Jean Pierre Delord

Population pharmacokinetics of erlotinib and its pharmacokinetic/pharmacodynamic relationships in head and neck squamous cell carcinoma.

UNLABELLEDnA clinical study was conducted to determine the safety and efficacy of neoadjuvant erlotinib treatment in patients with head and neck squamous cell carcinoma [Thomas F, Rochaix P, Benlyazid A, et al. Pilot study of neoadjuvant treatment with erlotinib in non-metastatic head and neck squamous cell carcinoma. Clin Cancer Res 2007;13:7086-92]. The aim of the present analysis was to explore the impact of several covariates on the pharmacokinetics of erlotinib and its main metabolite (OSI-420) and to determine PK/PD relationships.nnnPATIENTS AND METHODSnPlasma concentrations of erlotinib and OSI-420 of 42 patients were analysed using the NONMEM program to evaluate the impact of patients covariates on erlotinib pharmacokinetics. The presence of single nucleotide polymorphisms (SNP) in ABCB1 (2677G>T/A and 3435C>T), ABCG2 (421C>A) and CYP3A5 (6986G>A) was investigated. Pharmacokinetic/pharmacodynamic relationships between plasma drug exposure (AUC) and early drug response or toxicity were also studied.nnnRESULTSnThe covariates retained to predict erlotinib clearance were ALAT (alanine amino transferase), age and ABCG2 polymorphism. A significant link between drug exposure and the grade of skin rash was observed but early response to treatment was not correlated to the erlotinib AUC.nnnCONCLUSIONSnErlotinib treatment may present criteria justifying dose individualisation but further studies, including more patients, are necessary to define the modalities of this adaptation.

Formation of the eIF4F Translation–Initiation Complex Determines Sensitivity to Anticancer Drugs Targeting the EGFR and HER2 Receptors

Elucidating how cancer cells respond to antagonists of HER receptor family members is critical to understanding mechanisms of therapeutic resistance that arise in patients. In large part, resistance to such agents appears to arise from deregulation of the phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR pathway. mTOR-dependent phosphorylation of the translation repressor 4E-BP1 leads to its dissociation from eIF4E, thereby causing an increase in the formation of the eIF4F complex, which also comprises eIF4G and eIF4A. In this study, we show that trastuzumab, cetuximab, and erlotinib all decrease the formation of the eIF4F complex in breast, colon, and head and neck cancer cells, respectively. Ectopic expression of eIF4E restores the trastuzumab-dependent defect in eIF4F formation, renders cells resistant to the trastuzumab-mediated decrease in cell proliferation, and rescues breast cancer xenografts from inhibition by trastuzumab. In breast tumor specimens, the level of eIF4E expression is associated with the therapeutic response to a trastuzumab-based regimen. Together, our findings suggest that formation of the eIF4F complex may be a critical determinant of the response to anticancer drugs that target HER2 and epidermal growth factor receptor.

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.

Abstract LB-122: A phase I dose escalation study of NVP-BGJ398, a selective pan FGFR inhibitor in genetically preselected advanced solid tumors

The family of fibroblast growth factors (FGFs) and FGF receptors (FGFRs) plays a critical role in cell proliferation and survival. A variety of genetic alterations (e.g. amplifications, mutations, and translocations) of these receptors and ligands have been found in diverse types of tumors. NVP-BGJ398 is a potent, selective, and orally bioavailable inhibitor of the FGFR tyrosine kinases. It inhibits the proliferation of various FGFR-dependent cell lines at nano-molar concentrations including breast and lung cancers harboring FGFR1 amplification, FGFR2-amplified gastric cancer cell lines and FGFR3-mutated bladder cancers. Objectives of the study: The purpose of this phase I-First In Human dose-escalation study is to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RPTD) of NVP-BGJ398 when administered orally to adult patients with advanced solid tumors. Secondary objectives include safety, tolerability, pharmacokinetics and preliminary anti-tumor activity in FGFR-dependent cancer. Methods: Patients received BGJ398 daily in a 28-day cycle in escalating dose cohorts starting from 5mg once daily. After cohort 3, patients had to have FGFR1 or FGFR2 amplification or FGFR3 mutation. Dose limiting toxicities (DLTs) were pre-defined and included both severe events and those resulting in significant dosing delays. Preliminary data: 26 patients have been treated, including 10 patients with FGFR1-amplified breast and 3 patients with FGFR1-amplified squamous cell lung cancer. The dose was escalated from 5 mg to 150 mg over 7 dose cohorts. One DLT of delayed dose occurred following a grade 3 AST/ALT event at 100 mg. Adverse events (AE) were generally grade 1-2. The most frequently observed AEs were diarrhea (37%) fatigue (37%) and nausea (32%) Hyperphosphatemia was observed, with increasing frequency at higher doses of NVP-BGJ398, and could be managed with phosphate binders and diuretics. One lung cancer patient with an FGFR1/CEP8 ratio of 2.6 by FISH analysis responded to 100 mg of NVP-BGJ398 with a 33% reduction in target lesions by CT scan at 8 weeks, confirmed at 12 weeks, and a substantial SUV decrease on PET. These observations provide early evidence that inhibition of the FGFR pathway is effective in patients with FGFR dependent cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-122. doi:1538-7445.AM2012-LB-122

Preclinical Toxicity, Toxicokinetics, and Antitumoral Efficacy Studies of DTS-201, a Tumor-Selective Peptidic Prodrug of Doxorubicin

Purpose: There is a clear clinical need for cytotoxic drugs with a lower systemic toxicity. DTS-201 (CPI-0004Na) is a peptidic prodrug of doxorubicin that shows an improved therapeutic index in experimental models. The purpose of the current study was to complete its preclinical characterization before initiation of phase I clinical trials. Experimental Design: The preclinical development program consisted of a detailed assessment of the general and cardiac toxicity profiles of DTS-201 in mice, rats, and dogs, together with mass balance and antitumoral efficacy studies in rodents. Neprilysin and thimet oligopeptidase expression, two enzymatic activators of DTS-201, was also characterized in human breast and prostate tumor biopsies. Results: The target organs of DTS-201 toxicity in rodents and dogs are typically those of doxorubicin, albeit at much higher doses. Importantly, chronic treatment with DTS-201 proved to be significantly less cardiotoxic than with doxorubicin at doses up to 8-fold higher in rats. The mass balance study showed that [14C] DTS-201 does not accumulate in the body after intravenous administration. The improved therapeutic index of DTS-201 compared with free doxorubicin was confirmed in three tumor xenograft models of prostate, breast, and lung cancer. Neprilysin and/or thimet oligopeptidase are expressed in all experimental human tumor types thus far tested as well as in a large majority of human breast and prostate tumor biopsies. Conclusion: DTS-201 gave promising results in terms of general toxicity, cardiovascular tolerance, and in vivo efficacy in xenograft mouse models compared with free doxorubicin. Taken together, these results and the confirmation of the presence of activating enzymes in human tumor biopsies provide a strong rationale for a phase I clinical study in cancer patients.

Ovarian ascites-derived Hospicells promote angiogenesis via activation of macrophages

Within the microenvironment, Carcinoma-associated mesenchymal stem cells (Hospicells) are able to influence ovarian tumor development via, among others, the facilitation of angiogenesis in the tumor site allowing an accelerated tumor growth. We demonstrate the presence of a chemotactism between endothelial cells and Hospicells, and a cell line specific increased secretion of pro-angiogenic cytokines such as IL-6, IL-8 and VEGF from ovarian adenocarcinoma cells. Hospicells are also able to attract and activate macrophages to a M2 phenotype and allow them to secrete a huge quantity of pro-angiogenic cytokines, favorable to tumor progression of all the associated ovarian adenocarcinoma cells tested.

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.

Ado-trastuzumab emtansine-associated telangiectasias in metastatic breast cancer: a case series

Treatment of HER2-positive metastatic breast cancer with ado-trastuzumab emtansine (T-DM1), a novel antibody–drug conjugate, has resulted in both improved progression-free and overall survival. Recognition and treatment of diverse adverse events related to T-DM1 is critical for safety and tolerability. The most frequent adverse events with T-DM1 include fatigue, diarrhea, anemia, elevated transaminases, and mild-to-moderate hemorrhagic events, which are thought to be related to induced thrombocytopenia. Here, we present five case series of cutaneous and mucosal telangiectasias, definitely related to T-DM1. The development of telangiectasias represents a newly recognized adverse effect of T-DM1. We provide description and timing of the telangiectasias and review the mechanisms that may explain the formation of these vascular lesions in association with T-DM1.xa0Further, we describe associated bleeding events andxa0propose thatxa0induced telangiectasias could represent an additional cause of T-DM1-associated hemorrhage.

Intraoperative fluorescence imaging of peritoneal dissemination of ovarian carcinomas. A preclinical study

OBJECTIVEnImprovement of the management and outcome of ovarian cancers may require intraoperative detection and therapeutic intervention to treat minimal residual disease after complete surgery. The aim of this study was to validate the importance of fluorescence in the peroperative detection of human ovarian adenocarcinoma cells and to determine its efficiency in detecting infra millimetric tumor metastases.nnnMETHODSnA fluorescent RAFT-(cRGD)₄ tracer molecule (AngioStamp®) was used. The tracer is based on a biomarker, which has a very high affinity for the α(v)β₃ integrin, which is overexpressed in a large ratio of cancer cells and neovessel endothelial cells during angiogenesis. Infrared fluorescence was visualized with Fluobeam®, an open fluorescent imaging system that could potentially be used in peroperative conditions in the future.nnnRESULTSnThis novel technique allowed the specific detection of residual tumor deposits and inframillimetric metastases, smaller than 500μm, which were resected under fluorescent guidance. AngioStamp® was able to detect all types of cell lines, derived from human ovarian adenocarcinomas, before or after chemotherapy treatment in animals. The effectiveness of AngioStamp® for the detection of various human ovarian adenocarcinomas was assessed on 10 different fragments of tumor, implanted subcutaneously in nude mice. All implanted tumor fragments were visualized by AngioStamp®.nnnCONCLUSIONSnThe high rate of recurrence after apparently complete surgery and/or complete clinical response to chemotherapy implies that most patients have undetected minimal residual disease. Novel techniques such as laparoscopic or laparotomic fluorescence may prove to be crucial in reassessing the definition of primary outcome in ovarian cancer management.

Peritoneal pseudomyxoma arising from the urachus

Pseudomyxoma peritonei (PMP) arising from urachal tumors is extremely rare. To our knowledge, natural history, tumor biological behaviour, morbidity, treatment, and prognosis of PMP arising from the urachus are determined by the associated PMP. Management of urachal tumors with associated PMP should be based on aggressive locorregional therapy with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, similar to PMP arising from other origins.