Fabienne Thomas

Innovative Therapies for Children with Cancer pediatric phase I study of erlotinib in brainstem glioma and relapsing/refractory brain tumors

This multicenter phase I study aimed to establish the recommended dose (RD) of the epidermal growth factor receptor (EGFR) inhibitor erlotinib, given as monotherapy or with radiotherapy to children with malignant brain tumors. Group 1 included patients with refractory or relapsing brain tumors receiving erlotinib alone, and group 2 included newly diagnosed patients with brainstem gliomas receiving radiotherapy and erlotinib. A conventional 3 + 3 dose escalation and a continual reassessment method, respectively, were utilized in 4 dose levels: 75, 100, 125, and 150 mg/m² per day. Fifty-one children were enrolled (30 and 21, respectively); 50 received treatment. The RD of erlotinib was 125 mg/m² per day as monotherapy or in combination with radiotherapy. Overall, 230 adverse events in 44 patients were possibly treatment related (216, grades 1 and 2; 9, grade 3; 1, grade 4; 4, grade 5). Dermatologic and neurologic symptoms were common; intratumoral hemorrhage was confirmed in 3 patients. In group 1, 8 of 29 patients (28%) had stable disease with tumor regression approaching 50% in a malignant glioma and an anaplastic oligoastrocytoma. In group 2, overall survival was 12.0 months. EGFR overexpression by immunohistochemistry was found in 17 of 38 (45%) tumor samples analyzed, with a partial gain of 7p11.2 in 1 glioblastoma; phosphate and tensin homolog loss was frequent in brainstem glioma (15 of 19). Mean (95% CI) apparent clearance and volume of distribution for erlotinib were 4.0 L/h (3.4-4.5 L/h) and 98.6 L (69.8-127.0 L), respectively, and were independent of the dose level; mean half-life was 16.6 hours. Thus, erlotinib 125 mg/m² per day has an acceptable tolerability profile in pediatric patients with brain tumors and can be combined with radiotherapy.

Pilot Study of Neoadjuvant Treatment with Erlotinib in Nonmetastatic Head and Neck Squamous Cell Carcinoma

Purpose: To determine the safety and efficacy of erlotinib given as neoadjuvant treatment in patients with head and neck squamous cell carcinoma (HNSCC). Further objectives were to identify markers of response to erlotinib and to assess the pharmacodynamic effects of erlotinib in tumor cells. Experimental Design: Patients with locally advanced nonmetastatic HNSCC were treated with erlotinib 150 mg daily pending surgical management. Tumor samples were collected before and after erlotinib treatment and were analyzed using immunohistochemistry. Epidermal growth factor receptor copy number was determined in tumors using CISH analysis. Results: Between November 2003 and December 2005, 35 patients were included in the study. Neoadjuvant treatment with erlotinib in HNSCC patients was well tolerated and did not necessitate modification to routine surgical procedures. Among 31 evaluable patients, erlotinib was given for a median of 20 days. At the time of surgery, tumor shrinkage was observed in nine patients (29%). Immunohistochemistry analyses were done for 31 patients and showed a decrease in phosphorylated tyrosine residues and phosphorylated erk immunostaining after erlotinib treatment. In a retrospective analysis, baseline p21waf expression in the basal-like cell layer was statistically positively correlated with clinical response to treatment. Epidermal growth factor receptor copy number did not correlate with response to erlotinib. Conclusion: Neoadjuvant treatment of HNSCC with erlotinib was well tolerated. Baseline p21waf expression was associated with response to erlotinib and so might be useful as a tool to select patients for erlotinib therapy in this setting.

UGT1A1 genotype and irinotecan therapy: general review and implementation in routine practice

Irinotecan is a major drug in the treatment of advanced colorectal cancer. Its active form is the SN38 metabolite, which is cleared by the biliary route after glucuronidation by uridine diphosphate–glucuronosyltransferase 1A1 (UGT1A1). UGT1A1 activity exhibits a wide intersubject variability, in part related to UGT1A1 gene polymorphisms. The present review on the impact of the deficient UGT1A1*28 variant on irinotecan efficacy and toxicity was produced by a French joint workgroup comprising the Group of Clinical Onco‐pharmacology (GPCO‐Unicancer) and the National Pharmacogenetics Network (RNPGx). It clearly emerges that for irinotecan doses at least equal to 180 mg/m2, patients homozygous for the UGT1A1*28 allele are at increased risk of developing hematological and/or digestive toxicities. Irinotecan dose reduction is thus recommended in homozygous *28/*28 patients. In addition, this personalized medicine strategy aims to secure high‐dose irinotecan administration (≥240 mg/m2) that have proven to be safe in homozygous *1/*1 patients only. The clinical relevance of this test is discussed in terms of treatment efficacy improvement, as increasing the irinotecan dose appears to be safe in patients not bearing a deficient allele. Best execution practices, cost‐effectiveness, and result interpretation are discussed with the aim of facilitating the implementation of this analysis in clinical practice. The existence of networks of laboratories performing this test in routine hospital treatment, as in France, offers the prospect of widespread screening, thus guaranteeing equal access to safe treatment and optimized therapy for patients receiving irinotecan‐based therapy in advanced colorectal cancer.

Cystatin C as a New Covariate to Predict Renal Elimination of Drugs Application to Carboplatin

Background and objectiveThe individual dosing of drugs that are mainly eliminated unchanged in the urine is made possible by assessing renal function. Most of the methods used are based on serum creatinine (SCr) levels. Cystatin C(CysC) has been proposed as an alternative endogenous marker of the glomerular filtration rate (GFR). Carboplatin is one of the drugs for which elimination is most dependent on the GFR. A prospective clinical trial including 45 patients was conducted to assess the value of serum CysC as a predictor of carboplatin clearance (CL).MethodsThe patients were receiving carboplatin as part of established protocols. Carboplatin was administered as a daily 60-minute infusion at doses ranging from 290 to 1700mg. A population pharmacokinetic analysis was performed using the nonlinear mixed effect modelling NONMEM program according to a two-compartment pharmacokinetic model.ResultsData from 30 patients were used to test the relationships between carboplatin CL and morphological, biological and demographic covariates previously proposed for prediction of the GFR. The interindividual variability of carboplatin CL decreased from 31% (no covariate) to 14% by taking into account five covariates (SCr, CysC, bodyweight [BW], age and sex). Prospective evaluation of these relationships using the data from the other 15 patients confirmed that the best equation to predict carboplatin CL was based on these five covariates, with a mean absolute percentage error of 13% as an assessment of precision. NONMEM analysis of the whole dataset (n = 45 patients) was performed. The best covariate equation corresponding to the overall analysis was: CL (mL/min) = 110 · (SCr/75)−0.512 · (CysC/1.0)−0.327 · (BW/65)0.474 · (age/ 56)−0.387 · 0.854sex, with SCr in μmol/L, CysC in mg/L, BW in kilograms, age in years and sex = 0 if male and 1 if female. To put the value of CysC as an endogenous marker of the GFR into perspective, covariate equations without SCr were also evaluated; a better prediction was obtained by considering CysC together with age and BW (interindividual variability of 16.6% vs 23.3% for CysC alone).ConclusionCysC is a marker of drug elimination that is at least as good as SCr for predicting carboplatin CL. The model based on five covariates was superior to those based on only four covariates (with BW, age and sex combined with either SCr or CysC), indicating that CysC and SCr are not completely redundant to each other. Further pharmacokinetic evaluation is needed to determine whether SCr or CysC is the better marker of renal elimination of other drugs.

Serum Cystatin C is a Better Marker of Topotecan Clearance than Serum Creatinine

Purpose: To evaluate plasma cystatin level as a covariate to predict topotecan pharmacokinetics. Cystatin C, a member of the cystatin superfamily of cysteine proteinase inhibitors, has been recently proposed as an alternative endogenous marker of glomerular filtration. Renal function is known as a key factor of topotecan clearance. Experimental Design: Data were obtained from 59 patients who underwent drug monitoring for individual dosing of topotecan. Topotecan plasma concentrations versus time were analyzed using a nonlinear mixed effect model according to a two-compartment pharmacokinetic model and a first-order conditional estimation method. A proportional error model was used for residual and interpatient variabilities. Data-splitting was done randomly to create a model-building data set (44 patients) and a model validation data set (15 patients). Results: Using the building data set, four covariates significantly decreased the objective function value and interindividual variability on topotecan clearance (CL) when tested individually: ideal body weight (IBW), serum creatinine, age, and cystatin C level. The best model was: CL (L/hour) = 20.2 [cystatin C (mg/L) / 1.06]−0.60 [IBW (kg) / 57]0.95. Prospective evaluation using the validation data set confirmed that the model based on cystatin C had a better predictive value than the models based on serum creatinine or body surface area. Conclusion: Cystatin C is a marker of drug elimination which is superior to serum creatinine for topotecan. It deserves to be further explored as a promising covariate for drug dosing as well as selection criteria for clinical studies of drugs eliminated mainly or partially by the kidney.

Population Analysis of Erlotinib in Adults and Children Reveals Pharmacokinetic Characteristics as the Main Factor Explaining Tolerance Particularities in Children

Purpose: The aim of this pharmacokinetic–pharmacodynamic (PK–PD) analysis was to evaluate the pharmacologic characteristics of erlotinib and its main metabolite (OSI-420) in pediatric patients compared with those in adult patients. Experimental Design: Plasma concentrations of erlotinib and OSI-420 of 46 children with malignant brain tumors included in a phase I study and 42 adults with head and neck carcinoma were analyzed by a population-pharmacokinetic method (NONMEM). The effect of several covariates and single nucleotide polymorphisms (SNP) in ABCB1, ABCG2, and CYP3A5 on pharmacokinetic parameters was evaluated. PK/PD relationships between plasma drug exposure Area Under the Curve (AUC) at day 1 and skin toxicity were studied in children and compared with the relationship observed in adults. Results: A significant difference in erlotinib clearance (P = 0.0001), when expressed in L·h−1·kg−1, was observed between children and adults with mean values of 0.146 and 0.095, respectively (mean difference = 0.051 L·h−1·kg−1, SD = 0.0594). However, a common covariate model was obtained describing erlotinib clearance according to body weight, alanine aminotransferase, ABCB1, and CYP3A5 polymorphisms (2677G > T/A and 6986G > A) for both children and adult patients. The PK–PD relationship was very consistent between the children and adult groups with risk of skin toxicity rising with increasing erlotinib AUC. Conclusions: The nonlinear population approach applied to pharmacokinetic data combined with a pharmacokinetic–pharmacodynamic analysis revealed that the higher recommended dose in children (125 mg/m2/day) compared with adults (90 mg/m2/day) is mainly due to pharmacokinetic rather than pharmacodynamic particularities. Clin Cancer Res; 17(14); 4862–71. ©2011 AACR.

Contribution of the MDRD equation and of cystatin C for renal function estimates in cancer patients.

BackgroundSerum creatinine (SCr) and Cockcroft-Gault creatinine clearance (CG CrCL) are used to estimate glomerular filtration rate (GFR). Other markers have been proposed including serum cystatin C (cysC) and the Modification of Diet in Renal Disease (MDRD) study equation.Patients and MethodsWe have compared the diagnostic performances of SCr, cysC, CG CrCL, and the MDRD equation in 144 cancer patients. For reference we used either the measured or the predicted carboplatin clearance, which is around the GFR+25 mL/min.ResultsCysC was more sensitive than SCr (70.1% vs 13.4%) but was not very specific (61% for a cut-off =0.95 mL). CysC values were higher in 40 cancer patients vs 40 healthy controls with a similar and normal mean CG CrCL (1.08 vs 0.71 mg/L; p<0.001). CG and the MDRD equations gave similar values for Pearsons coefficient, ROC-plot AUC, and precision, except for patients with poor general status, where the MDRD equation was better (MAPE: 12.4% vs 19.6%, p<0.001; R.: 0.908 vs 0.813).ConclusionsIn cancer patients, cysC is a more sensitive indicator of the glomerular filtration rate than SCr, but its diagnostic performance is lower than for CG CrCL. There may be no advantage in replacing the CG equation by the MDRD equation except for patients with severe malnutrition and/or inflammation.

Prévalence de l’hypertonie oculaire et du glaucome dans une population française non sélectionnée

But Determiner la pression intra-oculaire sur un vaste echantillon d’hommes et de femmes, et apprecier la prevalence du glaucome a pression elevee et de l’hypertonie oculaire (HTIO) dans cette population. Methodes La mesure de la PIO a ete effectuee dans un centre de sante parisien sur 2 074 sujets (hommes/femmes : 1 384/690). Si la PIO etait superieure a 20 mmHg, une photographie du fond d’œil et un champ visuel etaient realises. Le champ visuel et le fond d’œil ont ete juges par quatre investigateurs chez 395 sujets. Resultats Chez les hommes âges de 18-39 ans, la PIO moyenne etait de 15,5 ± 3,1 mmHg et de 16,4 ± 3,5 mmHg chez les plus de 60 ans. Chez les femmes, elle atteignait respectivement 14,5 ± 3,3 mmHg et 15,9 ± 3,1 mmHg pour les memes tranches d’âge. Une PIO superieure a 21 mmHg etait observee chez 10,1 % des hommes et 6,4 % des femmes. Cette prevalence augmentait avec l’âge : de 5,3 % pour les hommes âges de 18-39 ans, a 15,5 % pour les hommes âges de 60 ans et plus. Chez les femmes, la prevalence passait de 3 % a 7,5 % pour les memes classes d’âge. Le diagnostic de glaucome etait etabli chez 2,2 % des hommes et 3,0 % des femmes. La prevalence du glaucome etait de 0,8 % chez les hommes les plus jeunes et 5,7 % chez les plus de 60 ans, et chez les femmes, respectivement de 0,6 % et 4,7 %. Discussion Cette etude confirme l’augmentation de la PIO avec l’âge, et la nature liee a l’âge des deux affections que constituent l’hypertonie oculaire et les glaucomes a pression elevee. Conclusion Cette etude transversale montre la faisabilite de la mesure de prevalence d’une hypertonie oculaire et du glaucome dans une population francaise non selectionnee.

Preclinical and Clinical Evidence that Deoxy-2-[18F]fluoro-D-glucose Positron Emission Tomography with Computed Tomography Is a Reliable Tool for the Detection of Early Molecular Responses to Erlotinib in Head and Neck Cancer

Purpose: There is a clinical need to identify predictive markers of the responses to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). Deoxy-2-[18F]fluoro-d-glucose positron emission tomography with computed tomography (18FDG-PET/CT) could be a tool of choice for monitoring the early effects of this class of agent on tumor activity. Experimental Design: Using models of human head and neck carcinoma (CAL33 and CAL166 cell lines), we first tested in vitro and in vivo whether the in vivo changes in 18FDG-PET/CT uptake were associated with the molecular and cellular effects of the EGFR-TKI erlotinib. Then, the pathologic and morphologic changes and the 18FDG-PET/CT uptake before and after erlotinib exposure in patients were analyzed. Results: Erlotinib strongly inhibited extracellular signal-regulated kinase-1/2 (ERK-1/2) phosphorylation both in the preclinical models and in patients. Western blotting, immunofluorescence, and immunohistochemistry showed that erlotinib did not modify Glut-1 expression at the protein level either in cell line models or in tumor tissue from mouse xenografts or in patients. Phospho-ERK-1/2 inhibition was associated with a reduction in 18FDG uptake in animal and human tumors. The biological volume was more accurate than the standardized uptake value for the evaluation of the molecular responses. Conclusion: These results show that the 18FDG-PET/CT response is a reliable surrogate marker of the effects of erlotinib in head and neck carcinoma. Clin Cancer Res; 16(17); 4434–45. ©2010 AACR.

Dendrogenin A drives LXR to trigger lethal autophagy in cancers

Dendrogenin A (DDA) is a newly discovered cholesterol metabolite with tumor suppressor properties. Here, we explored its efficacy and mechanism of cell death in melanoma and acute myeloid leukemia (AML). We found that DDA induced lethal autophagy in vitro and in vivo, including primary AML patient samples, independently of melanoma Braf status or AML molecular and cytogenetic classifications. DDA is a partial agonist on liver-X-receptor (LXR) increasing Nur77, Nor1, and LC3 expression leading to autolysosome formation. Moreover, DDA inhibited the cholesterol biosynthesizing enzyme 3β-hydroxysterol-Δ8,7-isomerase (D8D7I) leading to sterol accumulation and cooperating in autophagy induction. This mechanism of death was not observed with other LXR ligands or D8D7I inhibitors establishing DDA selectivity. The potent anti-tumor activity of DDA, its original mechanism of action and its low toxicity support its clinical evaluation. More generally, this study reveals that DDA can direct control a nuclear receptor to trigger lethal autophagy in cancers.Dendrogenin A, cholesterol metabolite, has tumor suppressive properties but the mechanisms are unknown. Here the authors show that Dendrogenin A can induce autophagy-mediated cell death in both melanoma and acute myeloid leukaemia.