Lurbinectedin (PM01183) has synergistic antitumor activity when combined with doxorubicin in mice with xenografted tumors. This phase I trial determined the recommended dose (RD) of doxorubicin ...(bolus) and PM01183 (1-h intravenous infusion) on day 1 every 3 weeks (q3wk), and obtained preliminary evidence of antitumor activity for this combination in small-cell lung cancer (SCLC).
Patients with advanced solid tumors received doxorubicin and PM01183 following a standard dose escalation design and expansion at the RD. Twenty-seven patients had relapsed SCLC: 12 with sensitive disease (platinum-free interval ≥90 days) and 15 with resistant disease (platinum-free interval <90 days).
Doxorubicin 50 mg/m2 and PM01183 4.0 mg flat dose was the RD. In relapsed SCLC, treatment tolerance at the RD was manageable. Transient and reversible myelosuppression (including neutropenia, thrombocytopenia, and febrile neutropenia) was the main toxicity, managed with dose adjustment and colony-stimulating factors. Fatigue (79%), nausea/vomiting (58%), decreased appetite (53%), mucositis (53%), alopecia (42%), diarrhea/constipation (42%), and asymptomatic creatinine (68%) and transaminase increases (alanine aminotransferase 42%; aspartate aminotransferase 32%) were common, and mostly mild or moderate. Complete (n = 2, 8%) and partial response (n = 13, 50%) occurred in relapsed SCLC, mostly at the RD. Response rates at second line were 91.7% in sensitive disease median progression-free survival (PFS)=5.8 months and 33.3% in resistant disease (median PFS = 3.5 months). At third line, response rate was 20.0% (median PFS = 1.2 months), all in resistant disease.
Doxorubicin 50 mg/m2 and PM01183 4.0 mg flat dose on day 1 q3wk has shown remarkable activity, mainly in second line, with manageable tolerance in relapsed SCLC, leading to further evaluation of this combination within an ongoing phase III trial.
To compare the frequency of electronic prescription errors when the prescription was validated by the clinical pharmacist vs. when it was not.
This prospective randomised controlled study was ...conducted in three phases. A randomised phase, in which patients were divided into control and intervention groups, and a pre- and post-intervention phase were consecutively performed to analyse the impact of pharmaceutical validation of prescriptions in a neonatal intensive care unit (NICU). This study was performed at a highly complex NICU at a tertiary hospital. All patients born during the study period who were admitted to the NICU, with a stay lasting ≥24 h, and received active pharmacological treatment were included in the study. Pharmaceutical validation was performed according to the paediatric pharmaceutical care model. A high level of validation was selected for this study. In the intervention group, discrepancies found during the review process were communicated to the medical team responsible for the patients and resolved on the same day.
In total, 240 patients were included in this study. Sixty-two patients were allocated to the pre-intervention (
= 38) or post-intervention (
= 24) groups, and 178 patients were randomly sorted into two groups, control (
= 82 newborns) and intervention (
= 96 newborns). During the randomisation phase, the number of prescription errors detected was significantly lower in the intervention group than that in the control group (129 vs. 270;
< 0.001). Similarly, prescription errors reaching the patient were significantly reduced from 40% (
= 108) in the control group to 1.6% (
= 2) in the intervention group. In the pre- and post-intervention periods, the prescription lines containing prescription errors decreased from 3.4% to 1.5% (
= 0.005).
This study showed that the pharmaceutical validation process decreased both the number of errors in the electronic prescribing tools and the number of prescription errors reaching the patient.
Loss-of-function studies have demonstrated the essential role of Notch in definitive embryonic mouse hematopoiesis. We report here the consequences of Notch gain-of-function in mouse embryo ...hematopoiesis, achieved by constitutive expression of Notch1 intracellular domain (N1ICD) in angiopoietin receptor tyrosine kinase receptor-2 (Tie2)-derived enhanced green fluorescence protein (EGFP(+)) hematovascular progenitors. At E9.5, N1ICD expression led to the absence of the dorsal aorta hematopoietic clusters and of definitive hematopoiesis. The EGFP(+) transient multipotent progenitors, purified from E9.5 to 10.5 Tie2-Cre;N1ICD yolk sac (YS) cells, had strongly reduced hematopoietic potential, whereas they had increased numbers of hemogenic endothelial cells. Late erythroid cell differentiation stages and mature myeloid cells (Gr1(+), MPO(+)) were also strongly decreased. In contrast, EGFP(+) erythro-myeloid progenitors, immature and intermediate differentiation stages of YS erythroid and myeloid cell lineages, were expanded. Tie2-Cre;N1ICD YS had reduced numbers of CD41(++) megakaryocytes, and these produced reduced below-normal numbers of immature colonies in vitro and their terminal differentiation was blocked. Cells from Tie2-Cre;N1ICD YS had a higher proliferation rate and lower apoptosis than wild-type (WT) YS cells. Quantitative gene expression analysis of FACS-purified EGFP(+) YS progenitors revealed upregulation of Notch1-related genes and alterations in genes involved in hematopoietic differentiation. These results represent the first in vivo evidence of a role for Notch signaling in YS transient definitive hematopoiesis. Our results show that constitutive Notch1 activation in Tie2(+) cells hampers YS hematopoiesis of E9.5 embryos and demonstrate that Notch signaling regulates this process by balancing the proliferation and differentiation dynamics of lineage-restricted intermediate progenitors.
Preclinical studies showed a synergistic effect for 5-fluorouracil and lurbinectedin against solid tumors. This phase I trial evaluated a combination of capecitabine plus lurbinectedin in patients ...with selected advanced solid tumors. Results in patients with relapsed metastatic breast cancer (MBC) are described.
Patients received capecitabine daily on day (D)1-D14 combined with lurbinectedin on D1, D8 or D1 every 3 weeks (q3w) intravenously, following a standard 3 + 3 escalation design and expansion at the recommended dose (RD).
Of the 81 enrolled patients, 28 had relapsed MBC: 20 with hormone receptor (HR)-positive tumors and 8 with triple-negative tumors; 3 treated in the D1,D8 schedule and 25 in the D1 schedule. The RD was capecitabine 1650 mg/m2 daily on D1-D14 plus lurbinectedin 2.2 mg/m2 on D1 q3w. Sixteen confirmed responses and two prolonged disease stabilizations (≥6 months) were observed overall response rate (ORR)/clinical benefit rate (CBR) = 57%/64% at all dose levels; 47%/60% at the RD. Twelve responses and both prolonged stabilizations occurred in HR-positive tumors (ORR/CBR = 60%/70% at all dose levels, 56%/78% at the RD). Four responses were found in triple-negative tumors (ORR and CBR = 50% at all dose levels; 33% at the RD). Myelotoxicity was reversible and manageable at the RD; most non-hematological toxicities were mild/moderate. No episodes of febrile neutropenia or severe palmar-plantar erythrodysesthesia syndrome occurred. No major pharmacokinetic drug–drug interaction was found between lurbinectedin, capecitabine or capecitabine metabolites.
The capecitabine/lurbinectedin combination showed encouraging clinical activity in relapsed MBC, especially in HR-positive tumors. Toxicity was manageable at the RD. Further development is warranted in relapsed MBC.
•Capecitabine daily on D1-D14 plus lurbinectedin on D1 q3w showed encouraging activity in relapsed MBC.•At the RD (capecitabine 1650 mg/m2 plus lurbinectedin 2.2 mg/m2), ORR was 47% and CBR after 6 months was 60%.•Antitumor activity at the RD was higher in patients with HR-positive tumors (ORR = 56%; CBR = 78% after 6 months).•Myelotoxicity was reversible and manageable at the RD, and most non-hematological toxicities were mild/moderate.•Further development of the capecitabine/lurbinectedin combination is warranted in relapsed MBC.
Lurbinectedin, a selective inhibitor of oncogenic transcription, has shown preclinical antitumor activity against homologous recombination repair-deficient models and preliminary clinical activity in ...BRCA1/2 breast cancer.
This phase II basket multitumor trial (NCT02454972) evaluated lurbinectedin 3.2 mg/m2 1-h intravenous infusion every 3 weeks in a cohort of 21 patients with pretreated germline BRCA1/2 breast cancer. Patients with any hormone receptor and human epidermal growth factor receptor 2 status were enrolled. The primary efficacy endpoint was overall response rate (ORR) according to RECIST v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety.
Confirmed partial response (PR) was observed in six patients ORR = 28.6%; 95% confidence interval (CI) 11.3% to 52.2% who had received a median of two prior advanced chemotherapy lines. Lurbinectedin was active in both BRCA mutations: four PRs in 11 patients (36.4%) with BRCA2 and two PRs in 10 patients (20.0%) with BRCA1. Median DoR was 8.6 months, median PFS was 4.1 months and median OS was 16.1 months. Stable disease (SD) was observed in 10 patients (47.6%), including 3 with unconfirmed response in a subsequent tumor assessment ORR unconfirmed = 42.9% (95% CI 21.8% to 66.0%). Clinical benefit rate (PR + SD ≥ 4 months) was 76.2% (95% CI 52.8% to 91.8%). No objective response was observed among patients who had received prior poly (ADP-ribose) polymerase inhibitors. The most common treatment-related adverse events (AEs) were nausea (61.9%), fatigue (38.1%) and vomiting (23.8%). These AEs were mostly grade 1/2. The most common grade 3/4 toxicity was neutropenia (42.9%: grade 4, 23.8%: with no febrile neutropenia).
This phase II study met its primary endpoint and showed activity of lurbinectedin in germline BRCA1/2 breast cancer. Lurbinectedin showed a predictable and manageable safety profile. Considering the exploratory aim of this trial as well as previous results in other phase II studies, further development of lurbinectedin in this indication is warranted.
•Loss of function due to mutations in the breast cancer gene, BRCA, leads to worse prognosis in breast cancer patients.•Lurbinectedin has previously shown antitumor activity in breast cancer patients with mutations in BRCA2.•This phase II basket study included a cohort of 21 patients with BRCA-mutated breast cancer treated with lurbinectedin.•The study showed antitumor activity and supports further investigation in this type of cancer.
PM00104 binds guanines at DNA minor grooves, impacting DNA replication and transcription. A phase I study was undertaken to investigate safety, dose-limiting toxicities (DLTs), recommended phase II ...dose (RP2D), pharmacokinetics (PKs) and preliminary antitumour activity of PM00104 as a 1- or 3-h infusion three-weekly.
Patients with advanced solid tumours received PM00104 in a dose escalation trial, as guided by toxicity and PK data.
A total of 47 patients were treated; 27 patients on the 1-h schedule (0.23-3.6 mg m(-2)) and 20 patients on the 3-h schedule (1.8-3.5 mg m(-2)). Dose-limiting toxicities comprised reversible nausea, vomiting, fatigue, elevated transaminases and thrombocytopenia, establishing the 1-h schedule RP2D at 3.0 mg m(-2). With the 3-h schedule, DLTs of reversible hypotension and neutropenia established the RP2D at 2.8 mg m(-2). Common PM00104-related adverse events at the RP2D comprised grade 1-2 nausea, fatigue and myelosuppression. In both schedules, PKs increased linearly, but doses over the 1-h schedule RP2D resulted in higher than proportional increases in exposure. A patient with advanced urothelial carcinoma had RECIST shrinkage by 49%, and three patients had RECIST stable disease ≥6 months.
PM00104 is well tolerated, with preliminary evidence of antitumour activity observed. The 1-h 3-weekly schedule is being assessed in phase II clinical trials.
Purpose
PM00104 (Zalypsis
®
) is a synthetic tetrahydroisoquinoline alkaloid with potent antiproliferative activity against tumor cell lines. This phase I study evaluated the safety, dose-limiting ...toxicities (DLTs), recommended dose for phase II trials (RD), pharmacokinetics (PK) and preliminary antitumor activity of PM00104 as a 24-h intravenous (i.v.) infusion every 3 weeks (q3wk).
Methods
Thirty-seven patients with refractory advanced solid tumors received PM00104 in a toxicity-guided dose escalation study design (3 + 3 patients per cohort). Plasma samples were collected for PK analysis.
Results
DLTs comprised severe neutropenia lasting >5 days (
n
= 4 patients), vomiting, thrombocytopenia, transaminase increases (
n
= 2 each), fatigue, tumor pain, myalgia, muscle stiffness, creatine phosphokinase increase and dosing delay >2 weeks due to moderate fatigue (
n
= 1 each). The RD was 4.0 mg/m
2
. Most PM00104-related adverse events at the RD were mild or moderate; the most common were nausea, vomiting and fatigue. Myelosuppression and transaminase increases were transient and manageable. PK parameters increased linearly with dose. Higher PM00104 PK exposure was related to a decrease in hemoglobin, neutrophils, platelets and white blood cells. Area under the curve was directly correlated with both incidence and severity of nausea and vomiting. Three patients with hepatocellular carcinoma, esophageal adenocarcinoma and prostate adenocarcinoma had response evaluation criteria in solid tumors stable disease ≥3 months.
Conclusions
PM00104 given as 24-h i.v. infusion q3wk has predictable and manageable toxicity, but resulted in more myelotoxicity (because of the higher dose level achieved as the RD) and a similar drug clearance compared to 1-h infusion schedules. Preliminary evidence of antitumor activity was observed.
Background and ImportanceInfusion-related reactions (IRR) are one of isatuximab’s most frequent and significant adverse reactions that may lead to treatment discontinuation despite premedicating with ...dexamethasone, paracetamol, and anti-H1 antihistamines. Similarly to daratumumab, adding montelukast as premedication could improve its tolerability. Additionally, there are no studies to date describing which risk factors (RF) may affect the likeliness of an isatuximab IRR.Aim and ObjectivesThe primary objective was to assess the impact of including montelukast as premedication on the incidence of IRR (iIRR) associated with the administration of isatuximab.Secondary objectives included describing the iIRR in a real-life setting and evaluating possible risk factors: food, environmental or medicine allergies; previous IRR; and infusion bag concentration.Material and MethodsMulticentric retrospective study conducted in one secondary and three tertiary hospitals. Eligibility criteria included adults having started isatuximab and excluded patients receiving off-label corticosteroid doses and those enrolled in clinical trials. Follow-up was carried out until September 2023, treatment discontinuation or death.Baseline characteristics were sex, age, treatment regimen, premedication regimen, number of isatuximab doses and occurrence of IRR. These numerical and categorical variables were expressed as number of observations and medians respectively.Odds ratios (OR) and Mann-Whitney U tests were calculated to evaluate qualitative and quantitative RF, respectively. Absolute risk reduction (ARR) and number needed to treat (NNT) were used to assess the impact of montelukast as premedication. 95% confidence intervals (95%CI) were applied.Results40 patients were included, with a median age of 66 (54 – 72) years, 60.0% being men. The median number of isatuximab doses per patient was 8 (4–18).The iIRR for cycle-one-day-one was 7.7% for the group premedicated with montelukast and 29.6% without. OR was 0.20 (95% CI 0.02 – 1.79), ARR was 0.22 (95% CI -0.01 – 0.44) and NNT was 5. No IRR were found for second or further doses in any patient and no risk factors were found.Conclusion and RelevanceIn our experience, iIRR observed for isatuximab was lower compared to pivotal clinical trials. The inclusion of montelukast as premedication might reduce IRR, which should be confirmed in subsequent studies.References and/or AcknowledgementsConflict of InterestNo conflict of interest.
Background and ImportanceElexacaftor/tezacaftor/ivacaftor (ETI) are bringing about a major change in the treatment of cystic fibrosis (CF) patients. However, continuing with other treatments such as ...nebulised antibiotics is necessary.Aim and ObjectivesTo assess the adherence to inhaled antibiotics before and after starting ETI. Secondary objectives: To assess effectiveness of ETI.Material and MethodsObservational, retrospective study carried out between March 2023 and September 2023, including patients who started with ETI before September 2022, 12 years of age or older when they started, and treated with at least one nebulised antibiotic.Variables: age, sex, change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV1) at month 12, difference in rate of pulmonary exacerbations 1 year before and after starting ETI, difference in Medication Possession Ratio (MPR) to nebulised antibiotics 1 year before and after starting ETI and MPR to ETI for 12 months.Data were collected from electronic medical records and pharmacy dispensing programs.A statistical analysis was performed using dependent samples t-test with IBM SPSS Statistics v21.0.The study was approved by Ethics Committee of the hospital.ResultsIn total, 33 patients were included, 21/33 (63.6%) were female. The mean age was 28.1 (±12.5). 14/33 (42.4%) patients had been previously treated with tezacaftor/ivacaftor.Percentage of predicted FEV1 was 17.8% higher (95% CI 11.8–23.7) at 12 months. Rate of pulmonary exacerbations was 70.2% lower (95% CI 43.3–97.2) and rate of severe pulmonary exacerbations was 86.1% lower (95% CI 43,2–128,9) 12 months after starting ETI. MPR to nebulised antibiotics was 22% lower (95% IC 7,5–36,5) 12 months after starting ETI. (P<0,001 for all comparisons). MPR to ETI was 89,7% (±18,5).Conclusion and RelevanceThe introduction of ETI to CF treatment has been a hopeful advance. ETI has shown a good efficacy in our population. However, the adherence to nebulised antibiotics decreased significantly. More studies are needed to evaluate the safety of withdrawing nebulised therapies post-ETI. A strategy to improve adherence in patients with CF has been initiated in collaboration with the CF unit of our hospital.References and/or Acknowledgements1. Song JT, et al. Research letter: The impact of elexacaftor/tezacaftor/ivacaftor on adherence to nebulised maintenance therapies in people with cystic fibrosis. J Cyst Fibros 2022;21:1080–1Conflict of InterestNo conflict of interest.
Background and ImportanceAcute kidney injury (AKI) is a highly prevalent condition among inpatients, usually attributed to pharmacological causes. One of the most clinically relevant drug-drug ...interactions (DDI) in this context is the triple whammy interaction (TWI), caused by the addition of three potential nephrotoxic groups of drugs: Non-steroidal anti-inflammatory drugs (NSAIDs), diuretics and ACE inhibitors/angiotensin receptor blockers (ARB).Aim and ObjectivesTo evaluate clinical significance of the TWI, as well as the role of pharmaceutical intervention (PI) in preventing possible adverse events due to this DDI.Material and MethodsObservational retrospective study that included patients who were prescribed the TWI over a period of 4 years (2018 to 2022). Data were collected using computerised medical records, nurse administration registry and PI data base. ICU patients were excluded from this study. Recommendation of monitoring serum creatinine and potassium, as well as discontinuing the triple therapy was carried out in all patients. Incidence of AKI was calculated according to AKIN criteria. Impact of PI was estimated based on average number of days patients received the combination and amount of time until complete resolution of AKI.Results34 patients were included and stratified according to their risk factors for developing AKI. 87,5% patients were considered at high risk. The first cause of admission was surgery in 62% of cases. Mean basal SCr was 0,99 (CI 95% 0,82–1,15). Acceptance of PI rate was estimated in 65,62%. Incidence of AKI was 29,4% (10/34), 8 of which were classified as AKIN 1. Mean duration of the triple therapy was 6,81 days (CI 95% = 3,47-10,15) in non-accepted PI group vs 3,17 days (CI 95% = 2,23-4,11) in the accepted PI group. AKI was detected more frequently in accepted PI patients (7/10). However, these patients recovered normal renal function faster than patients with no approved PI: 10 days (CI 95% = 5,41-14,58) vs 14,33 days (CI 95% = 8,52 – 20,14), respectively.Conclusion and RelevanceThe TWI can participate in acute kidney injury, particularly in high risk patients. Clinical pharmacists play an important role detecting patients at increased risk of AKI, preventing adverse events due to TW interaction, monitoring AKI biomarkers and recommending deprescription of possible nephrotoxic drugs.References and/or AcknowledgementsConflict of InterestNo conflict of interest
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