Antitumor activity of lurbinectedin (PM01183) and doxorubicin in relapsed small-cell lung cancer: results from a phase I study.

BACKGROUND: 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 AND METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Impact of pharmaceutical validation on prescribing errors in a neonatal intensive care unit. Randomised and controlled study.

Purpose: To compare the frequency of electronic prescription errors when the prescription was validated by the clinical pharmacist vs. when it was not. Methods: 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. Results: In total, 240 patients were included in this study. Sixty-two patients were allocated to the pre-intervention (n = 38) or post-intervention (n = 24) groups, and 178 patients were randomly sorted into two groups, control (n = 82 newborns) and intervention (n = 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; p < 0.001). Similarly, prescription errors reaching the patient were significantly reduced from 40% (n = 108) in the control group to 1.6% (n = 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% (p = 0.005). Conclusions: 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.

First-in-man phase I trial of two schedules of the novel synthetic tetrahydroisoquinoline alkaloid PM00104 (Zalypsis) in patients with advanced solid tumours.

BACKGROUND: 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. METHODS: Patients with advanced solid tumours received PM00104 in a dose escalation trial, as guided by toxicity and PK data. RESULTS: 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. CONCLUSION: 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.

Antitumor activity of lurbinectedin in combination with oral capecitabine in patients with metastatic breast cancer.

BACKGROUND: 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 AND METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Lurbinectedin, a selective inhibitor of oncogenic transcription, in patients with pretreated germline BRCA1/2 metastatic breast cancer: results from a phase II basket study.

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

A phase I pharmacokinetic study of PM00104 (Zalypsis) administered as a 24-h intravenous infusion every 3 weeks in patients with advanced solid tumors.

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.