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Objectives: To systematically assess the kind of placebos used in investigator-initiated randomized controlled trials (RCTs), from where they are obtained, and the hurdles that exist in obtaining them. Study Design and Setting: PubMed was searched for recently published noncommercial, placebo-controlled randomized drug trials. Corresponding authors were invited to participate in an online survey. Results: From 423 eligible articles, 109 (26%) corresponding authors (partially) participated. Twenty-one of 102 (21%) authors reported that the placebos used were not matching (correctly labeled in only one publication). The main sources in obtaining placebos were hospital pharmacies (32 of 107; 30%) and the manufacturer of the study drug (28 of 107; 26%). RCTs with a hypothesis in the interest of the manufacturer of the study drug were more likely to have obtained placebos from the drug manufacturer (18 of 49; 37% vs. 5 of 29; 17%). Median costs for placebos and packaging were US$ 58,286 (IQR US$ 2,428– US$ 160,770; n = 24), accounting for a median of 10.3% of the overall trial budget. Conclusion: Although using matching placebos is widely accepted as a basic practice in RCTs, there seems to be no standard source to acquire them. Obtaining placebos requires substantial resources, and using nonmatching placebos is common.

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We describe the large-scale, GMP-compliant production process of doxorubicin-loaded and anti-EGFR-coated immunoliposomes (anti-EGFR-ILs-dox) used in a first-in-man, dose escalation clinical trial. 10 batches of this nanoparticle have been produced in clean room facilities. Stability data from the pre-GMP and the GMP batch indicate that the anti-EGFR-ILs-dox nanoparticle was stable for at least 18 months after release. Release criteria included visual inspection, sterility testing, as well as measurements of pH (pH 5.0-7.0), doxorubicin HCl concentration (0.45-0.55 mg/ml), endotoxin concentration (1.21 IU/ml), leakage (10%), particle size (Z-average of Caelyx ± 20 nm), and particle uptake (uptake absolute:0.50 ng doxorubicin/μg protein; uptake relatively to PLD:5 fold). All batches fulfilled the defined release criteria, indicating a high reproducibility as well as batch-to-batch uniformity of the main physico-chemical features of the nanoparticles in the setting of the large-scale GMP process. In the clinical trial, 29 patients were treated with this nanoparticle between 2007 and 2010. Pharmacokinetic data of anti-EGFR-ILs-dox collected during the clinical study revealed stability of the nanocarrier in vivo. Thus, reliable and GMP-compliant production of anti-EGFR-targeted nanoparticles for clinical application is feasible.

Summary Background Results of preclinical studies have shown that EGFR immunoliposomes have substantial antitumour effects. We aimed to assess the tolerability, safety, pharmokinetics, and efficacy of anti-EGFR immunoliposomes loaded with doxorubicin (anti-EGFR ILs-dox) in patients with solid tumours. Methods In this first-in-man, open-label, phase 1 clinical study, we enrolled patients at University Hospital of Basel, Switzerland, who had EGFR-overexpressing advanced solid tumours no longer amenable to standard treatment. Anti-EGFR ILs-dox nanoparticles were constructed by covalently linking pegylated liposomes containing doxorubicin to antigen-binding fragments (Fab′) of cetuximab. We intravenously infused the nanoparticle at escalating doses (doxorubicin 5 mg/m 2 , 10 mg/m 2 , 20 mg/m 2 , 30 mg/m 2 , 40 mg/m 2 , 50 mg/m 2 , and 60 mg/m 2 ) once every 4 weeks for a maximum of six cycles. The primary endpoint was to establish the maximum tolerated dose. We analysed patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01702129. Findings Between Jan 30, 2007, and March 4, 2010, we gave the drug to 29 patients, three of whom were withdrawn from the study because we could not complete a safety assessment. Of the 26 patients assessed for the primary endpoint, two who received a dose of 60 mg/m 2 had dose-limiting toxicities (one had neutropenia and the other had anaemia); therefore, the maximum tolerated dose was defined as 50 mg/m 2 . At all lower doses, anti-EGFR ILs-dox was well tolerated; grade 1 skin toxicity occurred in two patients only. We recorded 22 serious adverse events (SAEs) in 17 patients, mostly due to tumour progression. Three SAEs were fatal. Only three SAEs (febrile neutropenia, septicaemia, and a fatal massive oral bleed) were probably or possibly related to study drug. No patients had palmar-plantar erythrodysaesthesia, alopecia, cardiotoxicity, or cumulative toxicity. Best response to treatment included one complete response, one partial response, and ten stable disease lasting 2–12 months (median 5·75 months). Interpretation Because anti-EGFR ILs-dox was well tolerated up to 50 mg doxorubicin per m 2 , and we recorded clinical activity, further assessment of this nanoparticle at this dose in phase 2 trials is warranted. Funding Cancer League Basel, Swiss Cancer League, Schoenmakers-Muller Foundation, and Werner Geissberger Foundation.

Objective To generate, validate and establish a web-based individualised opioid conversion calculator at the University Hospital Basel and to analyse its value and significance. Setting A 700-bed university hospital. Method Published data were screened by a Medline search using the keywords: opioid, rotation, switching, potency and dose ratio. Based on this data, the criteria for the conversion calculator were defined. A prospective process validation was performed prior to the approval. Five months after the introduction of the tool, an online survey was performed in order to evaluate its acceptance by users. In the last step, a manual calculation using a written table was compared with the calculator in a cross-over trial with 72 participants in order to assess the findings of the survey. Results The opioid conversion calculator could be generated for 24 combinations of 6 opioids for 5 different routes of administration. The validation of the calculator was performed successfully without discovering any major or critical defects. The proportion of correct answers increased from 68% using the table to 81% using the calculator (P < 0.001), the median time necessary to answer the ten questions was 8.9 min using the table and 4.8 min using the calculator. Conclusion A web-based opioid conversion calculator was planned, generated, validated and established at the hospital. Based on the results of the online survey and the results of our cross-over trial we conclude that the tool saves time compared to manual calculation and may contribute to patient safety by avoiding calculation errors. With this tool we contribute to the optimisation of processes in hospital and patient safety.

3029 Background: Immunoliposomes (ILs) combine antibody-mediated tumor recognition with liposomal delivery and, when designed for target cell internalization, provide intracellular drug release in order to increase specificity and efficacy of the encapsulated drug. In animal studies we have shown the ILs approach to be active and promising when targeting the epidermal growth factor receptor (EGFR). Methods: ILs were modularly manufactured under GMP conditions with Fab' fragments from MAb C225 (cetuximab), covalently linked to pegylated liposomes containing doxorubicin (PLD). This first in man single-center phase I clinical trial of anti-EGFR ILs-dox was designed for patients (pts) with various solid tumors, overexpressing EGFR (DAKO EGFR pharmDx-test). ILs-dox was administered i.v. q 4 weeks at a doxorubicin (dox) dose of 5, 10, 20, 30, 40, 50 and 60 mg/m2, 3 pts per dose level, for a maximum of 6 cycles. In addition to weekly safety monitoring, echocardiography was performed q 2 cycles, and pharmacokinet...