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Pneumatic transportation systems (PTS) were recently proposed as a method to carry ready-for-injection diluted monoclonal antibodies (mAbs) from the pharmacy to the bedside of patients. This method reduces transportation time and improves the efficiency of drug distribution process. However, mAbs are highly sensitive molecules for which subtle alterations may lead to deleterious clinical effects. These alterations can be caused by various external factors such as temperature, pH, pressure, and mechanical forces that may occur during transportation. Hence, it is essential to ensure that the mAbs transported by PTS remain stable and active throughout the transportation process. This study aims to determine the safety profile of PTS to transport 11 routinely used mAbs in a clinical setting through assessment of critical quality attributes (CQA) and orthogonal analysis. Hence, we performed aggregation/degradation profiling, post-translational modifications identification using complementary mass spectrometry-based methods, along with visible and subvisible particle formation determination by light absorbance and light obscuration analysis. Altogether, these results highlight that PTS can be safely used for this purpose when air is removed from the bags during preparation.

Purpose This first-in-human study was designed to evaluate the pharmacokinetic (PK) equivalence between HD204 and the European Union (EU)-sourced bevacizumab, between HD204 and the United States of America (US)-sourced bevacizumab, and between EU-sourced and US-sourced bevacizumab (NCT 03390673). Methods In this randomized, double-blind, 3-way parallel group, single-dose comparative PK study, healthy male subjects were randomized to receive a single 1 mg/kg intravenous dose of HD204, EU-sourced bevacizumab or US-sourced bevacizumab. PK parameters were calculated using non-compartmental methods. PK equivalence was determined using the pre-defined equivalence margin of 0.8-1.25 in terms of AUC.sub.(0-[infinity]) for the pairwise comparisons. Findings Baseline demographics for the 119 randomized subjects were similar across the three groups. The 90% CIs for the ratio of the geometric means of HD204 to US-sourced bevacizumab, HD204 to EU-sourced bevacizumab, and EU-sourced to US-sourced bevacizumab were all within the interval of 80% to 125% for AUC.sub.0-inf, thus demonstrating equivalency in the PK properties for all three treatment groups. Similarly, the ratio of the geometric means for AUC.sub.0-last and C.sub.max were all within the 80% and 125% margins, supporting the robustness of the primary findings. All other PK parameters, including the half-life (t1/2) clearance (CL), volume of distribution (Vd) and time of maximum concentration (t.sub.max ), were comparable. There was no difference between the 3 treatment arms in terms of vital signs, laboratory tests and adverse events. None of the subjects treated with HD204 had positive ADA results. Implications HD204 demonstrates equivalent pharmacokinetic profiles compared to those of both US-sourced and EU-sourced bevacizumab. (NCT 03390673).

IntroductionOvarian cancer (OC) is the most lethal gynecological cancer. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy appears to increase survival, and normothermic intraperitoneal chemotherapy (IPC) could improve overall survival (OS). Furthermore, intraperitoneal epinephrine could decrease the toxicity of chemotherapy by decreasing the systemic absorption of chemotherapy. The goal of this study was to assess the effects of CRS and IPC with intraperitoneal epinephrine, as first-line therapy, on the survival of patients with serous epithelial OC (EOC) with peritoneal metastases.MethodsA prospective monocentric database was retrospectively searched for all patients with advanced serous EOC treated by interval or consolidative CRS plus IPC with intraperitoneal epinephrine after neoadjuvant chemotherapy. OS and disease-free survival (DFS), postoperative complications, and prognostic factors were analyzed.ResultsFrom January 2003 to December 2017, 124 patients with serous EOC were treated with interval (n = 58) or consolidative (n = 66) complete CRS plus IPC with intraperitoneal epinephrine. The median follow-up was 77.8 months, the median OS was 60.8 months, and the median DFS was 21.2 months. In our multivariate analysis, a higher Peritoneal Cancer Index (PCI) and positive lymph node status resulted in worse OS, while higher World Health Organization score, higher PCI score, and positive lymph node status were risk factors for worse DFS. Grade 3 or higher surgical morbidity occurred in 27.42% of cases; only 3.2% had grade 3 renal toxicity and mortality was 0.8%.ConclusionCRS and IPC with intraperitoneal epinephrine in stage III EOC offer good OS and DFS with acceptable morbidity and mortality rates.

Cisplatin/gemcitabine association has been a standard of care for first‐line regimen in advanced biliary tract cancer nevertheless oxaliplatin/gemcitabine regimen is frequently preferred. Because comparative effectiveness in clinical outcomes of cisplatin‐ versus oxaliplatin‐containing chemotherapy is not available, a systematic review of studies assessing cisplatin/gemcitabine or oxaliplatin/gemcitabine chemotherapies in advanced biliary tract cancer was performed. Published studies evaluating cisplatin/gemcitabine or oxaliplatin/gemcitabine in advanced biliary tract cancer were included. Each study was weighted according to the number of patients included. The primary objective was to assess weighted median of medians overall survival (mOS) reported for both regimens. Secondary goals were to assess weighted median of medians progression‐free survival (mPFS) and toxic effects were pooled and compared within each arm. Thirty‐three studies involving 1470 patients were analyzed. In total, 771 and 699 patients were treated by cisplatin/gemcitabine and oxaliplatin/gemcitabine, respectively. Weighted median of mOS was 9.7 months in cisplatin group and 9.5 months in oxaliplatin group. Cisplatin‐based chemotherapy was significantly associated with more grade 3 and 4 asthenia, diarrhea, liver toxicity, and hematological toxicity. Sensitivity analysis including only the studies with the standard regimen of cisplatin (25–35 mg/m2 administered on days 1 and 8) showed that the weighted median of mOS increased from 9.7 to 11.7 months but Gem/CDDP regimen remained more toxic than Gemox regimen. These results suggest that the Gem/CDDP regimen with cisplatin (25–35 mg/m2) administered on days 1 and 8 is associated with survival advantage than Gemox regimen but with addition of toxicity. Cisplatin/gemcitabine association has been a standard of care for first‐line regimen in advanced biliary tract cancer nevertheless oxaliplatin/gemcitabine regimen is frequently preferred. Because comparative effectiveness in clinical outcomes of cisplatin‐ versus oxaliplatin‐containing chemotherapy is not available, a systematic review of studies assessing cisplatin/gemcitabine or oxaliplatin/gemcitabine chemotherapies in advanced biliary tract cancer was performed. The results suggest that the Gem/CDDP regimen with cisplatin (25–35 mg/m2) administered on days 1 and 8 is associated with survival advantage than Gemox regimen but with addition of toxicity.

Prestige Biopharma Ltd (Singapore) has developed HD201, a proposed biosimilar to reference product trastuzumab. As a part of the stepwise approach to ensure comparability between the biosimilar candidate and the reference medicinal product, a phase I study in healthy subjects was conducted to demonstrate the pharmacokinetic (PK) equivalence (NCT03776240). The primary objective of the study was to demonstrate (PK) equivalence of HD201, EU‐Herceptin®, and US‐Herceptin® given at 6 mg/kg as a 90‐min i.v. infusion to healthy male subjects. A pairwise comparisons based on the primary endpoint AUC0–inf and secondary PK endpoints, AUC0–last and Cmax were undertaken. PK equivalence was to be concluded if the 90% confidence interval (CI) for the ratio of geometric means for each criterion were within the equivalence margin of 80% to 125%. Secondary objectives included assessment of other PK parameters, safety, tolerability, and immunogenicity in the three arms. A total of 105 healthy male subjects (35/treatment) were randomized in this study. The 90% CI for the ratios of AUC0–inf, Cmax and AUC0–last, were within 80%–125% for the comparisons of HD201 to EU‐Herceptin® or US‐Herceptin® and EU‐Herceptin® to US‐Herceptin®. The frequency of subjects with TEAEs of special interest was slightly lower in the HD201 group (20.0%) compared to the other treatment groups (EU‐Herceptin®: 34.3%; US‐Herceptin®: 31.4%). Only 1 subject (EU‐Herceptin® group) developed anti‐drug antibodies prior to dosing. Overall, HD201 demonstrates PK similarity to both EU‐Herceptin® and US‐Herceptin®. The three study drugs also demonstrated similar safety profiles. TROIKA‐1: A Double‐blind, Randomized, Parallel Group, Study aimed to demonstrate the equivalent pharmacokinetic profile of HD201, a potential biosimilar candidate to trastuzumab, versus EU‐Herceptin® and US‐Herceptin® in Healthy Male Subjects.

Background This study searched for extra capsular tumour spread (ECS) as a prognostic factor for recurrence in terms of Disease Free Survival (DFS) and Overall Survival (OS). Patients and methods For this study, from a retrospective database of the Doubs cancer registry, 823 eligible women with node positive breast cancer treated from February 1984 to November 2000 were identified. The following factors were evaluated: ECS, numbers of involved nodes, histological tumour grade, tumour size, status of estrogen and progesterone receptors, and age of patient. A Cox proportional hazards method was used to search for significant factors related to OS and DFS length. Results In the multivariate analysis, factors related to DFS length were found to be: tumour grade (aHR 0.76, 95 % CI 0.61–0.96, p  = 0.02), ECS status (aHR 0.7, 95 % CI 0.49–0.96, p  = 0.03), progesterone (PgR) status (aHR 0.63, 95 % CI 0.44–0.85 p  = 0.008), number of nodes involved (aHR 0.75, 95 % CI 0.56–1, p  = 0.05). The multivariate analysis for OS found as significant factors: tumour grade (aHR 0.76, 95 % CI 0.61–0.95; p  = 0.02) and PgR status (aHR 0.8, 95 % CI 0.56–0.99, p  = 0.02). Conclusions This study might suggest taking into account ECS status in the adjuvant decision-making process.

Background Intra-peritoneal (i.p.) chemotherapy is an encouraging treatment option for ovarian cancer with peritoneum involvement in addition with intravenous (i.v.) chemotherapy. Intra-operative i.p. chemotherapy is an interesting method of administration by enhancing the diffusion of chemotherapy. This study had assessed the feasibility of intra-operative i.p. chemotherapy in patients with peritoneal carcinoma of ovarian cancer. Methods From January 2003 to February 2006, 47 patients with stage III ovarian cancer were treated with standard paclitaxel carboplatin intravenous chemotherapy and debulking surgery with intra-operative i.p. chemotherapy. After optimal cytoreductive surgery, defined by no unresectable residual disease > 1 cm, i.p. chemotherapy was performed during surgery. The peritoneal cavity was filled by 3 litres of isotonic saline pre-heated at 37 degrees and 90 mg of cisplatin. The sequence was repeated twice during 2 hours based on previous published studies which optimized the cisplatin dosage and exposure duration. Optimal diffusion was obtained by stirring by hands during the 2 hours. Results Median age was 59.6 years. No severe haematological or non-haematological toxicity induced by intra operative i.p. chemotherapy was reported. No patient died due to the complications of surgery or the i.p. chemotherapy. No neurotoxicity occurred, and one patients had renal impairment. Conclusion This study demonstrates the feasibility of intra-operative i.p. chemotherapy with cisplatin after optimal resection of peritoneal tumor nodules. Further randomized trials are planned to investigate the clinical benefit of this therapeutic modality.

The development of drug resistance is a major obstacle to effective cancer therapy. Several agents are in clinical development with the goal of overcoming resistance. Among them is cabazitaxel, a semisynthetic taxoid that is able to overcome a common mechanism of resistance that limits the efficacy of other chemotherapeutic agents, including the older taxanes. The promise of cabazitaxel as a second-line chemotherapy option for advanced prostate cancer has been confirmed clinically in the phase III TROPIC (Treatment of Hormone-Refractory Metastatic Prostate Cancer Previously Treated with a Taxotere-Containing Regimen) trial. This trial showed that cabazitaxel is the first chemotherapeutic agent to demonstrate a survival benefit in metastatic castration-resistant prostate cancer (mCRPC) since the approval of docetaxel. On this basis, the US FDA and the European Medicines Agency approved cabazitaxel in June 2010 and January 2011, respectively, for the treatment of patients with mCRPC who have previously been treated with docetaxel. The most prevalent toxicity was neutropenia and the use of primary prophylaxis with granulocyte-colony stimulating factor is recommended in high risk patients. This article presents the preliminary antitumour activity, safety, tolerability and pharmacokinetic data of cabazitaxel, and an overview of the current status of clinical development. [PUBLICATION ABSTRACT]

Lung cancers with ALK rearrangement represent less than 5% of all lung cancers. ALK inhibitors are currently used to treat first-line metastatic non-small cell lung cancer with ALK rearrangement. Compared to chemotherapy, ALK inhibitors have improved progression-free survival, overall survival, and quality of life for patients. The results of several phase 3 studies with a follow-up of over 6 years suggest that the life expectancy of these patients treated with targeted therapies is significantly higher than 5 years and could approach 10 years. Nevertheless, these treatments induce haematological toxicities, including neutropenia. Few data are available on neutropenia induced by ALK inhibitors and on the pathophysiological mechanism and therapeutic adaptations necessary to continue the treatment. Given the high efficacy of these treatments, managing side effects to avoid treatment interruptions is essential. Here, we have reviewed the data from published clinical studies and case reports to provide an overview of neutropenia induced by ALK inhibitors.

BackgroundBorderline ovarian tumors (BOTs) are tumors with a favorable prognosis but whose management by consensus is essential to limit the risk of invasive recurrence. This study aimed to conduct an inventory of surgical practices for BOT in France and to evaluate the conformity of the treatment according to the current French guidelines.MethodsThis retrospective, multicenter cohort study included nine referral centers of France between January 2001 and December 2018. It analyzed all patients with serous and mucinous BOT who had undergone surgery. A peritoneal staging in accordance with the recommendations was defined by performance of a peritoneal cytology, an omentectomy, and at least one peritoneal biopsy.ResultsThe study included 332 patients. A laparoscopy was performed in 79.5% of the cases. Treatment was conservative in 31.9% of the cases. The recurrence rate was significantly increased after conservative treatment (17.3% vs 3.1%; p < 0.001). Peritoneal cytology was performed for 95.5%, omentectomy for 83.1%, and at least one biopsy for 82.2% of the patients. The overall recurrence rate was 7.8%, and the recurrence was invasive in 1.2% of the cases. No link was found between the recurrence rate and the conformity of peritoneal staging. The overall rate of staging noncompliance was 22.9%.ConclusionThe current standards for BOT management seem to be well applied.