Olivier Madar

18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) imaging in the staging and prognosis of inflammatory breast cancer

To prospectively assess fluorodeoxyglucose positron emission tomography/computed tomography (FDG‐PET/CT) staging and prognosis value in patients with suspected inflammatory breast cancer (IBC).

Breast cancer recurrence diagnosis suspected on tumor marker rising: value of whole-body 18FDG-PET/CT imaging and impact on patient management.

Breast cancer recurrence is often suspected on tumor marker rising in asymptomatic patients. The value of fluorine‐18 fluorodeoxyglucose (18FDG)–positron emission tomography/computed tomography (PET/CT) imaging to detect recurrence and its subsequent impact on patient management were retrospectively assessed.

Single photon emission tomography/computed tomography (SPET/CT) and positron emission tomography/computed tomography (PET/CT) to image cancer

Hybrid systems associating the sharpness of anatomic images coming from computed tomography (CT) and radionuclide functional imaging (SPET or PET) are opening a new era in oncology. This multimodal imaging method is now routinely used for the diagnosis, extent, follow up, treatment response and detection of occult disease in different types of malignancies with a significant impact on the treatment strategy leading for a change for more than 68% of all investigated patients. J. Surg. Oncol. 2011;103:602–606.

Molecular Imaging of Neuroendocrine Cancer by Fusion SPET/CT

Neuroendocrine (NE) cancers are usually suspected on clinical symptoms related to their metabolically active peptide secretion into the circulatory system. The most effective treatment is surgery and a preoperative accurate localization of these slow growing tumors is needed. Combined anatomical (CT) and molecular imaging modalities using single-photon emission computed tomography (SPET) with radiolabeled pentetreotide have been developed in routine, and we report here the potential of SPECT/CT image fusion for diagnosis, staging, and evaluation of treatment efficacy of NE cancers.

Permeability and Release of Decontaminating Agent Used in Cytotoxic Reconstitution Units: Diffusion of Hydrogen Peroxide in IV Bags

Abstract Introduction Oxidant agents used for top-decontamination in cytotoxic reconstitution units may spread into IV bags. The amount of hydrogen peroxide passing through the bags and its release have been evaluated using wrapped or unwrapped infusion bags made of three layers of polyolefin (Freeflex®, Fresenius). Methods 3 experiments were carried out using 2 packages of 30 bags of polyolefin with (package A) or without (package B) overwrapping. A 43 min decontamination cycle with H2O2 has been used for each series of the experiment. A quantitative analysis has been performed by spectrophotometry at 562 nm, measuring a colored adduct formed by ferric iron and xylenol orange. To evaluate the release of H2O2, a sampling was performed from each bag at t0, t1, t2, t7, t21 days. Results A linear calibration curve over the concentration range of 0.00–2.70 ppm was used prior to each analysis. The concentration of H2O2 in overwrapped bags (A) was non-significantly different to 0 (p>0.05 Wilcoxon test) until 21 days. At t0 there was no significant difference between package A and B, but from day 2 H2O2 was detected in non-overwrapped bags (B) (First series, at t2 p=6.18×10–10 Wilcoxon test). The higher concentration was reached after 21 days (0.17 ppm). Conclusion/Discussion These results allow removing overwrapping for a lean production system, with an extemporaneous use. However, the graduate release of H2O2 and the absence of any toxicity threshold make it impossible to remove the overwrapping for a pre-empted production.

Validation of an ergonomic method to withdraw [99mTc] radiopharmaceuticals

The main objective of the present work was to ensure the quality of radiopharmaceutical syringes withdrawn with a system consisting of a spinal needle and an obturator IN-Stopper. Methods: Visual examinations and physicochemical tests were performed at baseline and 4 h for 99mTc-albumin nanocolloid and at baseline and 7 h for 99mTc-eluate, 99mTc-hydroxymethylene diphosphonate, and 99mTc-human serum albumin. Microbiologic validation was performed according to the European pharmacopoeia. Fingertip radiation exposure was evaluated to confirm the safety of the system. Results: The results showed stable visual and physicochemical properties. The integrity of the connector was not affected after 30 punctures (no cores). No microbiologic contamination was found on tested syringes. Concerning radiation safety, no overexposure was reported with the system. Conclusion: The system could be used 30 times. The stability of syringes withdrawing radiopharmaceuticals with this method is guaranteed up to 4 h for 99mTc-albumin nanocolloid and 7 h for 99mTc-eluate, 99mTc-hydroxymethylene diphosphonate, and 99mTc-human serum albumin.

Abstract 2049: Pharmacokinetic drug-drug interaction: a phase Ib dose escalation study of LY2780301 in combination with weekly paclitaxel

Introduction: LY2780301 is an orally available small molecule dual inhibitor of p70 S6 kinase and AKT. LY2780301 is an inhibitor of CYP3A4. By the one hand, Paclitaxel (PXL) undergoes extensive metabolism via CYP450 2C8 and CYP450 3A4 pathways. By the other hand, PXL induces weakly CYP3A4 activity. In this study we investigated for the first time, the potential pharmacokinetic (PK) drug-drug interaction (DDI) related to the combination of both drugs LY2780301 and PXL. Methods: Women with HER2- locally advanced or metastatic breast cancer, with and without PI3/AKT pathway activation, were treated with weekly administration of PXL on day1 (D1), D8 and D15. LY2780301 was administered by a daily flat dosing regimen starting at D3. Dose levels [DL, LY2780301 (mg/day)/PXL (mg/m2/week)] ranged from 400/70 to 500/80. For PK analysis, 7 time point samples were collected on D1 and D3 of cycle 1 for PXL and LY2780301 respectively. 7 samples were collected on D8 for both drugs. LY2780301 plasma concentrations were measured using Ultra Performance Liquid Chromatography (UPLC) coupled with tandem mass spectrometry validated method. PXL plasma concentrations were measured using UPLC coupled with UV validated method. A joint population PK (PK-POP) model has been developed for LY2780301 and its main metabolite. PK-POP modelling has been performed with a non linear mixed effect model program (Monolix version 4.3.2). Results: 12 patients, 35 to 67 years old, were treated. A total of 160 and 157 concentrations for LY2780301 and its metabolite were used respectively for PK-POP modeling. A one compartment open model adequately described LY2780301 and its metabolite concentration versus time courses respectively with the estimation of the fraction of absorbed dose (fm) of LY2780301 metabolised in that metabolite. The interindividual variabilities (ISV) could be well estimated for all structural parameters (clearance: CL, volume of distribution: V, L and the absorption constant: Ka). The population PK parameters obtained for the structural model were: Ka = 0.536 h−1, CL/F = 3.57 L/h, V/F = 85.2 L, CL/(F*fm) = 13.2 L/h, V2/(F*fm) = 13.2 L, fm = 0.747 for LY2780301 and its metabolite respectively. PXL increases LY2780301 CL from 3.57 to 4.4 L/h (p = 0.016). Conclusions: We have demonstrated a PK DDI between LY2780301 and PXL. PXL increases LY2780301 CL and decreases LY2780301 AUC. PXL PK modeling is ongoing in order to verify the effect of LY2780301 on PXL PK. Citation Format: Keyvan Rezai, Samuel Huguet, Olivier Madar, Jean-Marc Extra, Magali Provansal, Carole Tarpin, Nicolas Isambert, Jihane Pakradouni, Anthony Goncalves, Francois Lokiec. Pharmacokinetic drug-drug interaction: a phase Ib dose escalation study of LY2780301 in combination with weekly paclitaxel. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2049.

Abstract 1646: Synthesis of [11C]onapristone for clinical investigation

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Onapristone is a type I anti-progestin, which prevents the progesterone receptor (PR) monomers from dimerizing, inhibits ligand-induced phosphorylation and prevents association of the PR with its co-activators, thus preventing PR-induced transcription. Onapristone has the potential to treat patients with endometrial cancer, breast cancer, uterine sarcomas, a potential subset of ovarian cancer, prostate cancer and other tumors in which the progesterone receptor plays a role in growth, proliferation and metastasis. [11C]-radiolabeled onapristone and its visualization via PET-scan, coupled with pharmacokinetic (PK) studies, has the potential to determine tissue-specific and blood PK parameters including tumor/tissue and plasma concentrations, whole body distribution and half-life of onapristone. The aim of this study is the development of a rapid Good Manufacturing Product (GMP) synthesis of parentally administered [11C]onapristone. Methods: The production of [11C]-labeled radiopharmaceuticals used a Tracerlab® FX c-Pro (GEMS) synthesis module. Carbon-11 was produced at Institut Curie-Hopital Rene Huguenin via the 14N(p,α)11C nuclear reaction using a PETTrace cyclotron (GEMS) equipped with a carbon-11 target. Carbon-11 is delivered from the cyclotron as [11C]CO2 in the synthesis module, and reduced to [11C]CH4. Methane is halogenated to [11C]CH3I and converted to [11C]methyl triflate (CH3OTf). To prepare [11C]onapristone, the module was loaded with 1mg of N-desmethyl-onapristone (Arno Therapeutics) and 500µL of DMSO in the reaction vessel (Sigma®). [11C]CH3OTf was bubbled into the reaction vessel and heated at +50°C for 10 minutes. The reaction mixture was then diluted with 1 ml of mobile phase and purified using a semi-preparative HPLC column: Sunfire C18 5µm 250X10mm (Waters®), mobile phase: acetonitrile (Sigma®)/water (Waters®) 50/50 v/v; flow rate 4 mL/min. The product fraction was collected in 40mL of sterile water and was passed through a C18 SEP PAK (Waters®). This fraction was eluted with isotonic saline (Braun®) and ethanol (Sigma®). The resulting formulation was passed through a 0.22µm sterilizing filter into a sterile dose vial. Results: 10 tests were performed. Time of synthesis was 50 minutes. The amount of carbon-11 delivered was 12-14GBq for the irradiation parameters as follows: 10 min; 10µA. The decay-corrected yield of reducing [11C]CO2 to [11C]CH4 was >99%. The yields of preparing [11C]CH3I were 27-29%. Time retention of [11C]onapristone was 8.5-9.5 minutes and the non-decay-corrected radiolabelling yields were 1-2%. Conclusions: We have successfully developed a fully-automated production of [11C]onapristone ready for use in clinical trials. Citation Format: Olivier Madar, Julien Fouque, Stefan Proniuk, Keyvan Rezai, Samuel Huguet, Alexander Zukiwski, Erard M. Gilles, Alice S. Bexon, Francois Lokiec. Synthesis of [11C]onapristone for clinical investigation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1646. doi:10.1158/1538-7445.AM2014-1646

Abstract 2677: Comparison of different methods for radiochemical purity (RCP) control of 99mTc-tetrofosminin oncology.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background : The 99mTc-tetrofosmin is a radiopharmaceutical used in oncology for scintigraphic quantification of the myocardial perfusion. The reference method for quality control is thin layer chromatography, using TLC SA bands. This method is simple but only separates two types of impurities: free technetium and hydrolyzed technetium combined to hydrophilic impurities such as gluconate-99mTc and takes from 30 to 35 minutes. Alternative methods by planar or liquid chromatography have been developed (Whatman® (W) plate, Sep-Pak® or HPLC). The aim of our study is to evaluate each method versus the reference one. Methods : The reference method is a method using planar chromatography TLC SA tape, size 1 cm x 20 cm. Two marks were scored: one at 3 cm from the bottom indicates the deposit (10 μL of the preparation) and the other at 15 cm from the bottom the end of migration. Mobile phase was acetone: dichloromethane (65:35, v/v). The band marks were quantified by radioactive counting using a miniGITA® radiochromatograph (Raytest) equipped with a scintillation probe. The other planar chromatographic methods are W 1 (0.18 mm) and W 3MM (0.34 mm), the principle and the quantifying method are similar to reference method. SEP-Pak®(Waters) method uses a C18 chromatography column with 2 mobile phases (NaCl 0.9% and ethanol) and a sample volume between 25 to 50 μL. Activity was quantify with a calibrator CRC 25® (Capintec) The chromatographic system consisted in a Symmetry Shield® column RP18 5μm 100A (Waters) with a gamma detector Gammaram® (Lablogic). Empower® software (Waters) is used for peak integration. The mobile phase flowing at a rate of 1.0 mL / min consisted in a mixture of acetonitrile and Titrisol® buffer (Waters) (40:60, v/v), the sample volumes were no more than 10 to 30 μL. Results : The RCP was measured simultaneously by the different methods with 30 preparations. For HPLC, mean RCP = 97.21%, σ= 2.178% [91.6%-99.63%]. For TLC SA, mean RCP = 97.99%, σ= 1.135% [94.31%-99.86%]. For Sep-Pak® mean RCP = 97.15, σ= 1.133 [94.96%-99.55%], For W 3 MM mean RCP = 99.11 σ= 0.3252 [98.28%- 99.81%], For W 1 mean RCP = 98.32 σ= 0.5677 [97.01%-99.23%]. The results obtained by these methods were compared using the Wilcoxon t test.α = 0.05. The RCP obtained by TLC SA and SEP-Pak® method are significantly different (p = 0.026). The RCP obtained by TLC SA and W 1 and 3 MM methods are also significantly different (p w1 = 0.041, p w3 < 0.0001). The RCP obtained by either TLC SA or HPLC method are not significantly different (p = 0.497) Conclusions : A new HPLC method was developed for the control of the RCP 99mTc-tetrofosmin. The other methods differ from RCP (reference method). Whatman methods overestimate RCP values versus TLC SA or HPLC method. This study allows us to improve the detection of the cardiotoxic side effects due to chemotherapy more quickly than TLC SA method and permits early prevention of toxicity by dose adjustment of anticancer drugs. Citation Format: Olivier Madar, Keyvan Rezai, Emmanuelle Ledauphin, Eve Camps, Catherine Tainturier, Francois Lokiec. Comparison of different methods for radiochemical purity (RCP) control of 99mTc-tetrofosminin oncology. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2677. doi:10.1158/1538-7445.AM2013-2677

Abstract 3367: Massbalance, excretion and metabolism of [14C]-Pralatrexate (PDX) incancer patients in a phase I trial.

Background: PDX is a novel 10-deaza-aminopterin analogue of methotrex[[Unsupported Character - Codename s]]ate consisting of a mixture of R- and S-diastereomeric folate derivatives. PDX inhibits folate metabolism by binding to and inhibiting the enzyme dihydrofolate reductase (DHFR). PDX is the first drug approved by the US Food and Drug Admin[[Unsupported Character - Codename s]]istration (FDA) specifically for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma. Mass balance studies in animals and humans with radiolabeled compounds represent a standard part of the development process for new drugs. Isotopically labeled analogs of a drug or its metabolites play an important role in understanding the absorption, distribution, metabolism and excretion profiles of a compound. The objectives of this study were to determine the pharmacokinetics (PK), metabolism and routes of excretion of [ 14 C]-PDX and to characterize its metabolites in human plasma and urine. Methods: Four patients were administered intravenously with a mixture of 50 μCi of [ 14 C]-PDX (0.5 mg) and 224.5 mg of non radioactive PDX over a 3-5 minute infusion. Serial blood and plasma samples were drawn at: 0 (before PDX infusion), and up to 144 h after the start of infusion. Urine and fecal samples were collected for up to 168 h after the start of infusion. Expired air samples were collected up to 24 hours after administration. The radioactivity measurement in biological fluids was performed using liquid scintillation counting. Results: Mass balance was achieved with a mean recovery radioactivity in excreta= 82.9 % ± 20.0 % for the four patients. The mean recovery of radioactivity in urine, feces, and expired air were 34.1%, 38.7% and 10.1%, respectively, indicating renal and fecal excretions were the major route of elimination of [ 14 C]-PDX. A three-compartment open model adequately described [ 14 C]-PDX time radioactivity-concentration courses. The AUC 0-∞ , and clearance values for total radioactivity in plasma were 18.1 nCi.h/mL, and 3.95 L/h, respectively. Metabolite profiling will be performed using HPLC with beta radiation detector. Conclusions: This study quantified the mass balance of PDX and defined its substantial excretion in both urine and feces after IV administration. The PK of [ 14 C]-PDX was best described by a three compartment open model. The metabolite profiling of PDX is ongoing. Citation Format: Elodie Odore, Keyvan Rezai, Olivier Madar, Sophie Weill, Ahmad Awada, Bert Pronk, Esteban Cvitkovic, Francois Lokiec. Massbalance, excretion and metabolism of [ 14 C]-Pralatrexate (PDX) incancer patients in a phase I trial. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3367. doi:10.1158/1538-7445.AM2013-3367