Since prostate cancer is the most commonly diagnosed malignancy in men, the theranostic approach has become very attractive since the discovery of urea-based PSMA inhibitors. Different molecules have been synthesized starting from the Glu-urea-Lys scaffold as the pharmacophore and then optimizing the linker and the chelate to improve functional characteristics. This article aimed to highlight the quality aspects, which could have an impact on clinical practice, describing the development of an Investigational Medicinal Product Dossier (IMPD) for clinical trials with [¹⁷⁷Lu]Lu-PSMA-I&T in prostate cancer and other solid tumors expressing PSMA. The results highlighted some important quality issues of the final preparation: radiolabeling of PSMA-I&T with lutetium-177 needs a considerably longer time compared with the radiolabeling of the well-known [¹⁷⁷Lu]Lu-PSMA-617. When the final product was formulated in saline, the stability of [¹⁷⁷Lu]Lu-PSMA-I&T was reduced by radiolysis, showing a decrease in radiochemical purity (<95% in 24 h). Different formulations of the final product with increasing concentrations of ascorbic acid have been tested to counteract radiolysis and extend stability. A solution of 20 mg/mL of ascorbic acid in saline prevents radiolysis and ensures stability over 30 h.

The knowledge of the chemical stability of drugs prepared and administered in hospital is of paramount importance for establishing the methods and times of their preparation, as well as for ensuring patient safety. The objective of this work was to develop and validate a single chromatographic method, according to the International Conference on Harmonization (ICH), United States Pharmacopeia (USP) and the European Pharmacopoeia (Ph. Eur.) guidelines, to allow the determination of the chemical stability of 5 chemotherapy drugs. The high performance liquid chromatography coupled with diode array detection (HPLC-DAD) method developed was found to be linear (all analytical curves showed R² ≥ 0.999), sensitive, precise (RSDs < 3%) and accurate (recovery values ​​ranging between 95% and 105%). The method was demonstrated to be robust to small deliberate variations such as column temperature, pH and composition of the mobile phase and also able to determine drug decomposition products. Therefore, the method described here is perfectly able to identify and quantify the chemotherapy drugs analysed.

Results from the phase III Keynote-024 clinical trial established pembrolizumab monotherapy as the first-line standard of care for patients with metastatic NSCLC who have PD-L1 expression ≥ 50%, EGFR, and ALK wild-type tumors. However, given the differences between patients treated in routine clinical practice and those treated in a clinical trial, real-world data are needed to confirm the treatment benefit in standard practice. Given the lack of data on large cohorts of patients with long follow-ups, we designed an observational retrospective study of patients with metastatic NSCLC who were treated with pembrolizumab, starting from its reimbursement eligibility until December 2020. The primary endpoints were PFS and OS, determined using the Kaplan–Meier method. Response and safety were also evaluated. We followed 880 patients (median follow-up: 35.1 months) until February 2022. Median PFS and OS were 8.6 months (95% CI: 7.6–10.0) and 25.5 months (95% CI: 21.8–31.6), respectively. We also found that ECOG PS, PD-L1 expression, and habitual smoking were prognostic factors for PFS, while age, sex, ECOG PS, habitual smoking and histology had an impact on OS. Multivariable analysis confirms the prognostic role of PD-L1 for PFS and of ECOG for both PFS and OS. 39.9% of patients reported an adverse event, but only 6.3% of patients discontinued therapy due to toxicity. Our results suggest a long-term benefit of pembrolizumab in the first-line setting, as well as a safety profile consistent with the results of Keynote-024. Many collected variables appear to influence clinical outcome, but results from these exploratory unadjusted analyses should be interpreted with caution.

Objectives: Hydroxychloroquine has shown to have antiviral activity in vitro against coronaviruses, specifically SARS-CoV-2. It is believed to block virus infection by increasing endosomal pH required for virus cell fusion and glycosylation of viral surface proteins. In addition to its antiviral activity, hydroxychloroquine has an immune-modulating activity that may synergistically enhance its antiviral effect in vivo, making it a potentially promising drug for the prevention and the cure of SARS-CoV-19. However, randomized controlled trials are needed to assess whether it can be used safely to treat COVID-19 patients or to prevent infection. The main objective of the present study is to evaluate the efficacy of hydroxychloroquine for (I) the prevention of COVID-19 or related symptoms in SARS-CoV-2-exposed subjects, such as as household members/contacts of COVID-19 patients and (II) the treatment of early-phase asymptomatic or paucisymptomatic COVID-19 patients. Trial design: This is a controlled, open label, cluster-randomized, superiority trial with parallel group design. Subjects will be randomized either to receive hydroxychloroquine or to observation (2:1). Participants: SARS-CoV-2-exposed subjects, including household members and/or contacts of COVID-19 patients and healthcare professionals (Group 1) or patients with COVID-19 (positive PCR test on a rhinopharyngeal or oropharyngeal swab for SARS-CoV-2), asymptomatic or paucisymptomatic in home situations who are not undergoing treatment with any anti COVID-19 medication (Group 2), will be enrolled. Paucisymptomatic patients are defined as patients with a low number of mild symptoms. All subjects must be aged ≥18 years, male or female, must be willing and able to give informed consent and must not have any contraindications to take hydroxychloroquine (intolerance or previous toxicity for hydroxychloroquine/chloroquine, bradycardia or reduction in heart rhythm with arrhythmia, ischemic heart disease, retinopathy, congestive heart failure with use of diuretics, favism or glucose-6-phosphate dehydrogenase (G6PD) deficiency, diabetes type 1, major comorbidities such as advanced chronic kidney disease or dialysis therapy, known history of ventricular arrhythmia, any oncologic/hematologic malignancy, severe neurological and mental illness, current use of medications with known significant drug-drug interactions, and known prolonged QT syndrome or current use of drugs with known QT prolongation). The study is monocentric and will be conducted at Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS. Subjects will be enrolled from a large epidemic region (North-Central Italy). The Public Health Departments of several Italian regions will collaborate by identifying potentially eligible subjects. Intervention and comparator: The participants will be randomized (2:1 randomization) to receive either hydroxychloroquine (Arm A) or to Observation (Arm B). Hydroxychloroquine will be administered with the following schedule: Group1: A loading dose hydroxychloroquine 400 mg twice daily on day 1, followed by a weekly dose of hydroxychloroquine 200 mg twice daily on days 8, 15 and 22, for a total of one month of treatment. Group 2: A loading dose hydroxychloroquine 400 mg twice daily on day 1 followed by 200 mg twice daily for a total of 5-7 days. The comparator in this trial is observation given that currently neither treatment is administered to asymptomatic or paucisymptomatic subjects, nor prophylaxis is available for contacts. Hydroxychloroquine will be shipped to subjects within 24 hours of randomization. Given the extraordinary nature of the COVID-19 pandemic, only telephonic interviews will be carried out and electronic Patient Reported Outcomes (ePRO) completed. During treatment, each subject will be contacted every other day for the first week and weekly thereafter (Group 2) or weekly (Group 1) by a study physician to assess early onset of any COVID-19 symptom or any adverse reaction to hydroxychloroquine and to check subject compliance. Furthermore, all subjects will receive periodic ePROs which may be completed through smartphone or tablets to record drug self-administration and onset of any symptom or adverse event. All subjects will be followed up for a total of 6 months by periodic telephonic interviews and ePROs. Main outcomes: The primary endpoint/outcome measure for this trial is: for Group 1, the proportion of subjects who become symptomatic and/or swab-positive in each arm within one month of randomization; for Group 2, the proportion of subjects who become swab-negative in each arm within 14 days of randomization. Randomization: All household members and/or contacts of each COVID-19 index case, and the COVID-19 patient himself/herself, fulfilling all inclusion criteria will be grouped into a single cluster and this cluster will be randomized (2:1) to either arm A or arm B. Information on each subject will be recorded in specific data records. Randomization lists will be stratified according to the following factors regarding COVID-19 index cases: 1. COVID-19 risk level on the basis of province of residence (high vs. low/intermediate); 2. Index case is a healthcare professional (yes vs.no) 3. Index case with COVID-19 treatment (yes vs. no) An independent statistician not otherwise involved in the trial will generate the allocation sequence, and COVID-19 response teams will be unaware of the allocation of clusters. Randomization will be performed through an interactive web-based electronic data-capturing database. An Independent Data Monitoring Committee has been established. Blinding (masking): This study is open label. Numbers to be randomized (sample size): For Group 1, a sample size of about 2000 SARS-CoV-2-exposed subjects such as household members and/or contacts of COVID-19 patients will take part in the study. Assuming around 1.5-2.0 asymptomatic household members and/or contacts for each COVID-19 patient, we expect to identify approximately 1000-1300 COVID-19 index cases to be randomized. An interim analysis on efficacy is planned using standard alpha-spending function. For Group 2, sufficient power for primary objective (negative swab within 14 days of randomization) will be reached given a sample size of 300 asymptomatic or paucisymptomatic COVID-19 subjects in home situations not treated for COVID-19 (25%-30% of about 1000-1300 expected index cases). Since up to date reduced evidence about COVID-19 infection epidemiology, the continuous update of diagnostic and therapeutic approaches, the sample size estimation could be updated after a one third of population will be recruited and eventually modified according to a substantial protocol amendment. An interim analysis at 100 enrolled COVID-19 patients is planned. We have planned a Generalized Estimating Equation analysis, which is more efficient than a cluster level analysis, to take advantage of subject-specific covariates. The above reported sample size analysis is therefore to be considered conservative. Trial Status: The current version of the PROTECT trial protocol is ‘Final version, 15 April 2020’. The study started on 9^th May 2020. The first patient was enrolled on 14^th May 2020. Recruitment is expected to last through September 2020. Trial registration: The PROTECT trial is registered in the EudraCT database (no. 2020-001501-24) and in ClinicalTrials.gov (NCT04363827), date of registration 24 April 2020. Full protocol: The full PROTECT protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interests of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol (Protocol final version, 15^th April 2020). The study protocol has been reported in accordance with Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

In Italy, drug expenditure governance is achieved by setting caps based on the percentage increase in hospital spending compared to the previous year. This method is ineffective in identifying issues and opportunities as it does not consider an analysis of the number of treated cases and per capita consumption in local and regional settings. The IRCCS (Scientific hospitalization and treatment institute) Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori” in Meldola, has developed and adopted an effective management model designed to oversee pharmaceutical expenditure, guarantee prescription appropriateness and quality of care to patients. The budget setting follows a structured process which evaluates determining factors of the expenditure such as expected patients calculated according to the epidemiology and to national and regional indications of appropriateness, mean cost per patient calculated on the average period of demonstrated efficacy of the drug and use of drugs with the best cost-effectiveness ratio. Strict monitoring and integrated purchasing processes allow for immediate corrective actions on expenditures, as well as a continuous dialogue with the region in order to guarantee consistent funding of IRST activities. The model, presented in this article is efficient and implements concepts beyond the conventional “silos” approach and national and regional governance tools, in terms of patient centricity.

Background The delivery of intravenous medication by continuous infusion is necessary and widespread for treatment of patients with advanced cancer. Few scientific papers have focused on assessment of the chemical compatibility of these therapeutic mixtures. An analytical assessment of the physical and chemical compatibility of these combinations is needed. Objectives To determine the chemical and physical compatibility of binary mixtures of metoclopramide (MET) and midazolam (MID). Methods Mixtures of drugs were prepared under aseptic conditions in 0.9% sodium chloride at concentrations used in our clinical practice for continuous infusion. The samples were stored in polyethylene bags at room temperature in the presence of light for 15 days. Chemical compatibility was evaluated by high-performance liquid chromatography (HPLC). Physical compatibility was tested by visual inspection (for evidence of precipitation and colour change) and by pH determination. Results No changes in colour, precipitation of components, measurable losses of volume or notable changes in pH were seen. The combinations tested were compatible for 15 days (retained >95% of their initial concentration). Conclusions This study confirms the analytical compatibility of MET and MID, when mixed in 0.9% sodium chloride at concentrations employed in our clinical practice.