD screening to identify patients at risk of severe FP-toxicity.

There is increasing discussion in the Netherlands about the introduction of a threshold value for the costs per extra year of life when reimbursing costs of new drugs. The Medicines Committee ('Commissie Geneesmiddelen'), a division of the Netherlands National Healthcare Institute ('Zorginstituut Nederland'), advises on reimbursement of costs of new drugs. This advice is based upon the determination of therapeutic value of the drug and the results of economic evaluations. Mathematical models that predict future costs and effectiveness are often used in economic evaluations; these models can vary greatly in transparency and quality due to author assumptions. Standardisation of cost-effectiveness models is one solution to overcome the unwanted variation in quality. Discussions about the introduction of a threshold value can only be meaningful if all involved are adequately informed, and by high quality in cost-effectiveness research and, particularly, economic evaluations. Collaboration and discussion between medical specialists, patients or patient organisations, health economists and policy makers, both in development of methods and in standardisation, are essential to improve the quality of decision making.

Docetaxel (Taxotere(®)) is currently used intravenously as an anticancer agent and is primarily metabolized by Cytochrome P450 3A (CYP3A). The HIV protease inhibitor ritonavir, a strong CYP3A4 inhibitor, decreased first-pass metabolism of orally administered docetaxel. Anticancer effects of ritonavir itself have also been described. We here aimed to test whether ritonavir co-administration could decrease intratumoral metabolism of intravenously administered docetaxel and thus increase the antitumor activity of docetaxel in an orthotopic, immunocompetent mouse model for breast cancer. Spontaneously arising K14cre;Brca1(F/F) ;p53(F/F) mouse mammary tumors were orthotopically implanted in syngeneic mice lacking Cyp3a (Cyp3a(-/-)) to limit ritonavir effects on systemic docetaxel clearance. Over 3 weeks, docetaxel (20 mg/kg) was administered intravenously once weekly, with or without ritonavir (12.5 mg/kg) administered orally for 5 days per week. Untreated mice were used as control for tumor growth. Ritonavir treatment alone did not significantly affect the median time of survival (14 vs. 10 days). Median time of survival in docetaxel-treated mice was 54 days. Ritonavir co-treatment significantly increased this to 66 days, and substantially reduced relative average tumor size, without altering tumor histology. Concentrations of the major docetaxel metabolite M2 in tumor tissue were reduced by ritonavir co-administration, whereas tumor RNA expression of Cyp3a was unaltered. In this breast cancer model, we observed no direct antitumor effect of ritonavir alone, but we found enhanced efficacy of docetaxel treatment when combined with ritonavir. Our data, therefore, suggest that decreased docetaxel metabolism inside the tumor as a result of Cyp3a inhibition contributes to increased antitumor activity.

The fluoropyrimidines act by inhibiting thymidylate synthase (TS). Recent studies have shown that patients' risk of severe fluoropyrimidine-associated toxicity is affected by polymorphisms in the 5'-untranslated region of TYMS, the gene encoding TS. A GC substitution in the promoter enhancer region of TYMS, rs183205964 (known as the 2RC allele), markedly reduces TS activity in vitro, but its clinical relevance is unknown. We determined rs183205964 in 1605 patients previously enrolled in a prospective multicenter study. Associations between putative low TS expression genotypes (3RC/2RC, 2RG/2RC, and 2RC/2RC) and severe toxicity were investigated using univariable and multivariable logistic regression. Activity of TS and TYMS gene expression were determined in peripheral blood mononuclear cells (PBMCs) of a patient carrying genotype 2RC/2RC and of a control group of healthy individuals. Among 1,605 patients, 28 patients (1.7%) carried the 2RC allele. Twenty patients (1.2%) carried a risk-associated genotype (2RG/2RC, n=13; 3RC/2RC, n=6; and 2RC/2RC, n=1), the eight remaining patients had genotype 3RG/2RC. Early severe toxicity and toxicity-related hospitalization were significantly more frequent in risk-associated genotype carriers (OR 3.0, 95%CI 1.04-8.93, p=0.043 and OR 3.8, 95%CI 1.19-11.9, p=0.024, respectively, in multivariable analysis). The patient with genotype 2RC/2RC was hospitalized twice and had severe febrile neutropenia, diarrhea, and hand-foot syndrome. Baseline TS activity and gene expression in PBMCs of this patient, and a healthy individual with the 2RC allele, were found to be within the normal range. Our study suggests that patients carrying rs183205964 are at strongly increased risk of severe, potentially life-threatening, toxicity when treated with fluoropyrimidines.

Previously published pharmacokinetic (PK) models for sunitinib and its active metabolite SU12662 were based on a limited dataset or lacked important elements such as correlations between sunitinib and its metabolite. The current study aimed to develop an improved PK model that circumvented these limitations and to prove the utility of the PK model in treatment optimization in clinical practice.One thousand two hundred and five plasma samples from 70 cancer patients were collected from three PK studies with sunitinib and SU12662. A semi-physiological PK model for sunitinib and SU12662 was developed incorporating pre-systemic metabolism using non-linear mixed effects modelling (nonmem). Allometric scaling based on body weight was applied. The final model was used for simulation of the PK of different treatment regimens.Sunitinib and SU12662 PK were best described by a one and two compartment model, respectively. Introduction of pre-systemic formation of SU12662 strongly improved model fit, compared with solely systemic metabolism. The clearance of sunitinib and SU12662 was estimated at 35.7 (relative standard error (RSE) 5.7%) l h(-1) and 17.1 (RSE 7.4%) l h(-1), respectively for 70 kg patients. Correlation coefficients were estimated between inter-individual variability of both clearances, both volumes of distribution and between clearance and volume of distribution of SU12662 as 0.53, 0.48 and 0.45, respectively. Simulation of the PK model predicted correctly the ratio of patients who did not reach proposed PK targets for efficacy.A semi-physiological PK model for sunitinib and SU12662 in cancer patients was presented including pre-systemic metabolism. The model was superior to previous PK models in many aspects.

Everolimus is an orally administered anti-cancer drug that inhibits the mammalian target of rapamycin (mTOR) signal transduction route. Use of everolimus may be associated with insulin resistance, manifesting in impaired glucose tolerance or hyperglycaemia.A 74-year-old female patient with a locally recurrent breast cancer developed hyperglycaemia, which started 2 weeks after the initiation of treatment with everolimus 10 mg once daily. Metformin and insulin were administered to restore normoglycaemia.At the initiation of treatment with an mTOR inhibitor such as everolimus the treating physician should be aware of the occurrence of hyperglycaemia. Metformin is then the medicine of first choice.

New possibilities for genetic diagnostics are rapidly assuming a place in oncological clinical practice. Due to specific genetic aberrations, solid tumours characterised by their histological origin can now be further classified into subgroups. The further sub-classification of tumours has led to the development of therapies that target these genetic changes. Clinical research into these drugs in genetically characterised patient groups should be carried out more efficiently than is currently the case in oncological drug studies. In both primary tumours and metastases, the heterogeneity of the tumour genome and the changes within this make the identification of important genetic aberrations more difficult. In the Netherlands a network of hospitals and institutions is being set up - the Center for Personalized Cancer Treatment - to facilitate genome studies of tumours and clinical oncology studies and aimed at making the development of drugs more efficient.

The aim of the current work was to perform a clinical trial simulation (CTS) analysis to optimize a drug-drug interaction (DDI) study of vincristine in children who also received azole antifungals, taking into account challenges of conducting clinical trials in this population, and, to provide a motivating example of the application of CTS in the design of pediatric oncology clinical trials.A pharmacokinetic (PK) model for vincristine in children was used to simulate concentration-time profiles. A continuous model for body surface area versus age was defined based on pediatric growth curves. Informative sampling time windows were derived using D-optimal design. The CTS framework was used to different magnitudes of clearance inhibition (10%, 25%, or 40%), sample size (30-500), the impact of missing samples or sampling occasions, and the age distribution, on the power to detect a significant inhibition effect, and in addition, the relative estimation error (REE) of the interaction effect.A minimum group specific sample size of 38 patients with a total sample size of 150 patients was required to detect a clearance inhibition effect of 40% with 80% power, while in the case of a lower effect of clearance inhibition, a substantially larger sample size was required. However, for the majority of re-estimated drug effects, the inhibition effect could be estimated precisely (REE 25%) in even smaller sample sizes and with lower effect sizes.This work demonstrated the utility of CTS for the evaluation of PK clinical trial designs in the pediatric oncology population.

Regorafenib has recently been approved for the treatment of colorectal cancer. A bioanalytical liquid chromatography-tandem mass spectrometric assay for this multikinase inhibitor was developed and validated in plasma. The concentration range of the assay was 25-25,000 ng/mL. Protein precipitation with acetonitrile was used as sample pre-treatment with sorafenib as internal standard. The extract was diluted with methanol (25%, v/v) and then injected onto the sub-2 µm particle, bridged ethylsilicia hybrid trifunctional bonded C18 column. Isocratic elution using 0.02% (v/v) formic acid in a methanol-water mixture was used. Compounds were monitored by a triple quadrupole mass spectrometer in the selected reaction monitoring mode after positive electrospray ionization. Double logarithmic calibration was used; within-day precisions, between-day precisions, and accuracies were 3.2-9.2, 4.1-12.3 and 94.8-103.0%, respectively. High drug stability was observed under all relevant storage conditions. The assay was used to measure drug concentrations in a pharmacokinetic study in wild-type FVB mice.

A combined assay for the determination of paclitaxel, docetaxel and ritonavir in human feces and urine is described. The drugs were extracted from 200 μL urine or 50 mg feces followed by high-performance liquid chromatography analysis coupled with positive ionization electrospray tandem mass spectrometry. The validation program included calibration model, accuracy and precision, carry-over, dilution test, specificity and selectivity, matrix effect, recovery and stability. Acceptance criteria were according to US Food and Drug Administration guidelines on bioanalytical method validation. The validated range was 0.5-500 ng/mL for paclitaxel and docetaxel, 2-2000 ng/mL for ritonavir in urine, 2-2000 ng/mg for paclitaxel and docetaxel, and 8-8000 ng/mg for ritonavir in feces. Inter-assay accuracy and precision were tested for all analytes at four concentration levels and were within 8.5% and10.2%, respectively, in both matrices. Recovery at three concentration levels was between 77 and 94% in feces samples and between 69 and 85% in urine samples. Method development, including feces homogenization and spiking blank urine samples, are discussed. We demonstrated that each of the applied drugs could be quantified successfully in urine and feces using the described assay. The method was successfully applied for quantification of the analytes in feces and urine samples of patients.

To provide an overview of the incidence of peptic ulcer in patients who use systemic corticosteroids and of the underlying mechanism of action, in order to determine whether there is a need for gastric protection using proton pump inhibitors in these patients.Systematic literature review of published meta-analyses and case-control studies, supported by relevant literature on the effects of corticosteroids in relation to the development of ulcers.Analysis of literature was performed using the PubMed database with the search terms 'adrenal cortex hormones', 'peptic ulcer' and their synonyms. Meta-analyses and case-control studies with more than 1000 patients were included.The literature search resulted in 970 articles, of which 3 were classified as relevant meta-analyses and 3 as relevant case-control studies. All meta-analyses indicated that peptic ulcer is, at the most, a rare complication of systemic corticosteroid therapy occurring in less than 0.4-1.8% of patients. As the incidence is low, there is no indication for routine prophylaxis with proton pump inhibitors in combination with systemic corticosteroids. There is convincing evidence showing an increased risk of ulcers and a poorer recovery from these when NSAIDs and systemic corticosteroids are used concomitantly; this is a combination for which a proton pump inhibitor should be prescribed.Systemic corticosteroid therapy only rarely causes a peptic ulcer. Routine prophylaxis with proton pump inhibitors is therefore not indicated for short-term systemic corticosteroid use.

Eribulin mesilate is an inhibitor of microtubule dynamics that is approved for the treatment of late-stage metastatic breast cancer. Neutropenia is one of the major dose-limiting adverse effects of eribulin. The objective of this analysis was to develop a population pharmacokinetic-pharmacodynamic model for eribulin-associated neutropenia.A combined data set of 12 phase I, II and III studies for eribulin mesilate was analysed. The population pharmacokinetics of eribulin was described using a previously developed model. The relationship between eribulin pharmacokinetic and neutropenia was described using a semi-physiological lifespan model for haematological toxicity. Patient characteristics predictive of increased sensitivity to develop neutropenia were evaluated using a simulation framework.Absolute neutrophil counts were available from 1579 patients. In the final covariate model, the baseline neutrophil count (ANC0) was estimated to be 4.03 × 10(9) neutrophils l(-1) [relative standard error (RSE) 1.2%], with interindividual variability (IIV, 37.3 coefficient of variation % [CV%]). The mean transition time was estimated to be 109 h (RSE 1.8%, IIV 13.9CV%), the feedback constant (γ) was estimated to be 0.216 (RSE 1.4%, IIV 12.2CV%), and the linear drug effect coefficient (SLOPE) was estimated to be 0.0451 μg l(-1) (RSE 3.2%, IIV 54CV%). Albumin, aspartate transaminase and receival of granulocyte colony-stimulating factor (G-CSF) were identified as significant covariates on SLOPE, and albumin, bilirubin, G-CSF, alkaline phosphatase and lactate dehydrogenase were identified as significant covariates on mean transition time.The developed model can be applied to investigate optimal treatment strategies quantitatively across different patient groups with respect to neutropenia. Albumin was identified as the most clinically important covariate predictive of interindividual variability in the neutropenia time course.

The herbal medicine Echinacea purpurea (E. purpurea) has been shown to induce cytochrome P450 3A4 (CYP3A4) both in vitro and in humans. This study explored whether E. purpurea affects the pharmacokinetics of the CYP3A4 substrate docetaxel in cancer patients.Ten evaluable cancer patients received docetaxel (135 mg, 60 min IV infusion) before intake of a commercially available E. purpurea extract (20 oral drops three times daily) and 3 weeks later after a 14 day supplementation period with E. purpurea. In both cycles, pharmacokinetic parameters of docetaxel were determined.Before and after supplementation with E. purpurea, the mean area under the plasma concentration-time curve of docetaxel was 3278 ± 1086 and 3480 ± 1285 ng ml(-1) h, respectively. This result was statistically not significant. Nonsignificant alterations were also observed for the elimination half-life (from 30.8 ± 19.7 to 25.6 ± 5.9 h, P = 0.56) and maximum plasma concentration of docetaxel (from 2224 ± 609 to 2097 ± 925 ng ml(-1) , P = 0.30).The multiple treatment of E. purpurea did not significantly alter the pharmacokinetics of docetaxel in this study. The applied E. purpurea product at the recommended dose may be combined safely with docetaxel in cancer patients.

Capecitabine, 5-fluorouracil and tegafur form the group called the fluoropyrimidines, which is one of the most frequently prescribed group of anti-cancer drugs for the treatment of (metastatic) colorectal, gastric and breast cancer. The primary enzyme responsible for the inactivation of the fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD). Consequently, patients with an inborn partial DPD deficiency, induced, for example by the polymorphism DPYD*2A, are highly prone to severe, potentially lethal toxicity following a standard dose of fluoropyrimidines. In this article, based on three representative case reports and our prospective study in patients with cancer, we demonstrate the clinical value of prospective screening for DPD deficiency in patients being treated with fluoropyrimidine-based anti-cancer therapy. The results show that upfront genotyping for DPYD*2A followed by a fluoropyrimidine dose reduction of 50% (on average) in patients heterozygous polymorphic for DPYD*2A, significantly reduces the incidence of severe to potentially lethal toxicity compared to historical control patients given full-dose therapy.

The safety, tolerability, and efficacy of the mixture of botanical compounds known as LCS101 were evaluated in the prevention of chemotherapy-induced hematological toxicity in breast cancer patients in a prospective, controlled study.

To evaluate dosing and intervention strategies for the phase II programme of a VEGF receptor inhibitor using PK-PD modelling and simulation, with the aim of maximizing (i) the number of patients on treatment and (ii) the average dose level during treatment.A previously developed PK-PD model for lenvatinib (E7080) was updated and parameters were re-estimated (141 patients, once daily and twice daily regimens). Treatment of lenvatinib was simulated for 16 weeks, initiated at 25 mg once daily. Outcome measures included the number of patients on treatment and overall drug exposure. A hypertension intervention design proposed for phase II studies was evaluated, including antihypertensive treatment and dose de-escalation. Additionally, a within-patient dose escalation was investigated, titrating up to 50 mg once daily unless unacceptable toxicity occurred.Using the proposed antihypertension intervention design, 82% of patients could remain on treatment, and the mean dose administered was 21.5 mg day⁻¹. The adverse event (AE) guided dose titration increased the average dose by 4.6 mg day⁻¹, while only marginally increasing the percentage of patients dropping out due to toxicity (from 18% to 20.8%).The proposed hypertension intervention design is expected to be effective in maintaining patients on treatment with lenvatinib. The AE-guided dose titration with blood pressure as a biomarker yielded a higher overall dose level, without relevant increases in toxicity. Since increased exposure to lenvatinib seems correlated with increased treatment efficacy, the adaptive treatment design may thus be a valid approach to improve treatment outcome.

Myelodysplastic syndrome, a disorder of haematopoiesis, is associated with anaemia and an increased risk of infections, bleeding and the development of acute myeloid leukaemia. The disorder occurs mainly in later life. Until recently the only therapy that could induce sustained remission was allogeneic stem cell transplantation. However in elderly patients caution is needed with this therapy. Increasing awareness of the role of epigenetic changes in cancer development has led to the rediscovery of the cytidine analogues azacitidine and decitabine. At low doses these drugs inhibit DNA methylation. The efficacy of these drugs was demonstrated in the treatment of patients with myelodysplastic syndrome. These drugs showed low toxicity and were relatively well-tolerated in elderly patients. The results with azacitidine and decitabine have demonstrated that manipulation of the epigenetic process offers new antineoplastic treatment options.

Eribulin mesylate is a non-taxane microtubule dynamics inhibitor that was recently approved for treatment of metastatic breast cancer. The aim of this study was to determine the effect of rifampicin, a CYP3A4 inducer, on the plasma pharmacokinetics of eribulin in patients with solid tumours.An open-label, non-randomized phase I study was carried out. Patients received intravenous 1.4 mg m(-2) eribulin mesylate on days 1 and 15 and oral rifampicin 600 mg on days 9 to 20 of a 28 day cycle. Pharmacokinetic sampling for determination of eribulin plasma concentrations was performed up to 144 h following administration. AUC(0,∞) and C(max) for eribulin exposure without or with co-administration of rifampicin were subjected to an analysis of variance (anova) and corresponding 90% confidence intervals (CI) were calculated. Subsequently, patients were allowed to continue eribulin mesylate treatment with 1.4 mg m(-2) eribulin mesylate on days 1 and 8 of a 21 day cycle. Also the adverse event profile and anti-tumour activity were assessed.Fourteen patients were included and 11 patients were evaluable for pharmacokinetic analysis. Co-administration of rifampicin had no effect on single dose exposure to eribulin (geometric least square means ratio: AUC(0,∞) = 1.10, 90% CI 0.91, 1.34 and C(max) = 0.97, 90% 0.81, 1.17). The most common treatment-related grade ≥3 adverse events were grade 3 neutropenia (4/14, 29%), leucopenia and fatigue (both 3/14, 21%).These results indicate that eribulin mesylate may be safely co-administered with compounds that are CYP3A4 inducers.

There is no consensus regarding optimal dosing of high dose methotrexate (HDMTX) in patients with primary CNS lymphoma. Our aim was to develop a convenient dosing algorithm to target AUC(MTX) in the range between 1000 and 1100 µmol l(-1) h.A population covariate model from a pooled dataset of 131 patients receiving HDMTX was used to simulate concentration-time curves of 10,000 patients and test the efficacy of a dosing algorithm based on 24 h MTX plasma concentrations to target the prespecified AUC(MTX) . These data simulations included interindividual, interoccasion and residual unidentified variability. Patients received a total of four simulated cycles of HDMTX and adjusted MTX dosages were given for cycles two to four.The dosing algorithm proposes MTX dose adaptations ranging from +75% in patients with MTX C(24)0.5 µmol l(-1) up to -35% in patients with MTX C(24)12 µmol l(-1). The proposed dosing algorithm resulted in a marked improvement of the proportion of patients within the AUC(MTX) target between 1000 and 1100 µmol l(-1) h (11% with standard MTX dose, 35% with the adjusted dose) and a marked reduction of the interindividual variability of MTX exposure.A simple and practical dosing algorithm for HDMTX has been developed based on MTX 24 h plasma concentrations, and its potential efficacy in improving the proportion of patients within a prespecified target AUC(MTX) and reducing the interindividual variability of MTX exposure has been shown by data simulations. The clinical benefit of this dosing algorithm should be assessed in patients with primary central nervous system lymphoma (PCNSL).

Cardiotoxicity and extravasation injuries are extremely serious complications of anthracycline use. Both complications are probably caused by oxidative stress. Dexrazoxane has been approved as a cardioprotective agent and as an antidote in extravasation of anthracyclines. Randomized clinical trials have shown that dexrazoxane is the only cardioprotective agent proven to be effective in the treatment of anthracycline-induced cardiotoxicity. In these clinical studies dexrazoxane decreased the incidence of cardiac events and heart failure. Possible adverse effects of dexrazoxane when administered as a cardioprotective agent are a decreased antitumor effect of anthracyclines and the onset of secondary malignancies in children. As an antidote in anthracycline extravasation, clinical studies showed dexrazoxane to be highly efficacious in preventing the need for surgical resection. Dexrazoxane can be considered as the treatment of first choice for this indication. Dexrazoxane is well tolerated in general. The most commonly reported side effects are leukopenia, thrombocytopenia and local reactions at the infusion site.

To explore the potential of peptide fragments derived from inter-alpha-trypsin inhibitor heavy chain-4 (ITIH(4)) as serum markers for different cancer types, sensitive and specific analytical assays are required. Liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS) would be suitable; however, a previously developed method for quantification of eight ITIH(4) fragments (ITIH(4)-21, -22, -25, -26, -27, -28, -29 and -30) was found to be insensitive for clinical use. A more sensitive LC/MS/MS assay has now been developed and validated, which was further optimized to facilitate analyses of large sets of clinical serum samples. Benefits compared to the previous method include reduction of sample volume (100 microL), omission of protein precipitation and evaporation and transferring solid-phase extraction (SPE) to a 96-well format. Chromatographic separation on an XBridge BEH300 C(18) column, using a water/methanol gradient containing acetic acid, was coupled to triple quadrupole mass spectrometric detection, applying heated electrospray ionization. Method validation revealed deviations from nominal concentrations below 10.1% and intra- and inter-assay precisions below 17.4 and 20.0%, respectively, at the lower limit of quantification (LLOQ) for all peptides. The reported changes resulted in more rapid and efficient analyses and reduced LLOQs for the six less abundant peptides (1.2; 1.0; 1.2; 2.0; 2.0 and 2.0 ng/mL vs. 2.1; 2.0; 2.5; 2.6; 2.2 and 2.4 ng/mL for ITIH(4)-21, -22, -25, -27, -28 and -29, respectively). The method has shown its applicability by quantifying all peptides in appropriate concentration ranges in serum from healthy volunteers and application to clinical samples from breast cancer patients.

Deoxycytidine analogs (dCa's) are nucleosides widely used in anticancer and anti (retro) viral therapies. Intracellularly phosphorylated dCa anabolites are considered to be their main active metabolites. This article reviews the literature on the formation and pharmacological activity of deaminated dCa nucleotides. Most dCa's are rapidly deaminated into deoxyuridine analogs (dUa's) which are only slowly phosphorylated and therefore relatively inactive. dUa nucleotides are, however, also formed via deamination of dCa monophosphates by deoxycytidine monophosphate deaminase (dCMPD). dUa-monophosphates can interact with thymidylate synthase (TS), whereas dUa-triphosphates are incorporated into nucleic acids and interfere with polymerases. Administration of dCa's as monophosphate prodrugs or co-administration of the cytidine deaminase inhibitor tetrahydrouridine (THU) does not prevent dUa nucleotide formation which is, on the other hand, influenced by the dose and dCMPD activity. Taken together, these observations show that the formation of dUa nucleotides is a common phenomenon in treatment with dCa's and these compounds may play a role in treatment outcome. We conclude that more attention should be given to these relatively unknown, but potentially important metabolites.

A novel assay for the simultaneous quantification of the widely used anticancer agent 2',2'-difluorodeoxycytidine (gemcitabine; dFdC), its deaminated metabolite 2',2'-difluorodeoxyuridine (dFdU) and their mono-, di- and triphosphates (dFdCMP, dFdCDP, dFdCTP, dFdUMP, dFdUDP and dFdUTP) in peripheral blood mononuclear cells (PBMCs) is described. Separation of all eight compounds was achieved within 15 min using a porous graphitic carbon column (Hypercarb) with a gradient from 0 to 25 mM ammonium bicarbonate in acetonitrile/water (15:85, v/v). Calibration ranges in PBMC lysate from 4.29 to 429, 29.0 to 2900, 31.4 to 3140 and 36.9 to 3690 nM for dFdC, dFdCMP, dFdCDP and dFdCTP and from 42.1 to 4210, 25.4 to 2540, 43.2 to 4320 and 52.7 to 5270 nM for dFdU, dFdUMP, dFdUDP and dFdUTP, respectively, were validated. Accuracies were within 82.3-119% at the lower limit of quantification (LLOQ) and the precisions were less than 20.0%. At the other tested levels accuracies were within 91.4-114% and precisions less than 14.9%. Mixtures of (13)C,(15)N(2)-labeled dFdC and dFdU nucleotides were synthesized and used as internal standards. Whole blood samples showed extensive ongoing dFdC metabolism when stored at room temperature, but not on ice-water, which made the addition of enzyme inhibitors unnecessary. Stock solutions and samples were stable under all analytically relevant conditions. The method was successfully applied to clinical samples.

Renal cell carcinoma (RCC) is the most lethal urological cancer, and survival greatly depends on early diagnosis. Therefore, reliable, new biomarkers for detection of RCC are required. We assessed serum protein profiles of samples from two institutes with SELDI-TOF MS in duplicate on CM10 chips at pH 6.0 (set 1: 37 RCC + 32 healthy controls (HC), set 2: 20 RCC + 25 HC). Mean peak intensities of detected proteins were compared between RCC and HC with non-parametric testing. Classification trees were built with discriminating peaks using one sample set as training set and the other as independent validation set. We found 15 peaks significantly different (p0.01) between RCC and HC. Two classification trees could be built with these peaks. Tree A achieved 75% sensitivity and 85% specificity for cross-validation and 76 and 65% for independent validation. Tree B had 71 and 62% sensitivity and specificity for cross-validation and 83 and 82% for independent validation. Although two serum protein profiles comprising 5 protein peaks were found that could separate RCC from HC, the sensitivity and specificity is not sufficient to recommend large scale use. Upon structural identification and quantitative validation, however, these proteins might prove suitable markers in the follow up of RCC patients.