Pharmacy Workload in Clinical Trial Management: A Preliminary Complexity Assessment Tool for Sponsored Oncology and Haematology Trials.

Investigational drug services need to be organised in a structured approach, especially for sites with a large number of ongoing clinical trials. The aim of this study was to develop a tool to assess the complexity of pharmacy involvement in a sponsored oncology clinical trial. Categorisation into ordinal complexity categories was used to assess the complexity of the clinical trials for consistent pharmacy grant applications. The 15 items of the tool were divided into three sections, and individual item scores were agreed upon among four pharmacists with experience in the conduct of clinical trials at two different centres. A final version of the tool, named Pharm-CAT, was approved. The pharmacists were instructed to use Pharm-CAT to assign a score to each new sponsored trial. To determine the cut-offs for the complexity categories, the scores were sorted in ascending order and the cut-offs corresponding to the first and third tertiles of the score distribution were selected. To verify the reproducibility of the results, Pharm-CAT was applied by two pharmacists independently for each trial. Pharm-CAT proved to be user-friendly. Sixty clinical trials were evaluated and a total of 120 scores were recorded. Low-complexity scores ranged from 0 to 19, medium-complexity scores ranged from 20 to 25, and high-complexity scores were 26 or higher. The average score recorded was 22.88 points. Prospective multicentre validation of Pharm-CAT is needed to confirm its applicability.

Recurrent pneumothorax in a patient with liposarcoma as either a complication of lung micrometastasis or a potential adverse event from antibiotic therapy: A case report.

Spontaneous pneumothorax (PNX) is an infrequent manifestation of primary lung cancer, soft tissue sarcoma and metastasis. There are no easily accessible data in the literature regarding the correlation between PNX and antibiotics, whereas cases of PNX following chemotherapy have been observed. Only 1-10% of treatment-related adverse events are estimated to be reported to the Food and Drug Administration. The present study described a case of PNX of the left lung in a 70-year-old treatment-naive patient with retroperitoneal liposarcoma. The PNX developed after 8 days of treatment with levofloxacin and after 6 days of piperacillin/tazobactam treatment for a suspicious inflammatory area in the right lung detected by an FDG-PET scan before the patient started chemotherapy. A chest CT scan confirmed the presence of metastasis in the right lung, but neither FDG-PET/CT nor CT showed metastatic disease in the left lung. A total of 14 days after the end of the third cycle of doxorubicin (2 months after the initial diagnosis of PNX), the patient manifested a massive PNX of the right lung. In conclusion, these findings indicated that spontaneous PNX could be linked to the use of some antibiotics.

Antimicrobial prophylaxis in patients with immune thrombocytopenia treated with rituximab: a retrospective multicenter analysis.

The primary aim of this study was to describe the use of primary anti-infective prophylaxis (AP) in common clinical practice in patients affected by immune thrombocytopenia (ITP) and treated with RTX. Population studied consisted of patients affected by ITP (age ≥ 18 years) who had received at least one dose of RTX from January 2008 to June 2018. Five Italian haematology centres participated in the current study. Data were retrospectively collected: demographic data (age, gender), concomitant comorbidities and previous therapies for ITP, characteristics of AP, the occurrence of infections and their management. The ITP cohort consisted of 67 patients sub-grouped into two categories according to the administration of AP: (1) treated with AP (N= 34; 51%) and (2) not treated with AP (N=33, 49%). AP consisted of combined trimethoprim/sulfamethoxazole (TMP/SMX) and acyclovir (AC) in half of patients. TPM/SMX as a single agent was adopted in 32% patients and one patient received only AC. Overall, infections were experienced in 15% of patients during follow-up with a similar proportion in the 2 groups (treated and not treated) of patients (14.7% vs 15%). Clinical course of infections was however, less severe in patients treated with AP, where all infections were grade 2 and did not require hospitalization. In neither group of patients was reported Pneumocystis pneumonia. In conclusion, despite the absence of clear evidence, our analysis shows that AP in patients with ITP receiving RTX is frequently adopted, even if in the absence of well-defined criteria. Prophylaxis administration is quite consistent within the same haematological Center; thus, it seems related to clinicians' experience.

Stability of calcium levofolinate reconstituted in syringes and diluted in NaCl 0.9% and glucose 5% polyolefin/polyamide infusion bags.

PURPOSE: Calcium levofolinate (CaLev) for intravenous administration is commercially available as a powder that must be reconstituted for injection or reconstituted and then diluted before administration. The lack of stability data on CaLev solutions renders necessary extemporaneous manual preparation, preventing the use of automated/semi-automated systems, with a consequent loss in terms of quality and safety. METHODS: The present work assessed the chemical-physical and microbiological stability of CaLev prepared in sodium chloride 0.9%, glucose 5% and water for injections and stored in polyolefin/polyamide bags and polypropylene syringes at 2-8°C protected from light. For this purpose, we developed and validated a new rapid High Performance Liquid Chromatography with Ultra Violet Diode-Array Detection (HPLC-UV-DAD) method. RESULTS: The samples tested were stable for 14 days, retaining >95% of their initial concentration and showing no change in colour, turbidity or pH. Microbiological tests performed on the samples were negative. CONCLUSIONS: Our results confirmed the analytical stability of CaLev in NaCl 0.9%, glucose 5% and water for injection at concentrations used in clinical practice at our institute. This enables our centralized laboratory to organize the preparation of this drug in advance and the use of robots rather than manual preparation reduces the workload and the risk of preparation errors.

CPX-351 daunorubicin-cytarabine liposome: a novel formulation to treat patients with newly diagnosed secondary acute myeloid leukemia.

Over the last few years, we assisted to an increasing knowledge about acute myeloid leukemia (AML) pathobiology. However, outcomes remain unsatisfactory particularly for adult patients over 60 years old. Not surprisingly several cases of therapy-related AML (tAML) and secondary AML, both characterized by poorer prognosis, are more common in older population. For several decades initial therapy for AML remained unchanged and typically treatment consisted of an anthracycline combined with continuous infusion of cytarabine for 7 days, the so-called "7+3" standard regimen. The efforts made by the researchers to improve this standard schedule, have led to only modest improvement in the response rate (RR) but no change in overall survival (OS), until the recent evolution seen with new target specific mutation therapies. In 2017, a new liposomal-encapsulated formulation with daunorubicin and cytarabine (CPX-351) was approved by the US Food and Drug Administration for the treatment of newly diagnosed tAML or AML with myelodysplasia-related changes (AML-MRCs). Based on the findings that ratiometric delivery may be more effective than administration of either drug at their maximum tolerated dose (MTD), CPX-351 was designed to deliver a fixed 5:1 molar ratio of the two molecules historically used in the standard "7+3" regimen, cytarabine and daunorubicin respectively. CPX-351 did show improvements of overall survival compared to traditional "7+3" in newly diagnosed secondary and therapy-related AML in adult patients. However, questions remain regarding how to select across AML patient subgroups to maximize the clinical benefit. Possible future directions include evaluating CPX-351 dose intensification, combining this liposomal formulation with targeted therapies and not least important a better understanding about the mechanism of improved responses in tAML and AML-MRC, two entities recognized to be less chemo-sensitive than other hematologic malignancies. In summary, CPX-351 offers finally something new in the landscape of AML therapy. Herein we will review the rationale behind this new drug product development, the main pharmacological characteristics, and discuss the results of clinical trials that led to its FDA approval at first and by EMA in 2018.

Tagraxofusp and anti-CD123 in blastic plasmacytoid dendritic cell neoplasm: a new hope.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy, characterized by poor prognosis if treated with conventional therapy. Allogenic hematologic stem cell transplant can improve survival and can be curative, but it is available in a small percentage of patients given that the median age at diagnosis is 70 years. In this scenario it is assumed that only the development of precision medicine-driven therapy will change BPDCN patient prognosis. CD123 (the α-subunit of interleukin (IL)-3 receptor) is over-expressed on BPDCN cells surface and seems to be the ideal marker to develop antibody-based therapies. Tagraxofusp (Elzonris®), a recombinant immunotoxin consisting of human interleukin-3 fused to a truncated diphtheria toxin, has been approved by FDA in December 2018 for the treatment of BPDCN in adult and pediatric patients. tagraxofusp has shown promising clinical activity, with a high overall response rate and quite manageable safety profile even in elderly patients. It seems to improve overall survival too, but comparative trials are necessary to confirm this. Adverse events are commonly reported and the most important are transaminitis, thrombocytopenia and capillary leak syndrome (CLS). Therefore, to prevent the onset of severe CLS is recommended to reserve tagraxofusp for patients with preserved hepatic and cardiac functions, and to strictly observe serum albumin level. Further studies are required to resolve many several unanswered questions about tagraxofusp. In this review, we will resume and discuss pharmacological characteristic of tagraxofusp, results of clinical trials leading to its approval by FDA in 2018 and future perspectives about its use in BPDCN and other hematological malignancies.

Validation of RP-HPLC method to assess the compatibility of metoclopramide and midazolam intravenous mixture used in patients with cancer.

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.

Resource utilization and cost saving analysis of subcutaneous versus intravenous trastuzumab in early breast cancer patients.

We conducted an economic evaluation of intravenous (IV) vs subcutaneous (SC) trastuzumab for the treatment of patients with early breast cancer (EBC). Data of patients receiving adjuvant IV trastuzumab at our institute in 2014 were used to study three different treatment scenarios: 1) IV trastuzumab, 2) SC trastuzumab, and 3) IV trastuzumab during chemotherapy followed by SC trastuzumab. Our cohort included 114 patients with a median weight of 63.75 kg. Scenario 2 was the most time-saving treatment, with 71.7% reduction in preparation time and 89.3% reduction in chair time compared to scenario 1. Considering full costs, the mean costs per patient/year were € 14,233 ± 8,698 for scenario 1, € 14,272 ± 8,312 for scenario 2, and € 14,535 ± 8,646 for scenario 3 (p = 0.959). When mean body weight was > 65.2 kg, the mean cost was lower in scenario 2 than in scenario 1. Scenario 2 proved a valuable time-saving and cost-saving option. A shift from IV to SC trastuzumab should be considered, especially in capacity-constrained oncology departments.