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The lung microbiota is a complex community of microorganisms that colonize the respiratory tract of individuals from, or even before, birth. Although the lungs were traditionally believed to be sterile, recent research has shown that there is a diversity of bacterial species in the respiratory system. Knowledge about the lung microbiota in newborns and its relationship with bacterial infections is of vital importance to understand the pathogenesis of respiratory diseases in neonatal patients undergoing mechanical ventilation. In this article, the current evidence on the composition of the lung microbiota in newborns will be reviewed, as well as the risks that an altered microbiota can impose on premature newborns. Although advances in neonatal intensive care units have significantly improved the survival rate of preterm infants, the diagnosis and treatment of ventilator-associated pneumonia has not progressed in recent decades. Avoiding dysbiosis caused by inappropriate use of antibiotics around birth, as well as avoiding intubation of patients or promoting early removal of endotracheal tubes, are among the most important preventive measures for ventilator-associated pneumonia. The potential benefit of probiotics and prebiotics in preventing infectious, allergic or metabolic complications in the short or long term is not clearly established and constitutes a very important field of research in perinatal medicine.

Objective: To evaluate the efficiency of the sepsis risk calculator and the serial clinical observation in the management of late preterm and term newborns with infectious risk factors., Method: Single-center, observational, two-phase cohort study comparing the rates of neonates born ≥35 weeks' gestation, ≥2000 g birthweight, and without major congenital anomalies, who were screened and/or received antibiotics for early-onset neonatal sepsis risk at our center during two periods, before (January/2018-June/2019) and after (July/2019-December/2020) the implementation of the sepsis risk calculator., Results: A total of 1796 (Period 1) and 1867 (Period 2) patients with infectious risk factors were included. During the second period, tests to rule out sepsis were reduced by 34.0 % (RR, 95 %CI): 0.66 (0.61, 0.71), blood cultures by 13.1 %: 0.87 (0.77, 0.98), hospital admissions by 13.5 %: 0.86 (0.76, 0.98) and antibiotic administration by 45.9 %: 0.54 (0.47, 0.63). Three cases of early-onset neonatal sepsis occurred in the first period and two in the second. Clinical serial evaluation would have detected all true cases., Conclusions: The implementation of a sepsis risk calculator in the management of newborns ≥35 weeks GA, ≥2000 g birthweight, without major congenital anomalies, with infectious risk factors is safe and adequate to reduce laboratory tests, blood cultures, hospital admissions, and antibiotics administration. Serial clinical observation, in addition, could be instrumental to achieve or even improve this goal., Competing Interests: Conflicts of interest No financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article., (Copyright © 2023 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

Background: The endocardium is a crucial signaling center for cardiac valve development and maturation. Genetic analysis has identified several human endocardial genes whose inactivation leads to bicuspid aortic valve formation and calcific aortic valve disease, but knowledge is very limited about the role played in valve development and disease by noncoding endocardial regulatory regions and upstream factors., Methods: We manipulated Notch signaling in mouse embryonic endocardial cells by short-term and long-term coculture with OP9 stromal cells expressing Notch ligands and inhibition of Notch activity. We examined the transcriptional profile and chromatin accessibility landscape for each condition, integrated transcriptomic, transcription factor occupancy, chromatin accessibility, and proteomic datasets. We generated in vitro and in vivo models with CRISPR-Cas9-edited deletions of various noncoding regulatory elements and validated their regulatory potential., Results: We identified primary and secondary transcriptional responses to Notch ligands in the mouse embryonic endocardium, and a NOTCH-dependent transcriptional signature in valve development and disease. By defining the changes in the chromatin accessibility landscape and integrating with the landscape in developing mouse endocardium and adult human valves, we identify potential noncoding regulatory elements, validated selected candidates, propose interacting cofactors, and define the timeframe of their regulatory activity. Additionally, we found cooperative transcriptional repression with Hippo pathway by inhibiting nuclear Yap (Yes-associated protein) activity in the endocardium during cardiac valve development., Conclusions: Sequential Notch-dependent transcriptional regulation in the embryonic endocardium involves multiple factors. Notch activates certain noncoding elements through these factors and simultaneously suppresses elements that could hinder cardiac valve development and homeostasis. Biorxviv: https://www.biorxiv.org/content/10.1101/2023.03.23.533882v1.full., Competing Interests: Disclosures None.

Second-line treatment of endometrial cancer is an unmet medical need. Lurbinectedin showed promising antitumor activity in a phase I study in combination with doxorubicin in advanced endometrial cancer. This phase 2 Basket trial evaluated lurbinectedin 3.2 mg/m 2 1-h intravenous infusion every 3 weeks in a cohort of 73 patients with pretreated endometrial cancer. The primary 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), safety and an exploratory translational study. Confirmed complete (CR) and partial response (PR) was reported in two and six patients, respectively (ORR = 11.3%; 95%CI, 5.0-21.0%). Median DoR was 9.2 months (95%CI, 3.4-18.0 months), median PFS was 2.6 months (95%CI, 1.4-4.0 months) and median OS was 9.3 months (95%CI, 6.1-12.8 months). Molecular subtypes showed differences in PFS rate at 6 months (p53abn 23.7% vs. "No Specific Molecular Profile" [NSMP] 42.9%) and median OS (p53abn 6.6 months vs. NSMP 16.1 months). The most common treatment-related adverse events (mostly grade 1/2) were fatigue (54.8% of patients), nausea (50.7%), vomiting (26.0%) decreased appetite (17.8%). and constipation, (19.2%). The most common grade 3/4 toxicity was neutropenia (43.8%; grade 4, 19.2%; febrile neutropenia, 4.1%). In conclusion, considering the exploratory aim of this trial and the hints of antitumor activity observed together with a predictable and manageable safety profile, further biomarker-based development of lurbinectedin is recommended in this indication in combination with other agents. Clinicaltrials.gov identifier: NCT02454972., (© 2023. The Author(s).)

Importance: Nonsyndromic bicuspid aortic valve (nsBAV) is the most common congenital heart valve malformation. BAV has a heritable component, yet only a few causative genes have been identified; understanding BAV genetics is a key point in developing personalized medicine., Objective: To identify a new gene for nsBAV., Design, Setting, and Participants: This was a comprehensive, multicenter, genetic association study based on candidate gene prioritization in a familial cohort followed by rare and common association studies in replication cohorts. Further validation was done using in vivo mice models. Study data were analyzed from October 2019 to October 2022. Three cohorts of patients with BAV were included in the study: (1) the discovery cohort was a large cohort of inherited cases from 29 pedigrees of French and Israeli origin; (2) the replication cohort 1 for rare variants included unrelated sporadic cases from various European ancestries; and (3) replication cohort 2 was a second validation cohort for common variants in unrelated sporadic cases from Europe and the US., Main Outcomes and Measures: To identify a candidate gene for nsBAV through analysis of familial cases exome sequencing and gene prioritization tools. Replication cohort 1 was searched for rare and predicted deleterious variants and genetic association. Replication cohort 2 was used to investigate the association of common variants with BAV., Results: A total of 938 patients with BAV were included in this study: 69 (7.4%) in the discovery cohort, 417 (44.5%) in replication cohort 1, and 452 (48.2%) in replication cohort 2. A novel human nsBAV gene, MINDBOMB1 homologue MIB1, was identified. MINDBOMB1 homologue (MIB1) is an E3-ubiquitin ligase essential for NOTCH-signal activation during heart development. In approximately 2% of nsBAV index cases from the discovery and replication 1 cohorts, rare MIB1 variants were detected, predicted to be damaging, and were significantly enriched compared with population-based controls (2% cases vs 0.9% controls; P = .03). In replication cohort 2, MIB1 risk haplotypes significantly associated with nsBAV were identified (permutation test, 1000 repeats; P = .02). Two genetically modified mice models carrying Mib1 variants identified in our cohort showed BAV on a NOTCH1-sensitized genetic background., Conclusions and Relevance: This genetic association study identified the MIB1 gene as associated with nsBAV. This underscores the crucial role of the NOTCH pathway in the pathophysiology of BAV and its potential as a target for future diagnostic and therapeutic intervention.

Background: The complex genetics underlying human cardiac disease is evidenced by its heterogenous manifestation, multigenic basis, and sporadic occurrence. These features have hampered disease modeling and mechanistic understanding. Here, we show that 2 structural cardiac diseases, left ventricular noncompaction (LVNC) and bicuspid aortic valve, can be caused by a set of inherited heterozygous gene mutations affecting the NOTCH ligand regulator MIB1 (MINDBOMB1) and cosegregating genes., Methods: We used CRISPR-Cas9 gene editing to generate mice harboring a nonsense or a missense MIB1 mutation that are both found in LVNC families. We also generated mice separately carrying these MIB1 mutations plus 5 additional cosegregating variants in the ASXL3 , APCDD1 , TMX3, CEP192 , and BCL7A genes identified in these LVNC families by whole exome sequencing. Histological, developmental, and functional analyses of these mouse models were carried out by echocardiography and cardiac magnetic resonance imaging, together with gene expression profiling by RNA sequencing of both selected engineered mouse models and human induced pluripotent stem cell-derived cardiomyocytes. Potential biochemical interactions were assayed in vitro by coimmunoprecipitation and Western blot., Results: Mice homozygous for the MIB1 nonsense mutation did not survive, and the mutation caused LVNC only in heteroallelic combination with a conditional allele inactivated in the myocardium. The heterozygous MIB1 missense allele leads to bicuspid aortic valve in a NOTCH-sensitized genetic background. These data suggest that development of LVNC is influenced by genetic modifiers present in affected families, whereas valve defects are highly sensitive to NOTCH haploinsufficiency. Whole exome sequencing of LVNC families revealed single-nucleotide gene variants of ASXL3 , APCDD1 , TMX3, CEP192 , and BCL7A cosegregating with the MIB1 mutations and LVNC. In experiments with mice harboring the orthologous variants on the corresponding Mib1 backgrounds, triple heterozygous Mib1 Apcdd1 Asxl3 mice showed LVNC, whereas quadruple heterozygous Mib1 Cep192 Tmx3;Bcl7a mice developed bicuspid aortic valve and other valve-associated defects. Biochemical analysis suggested interactions between CEP192, BCL7A, and NOTCH. Gene expression profiling of mutant mouse hearts and human induced pluripotent stem cell-derived cardiomyocytes revealed increased cardiomyocyte proliferation and defective morphological and metabolic maturation., Conclusions: These findings reveal a shared genetic substrate underlying LVNC and bicuspid aortic valve in which MIB1-NOTCH variants plays a crucial role in heterozygous combination with cosegregating genetic modifiers.

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/m 2 daily on D1-D14 plus lurbinectedin 2.2 mg/m 2 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., Competing Interests: Disclosure VB reports employment as Director of Clinical Cancer Research, NEXT Madrid, Universitary Hospital QuirónSalud Pozuelo; institutional financial support for clinical trials from Abbvie, ACEO, Adaptaimmune, Amcure, AMGEN, Amunix, AstraZeneca, BMS Cytomx, GSK, Genentech/Roche, H3, Incyte, Janssen, Kura, Lilly, Loxo, Nektar, Macrogenics, Menarini, Merck, Merus, Nanobiotix, Novartis, Pfizer, PharmaMar, Principia, PUMA, Sanofi, Taiho, Tesaro, BeiGene, Transgene, Takeda, Incyte, Innovio, MSD, PsiOxus, Seattle Genetics, Mersana, Daiichi, Nektar, Astellas, ORCA, Boston Therapeutics, Dynavax, DebioPharm, Boehringer Ingelheim, Regeneron, Millennium, Synthon, Spectrum, Rigontec and Zenith; advisory board/consultant position with Puma Biotechnology, Ideaya Biosciences, Loxo Therapeutics, CytomX Therapeutics, Guidepoint, Oncoart and IDMC Nanobiotix NANORAY-312; honoraria (for speaking) from Eli Lilly and MSD; and travel/inscription/accommodation from Bayer (ESMO GI), all outside the submitted work. PA reports non-financial support from MSD, Roche, Pfizer and Amgen; and personal fees from Boehringer Ingelheim, Macrogenics, Amcure, Synthon, Servier, G1 Therapeutics, Roche, Novartis, Amgen, Radius, Deloitte, Menarini and Gilead, all outside the submitted work. CK reports personal fees for salary as full-time employee and stock ownership from Pharma Mar, outside the submitted work. XELE, MS and MCY report personal fees for salary as full-time employees from Pharma Mar, outside the submitted work. CFT was an employee of Pharma Mar at the time the study was carried out. JT reports scientific consultant position with Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Scandion Oncology, Servier, Sotio Biotech, Taiho, Tessa Therapeutics and TheraMyc; and educational collaboration with Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER), all outside the submitted work. All other authors have declared no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Lurbinectedin and paclitaxel showed synergism in preclinical studies and have non-completely overlapping toxicity profiles. This phase I trial evaluated a combination of paclitaxel and lurbinectedin with/without bevacizumab in advanced tumors. This trial was divided into Group A, which evaluated weekly paclitaxel (60 or 80 mg) plus lurbinectedin (3.0-5.0 mg flat dose [FD] or 2.2 mg/m 2 ) every 3 weeks in advanced solid tumors; and Group B, which evaluated bevacizumab (BEV, 15 mg/kg) added to the recommended dose (RD) defined in Group A in advanced epithelial ovarian or non-small cell lung cancer (NSCLC). 67 patients (A, n = 55; B, n = 12) were treated. The RD was paclitaxel 80 mg/m 2 on Day (D)1,D8 plus lurbinectedin 2.2 mg/m 2 on D1. At this RD, myelotoxicity was reversible and manageable, and most non-hematological toxicities were mild/moderate. Adding BEV did not notably change tolerability. Twenty-five confirmed responses were observed: 20/51 evaluable patients in Group A (overall response rate [ORR] = 39% at all dose levels and at the RD), and 5/10 evaluable patients in Group B (ORR = 50%). Most responders had breast (n = 7/12 patients), small cell lung (SCLC) (n = 5/7), epithelial ovarian (n = 3/9) and endometrial cancer (n = 3/11) in Group A, and epithelial ovarian (n = 3/4) and NSCLC (n = 2/6) in Group B. Clinical benefit rate was 61% in Group A (58% at the RD), and 90% in Group B. No major pharmacokinetic drug-drug interactions were observed. Paclitaxel/lurbinectedin and paclitaxel/lurbinectedin/BEV are feasible combinations. Further development is warranted of paclitaxel/lurbinectedin in SCLC, breast, and endometrial cancer, and of paclitaxel/lurbinectedin/BEV in epithelial ovarian cancer., (© 2022. The Author(s).)

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/m 2 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., Competing Interests: Disclosure VB received grants as consultant or advisory role from Puma Biotechnology, Ideaya Biosciences, Loxo Therapeutics, CytomX Therapeutics, Guidepoint, Oncoart; honoraria as speaker from Eli Lilly; and institutional financial support for clinical trials from AbbVie, ACEO, Adaptaimmune, Amcure, AMGEN, AstraZeneca, BMS Cytomx, GSK, Genentech/Roche, H3, Incyte, Janssen, Kura, Lilly, Loxo, Nektar, Macrogenics, Menarini, Merck, Merus, Nanobiotix, Novartis, Pfizer, PharmaMar, Principia, PUMA, Sanofi, Taiho, Tesaro, BeiGene, Transgene, Takeda, Incyte, Innovio, MSD, PsiOxus, Seattle Genetics, Mersana, GSK, Daiichi, Nektar, Astellas, ORCA, Boston Therapeutics, Dynavax, DebioPharm, Boehringer Ingelheim, Regeneron, Millennium, Synthon, Spectrum, Rigontec, and Zenith. BP received consulting fees from AstraZeneca and Pfizer for her institution and from Myriad and Pierre Fabre for herself; payment or honoraria for lectures, presentations, speakers bureaus or educational events from Daiichi-Sankyo, Novartis and Puma; support for attending meetings and/or travel from AstraZeneca, Pierre Fabre and MSD; and participation on a Data Safety Monitoring Board or Advisory Board from Novartis, Astra Zeneca and Daiichi-Sankyo. VM received grants or contracts as principal investigator or institutional funding from AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer Beigene BioInvent International AB, BMS, Boehringer, Boheringer, Boston, Celgene, Daichii Sankyo, DEBIOPHARM,Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics and Upshersmith; consulting fees from Roche, Bayer, BMS, and Janssen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, Bayer, BMS; and participation on a Data Safety Monitoring Board or Advisory Board from Basilea. CF, CK, VA, MS and AZ have personal fees for salary as full time employees from PharmaMar S.A. CF, CK, VA and AZ are stock ownership of PharmaMar S.A. FL received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, and support for attending meetings and/or travel, and participation on a Data Safety Monitoring Board or Advisory Board from Roche, Merck, Amgen, Lilly, Servier, MSD, BMS and Sanofi. AA received consulting fees from Gilead, Lilly and Seagen; payment for expert testimony from Pfizer; and leadership or fiduciary role in ECO Foundation. VS received grants from PharmaMar, Eli Lilly/LOXO Oncology, Blueprint Medicines Corporation, Turning Point Therapeutics and Boston Pharmaceuticals; and grants from Helsinn Pharmaceuticals during the conduct of the study; in addition, VS received a grant and advisory board/consultant position with Eli Lilly/Loxo Oncology during the conduct of the study; research grants from Roche/Genentech, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, D3, Pfizer, Multivir, Amgen, AbbVie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Altum, Dragonfly Therapeutics, Takeda, National Comprehensive Cancer Network, NCI-CTEP, University of Texas MD Anderson Cancer Center, Turning Point Therapeutics, Boston Pharmaceuticals, Novartis, PharmaMar and Medimmune; an advisory board/consultant position with Helsinn, Incyte, QED Pharma, Daiichi-Sankyo, Signant Health, Novartis, Relay therapeutics, Roche and Medimmune; travel funds from PharmaMar, Incyte, ASCO, ESMO; and other support from Medscape, all outside the submitted work. All other authors have declared no conflicts of interest. Data Sharing Individual participant data are not publicly available since this requirement was not anticipated in the study protocol considering that this trial started patient enrollment in 2015. Clinical trial summary results were placed in the European Clinical Trials Database (EudraCT; https://eudract.ema.europa.eu; study 2014-003773-42) and ClinicalTrials.gov (identifier: NCT02454972)., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Patients with neuroendocrine tumours (NETs) need alternative therapies after failure of first-line therapy., Patients and Methods: This phase II trial evaluated lurbinectedin, a selective inhibitor of oncogenic transcription, at 3.2 mg/m 2 as a 1-h intravenous infusion every 3 weeks in 32 NETs patients treated in the second- or third-line setting. The primary efficacy endpoint was overall response rate (ORR) according to RECIST v1.1 assessed by the investigators. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety., Results: Two of 31 evaluable patients had confirmed partial responses (ORR = 6.5%; 95%CI, 0.8-21.4%). Median DoR was 4.7 months (95% CI, 4.0-5.4 months), median PFS was 1.4 months (95% CI, 1.2-3.0 months) and median OS was 7.4 months (95% CI, 3.4-16.2 months). Lurbinectedin showed an acceptable, predictable and manageable safety profile. The most common grade 3/4 toxicity was neutropenia (40.6%; grade 4, 12.4%; febrile neutropenia, 3.1%)., Conclusions: Considering the exploratory aim of this trial that evaluated a heterogeneous population of NETs patients, and the signs of antitumour activity observed (two confirmed partial responses and seven long disease stabilisations), further development of lurbinectedin is warranted in a more selected NETs population., Trial Registration Number: Sponsor Study Code: PM1183-B-005-14. EudraCT number: 2014-003773-42., Clinicaltrials: gov reference: NCT02454972., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Cristian Fernández, Carmen Kahatt, Vicente Alfaro, Mariano Siguero and Ali Zeaiter are permanent employees of PharmaMar. Victor Moreno reports consulting fees from Roche, Bayer, BMS, Janssen and Basilea. Vivek Subbiah reports grants from Pharmamar, Eli Lilly/LOXO Oncology, Blueprint Medicines Corporation, Turning Point Therapeutics, Boston Pharmaceuticals; and grants from Helsinn Pharmaceuticals during the conduct of the study; in addition, Vivek Subbiah reports a grant and advisory board/consultant position with Eli Lilly/Loxo Oncology during the conduct of the study; research grants from Roche/Genentech, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Altum, Dragonfly Therapeutics, Takeda, National Comprehensive Cancer Network, NCI-CTEP, University of Texas MD Anderson Cancer Center, Turning Point Therapeutics, Boston Pharmaceuticals, Novartis, Pharmamar, Medimmune; an advisory board/consultant position with Helsinn, Incyte, QED Pharma, Daiichi-Sankyo, Signant Health, Novartis, Janssen, Relay Therapeutics, Roche, Medimmune; travel funds from Pharmamar, Incyte, ASCO, ESMO; other support from Medscape; all outside the submitted work. No disclosures were reported by the other authors., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Lurbinectedin suppresses the oncogenic transcription factor EWS-FLI1 through relocalization to the nucleolus, and delays tumor growth in mice bearing Ewing sarcoma xenografts. On the basis of this rationale, lurbinectedin was evaluated in patients with relapsed Ewing sarcoma., Patients and Methods: This open-label, single-arm, Basket phase II trial included a cohort of 28 treated adult patients with confirmed Ewing sarcoma, measurable disease as per Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1, Eastern Cooperative Oncology Group performance status ≤2, adequate organ function, no central nervous system metastasis, and pretreated with ≤2 chemotherapy lines for metastatic/recurrent disease. Patients received lurbinectedin 3.2 mg/m2 as a 1-hour infusion every 3 weeks. Primary endpoint was overall response rate (ORR) as per RECIST v.1.1. Secondary endpoints included time-to-event parameters and safety profile., Results: ORR was 14.3% [95% confidence interval (CI), 4.0%-32.7%], with median duration of response of 4.2 months (95% CI, 2.9-5.5 months). Median progression-free survival was 2.7 months (95% CI, 1.4-4.3 months), clinical benefit rate was 39.3%, and disease control rate was 57.1%. With 39% censoring, median overall survival was 12.0 months (95% CI, 8.5-18.5 months). Most common grade 3/4 adverse events were neutropenia (57%), anemia, thrombocytopenia, and treatment-related febrile neutropenia (14% each). No deaths or discontinuations were due to toxicity., Conclusions: Lurbinectedin was active in the treatment of relapsed Ewing sarcoma and had a manageable safety profile. Lurbinectedin could represent a valuable addition to therapies for Ewing sarcoma, and is currently being evaluated in combination with irinotecan in advanced Ewing sarcoma in a phase Ib/II trial., (©2022 The Authors; Published by the American Association for Cancer Research.)

Mutations in the G protein–coupled receptor GPR126/ADGRG6 cause human diseases, including defective peripheral nervous system (PNS) myelination. To study GPR126 function, we generated new genetic mice and zebrafish models. Murine Gpr126 is expressed in developing heart endocardium, and global Gpr126 inactivation is embryonically lethal, with mutants having thin-walled ventricles but unaffected heart patterning or maturation. Endocardial-specific Gpr126 deletion does not affect heart development or function, and transgenic endocardial GPR126 expression fails to rescue lethality in Gpr126 -null mice. Zebrafish gpr126 mutants display unaffected heart development. Gpr126 is also expressed in placental trophoblast giant cells. Gpr126 -null mice with a heterozygous placenta survive but exhibit GPR126-defective PNS phenotype. In contrast, Gpr126 -null embryos with homozygous mutant placenta die but are rescued by placental GPR126 expression. Gpr126 -deficient placentas display down-regulation of preeclampsia markers Mmp9 , Cts7 , and Cts8 . We propose that the placenta-heart axis accounts for heart abnormalities secondary to placental defects in Gpr126 mutants.

Objective: Second-line treatment of endometrial cancer is an unmet medical need. We conducted a phase I study evaluating lurbinectedin and doxorubicin intravenously every 3 weeks in patients with solid tumors. The aim of this study was to characterise the efficacy and safety of lurbinectedin and doxorubicin for patients with endometrial cancer., Methods: Thirty-four patients were treated: 15 patients in the escalation phase (doxorubicin 50 mg/m 2 and lurbinectedin 3.0-5.0 mg) and 19 patients in the expansion cohort (doxorubicin 40 mg/m 2 and lurbinectedin 2.0 mg/m 2 ). All histological subtypes were eligible and patients had received one to two prior lines of chemotherapy for advanced disease. Antitumor activity was evaluated every two cycles according to the Response Evaluation Criteria in Solid Tumors version 1.1. Adverse events were graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4., Results: Median age (range) was 65 (51-78) years. Eastern Cooperative Oncology Group performance status was up to 1 in 97% of patients. In the escalation phase, 4 (26.7%) of 15 patients had confirmed response: two complete and two partial responses (95% CI 7.8% to 55.1%). Median duration of response was 19.5 months. Median progression-free survival was 7.3 (2.5 to 10.1) months. In the expansion cohort, confirmed partial response was reported in 8 (42.1%) of 19 patients (95% CI 20.3% to 66.5%). Median duration of response was 7.5 (6.4 to not reached) months, median progression-free survival was 7.7 (2.0 to 16.7) months and median overall survival was 14.2 (4.5 to not reached) months. Fatigue (26.3% of patients), and transient and reversible myelosuppression (neutropenia, 78.9%; febrile neutropenia, 21.1%; thrombocytopenia, 15.8%) were the main grade 3 and higher toxicities in the expanded cohort., Conclusions: In patients with recurrent advanced endometrial cancer treated with doxorubicin and lurbinectedin, response rates (42%) and duration of response (7.5 months) were favorable. Further evaluation of doxorubicin and lurbinectedin is warranted in this patient population., Competing Interests: Competing interests: RK reports personal fees from Eisai. GSK, Clovis, Basilea, AstraZeneca, Roche, InCyte, and PharmaMar; non-financial support from GSK, Clovis, Basilea, AstraZeneca and Roche; and a grant from Clovis, outside the submitted work. VM reports personal fees and other (travelling support, speaker’s bureau) from Bayer, BMS, Pieris, Roche, Janssen, Regeneron/Sanofi and Nanobiotix, and a grant from Medscape/Bayer, outside the submitted work. VB reports personal fees from Oncoart, Guidepoint, PUMA, Cytomx, Loxo Therapeutics, and institutional financial support for clinical trials from Abbvie, ACEO, Adaptaimmune, Amcure, AMGEN, AstraZeneca, BMS Cytomx, GSK, Genentech/Roche, H3, Incyte, Janssen, Kura, Lilly, Loxo, Nektar, Macrogenics, Menarini, Merck, Merus, Nanobiotix, Novartis, Pfizer, PharmaMar, Principia, PUMA, Sanofi, Taiho, Tesaro, BeiGene, Transgene, Takeda, Incyte, Innovio, MSD, PsiOxus, Seattle Genetics; Mersana; GSK; Daiichi; Nektar; Astellas; ORCA; Boston Therapeutics; Dynavax, DebioPharm, Boehringer Ingelheim, Regeneron, Millennium, Synthon, Spectrum, Rigontec, and Zenith, outside the submitted work. EMG reports advisory/consultancy honorariums from AstraZeneca-MSD, Clovis Oncology, GSK-Tesaro, PharmaMar and Roche; she has received speaker bureau/expert testimony honorariums from AstraZeneca, PharmaMar, Roche and GSK; and has received travel/accommodation/expenses from Roche, Tesaro: A GSK Company and Baxter. IR reports personal fees and non-financial support from Pharmamar; grants, personal fees and non-financial support from Roche; personal fees from Clovis; personal fees from GSK; and grants, personal fees and non-financial support from AstraZeneca, outside the submitted work. EC reports grants and personal fees from Astellas, Novartis, Nanobiotix, Pfizer, Janssen-Cilag, PsiOxus Therapeutics, Merck, BMS, Seattle Genetics, Boehringer Ingelheim, AstraZeneca, Roche/Genentech, Servier, Celgene, Abbvie, Amcure, Alkermes, PharmaMar, BeiGene and GLG; personal fees from Medscape, Gilead, Pierre Fabre, Cerulean Pharma, EUSA, Gerhmann Consulting, Guidepoint, OncoDNA; and grants from ACEO, Adaptaimmune, AMGEN, Cytomx, GSK, H3, Incyte, Kura, Lilly, Nektar, Loxo, Macrogenics, Menarini, Merus, Principia, PUMA, Sanofi, Taiho, Tesaro, Transgene, Takeda, Innovio, MSD, Mersana, Daiichi, ORCA, Boston Therapeutics, Dynavax, DebioPharm, Regeneron, Millenium, Synthon, Spectrum and Rigontec, outside the submitted work. NB reports personal fees and non-financial support from BMS and Merck Serono, and personal fees from AstraZeneca, BioNTech, Eisai and MSD, outside the submitted work. CK, JAL-V, MS, VA and AZ report grants from the Centro para el Desarrollo Tecnológico Industrial (CDTI) during the conduct of the study; and personal fees for salary as full time employee and stock ownership from Pharma Mar, outside the submitted work. MF reports grants from Merck Educational Grant for EACH study, grants from MSD Educational Grant for POPPY study, grants from Boehringer Ingelheim Educational Grant for DARWIN1 study, grants from AstraZeneca Educational Grant for ORCA2 study, personal fees from Achilles Advisory and Consultancy Work, personal fees from AstraZeneca Advisory and Consultancy Work, personal fees from BMS Advisory and Consultancy Work, personal fees from Merck Advisory and Consultancy Work, personal fees from MSD Advisory and Consultancy Work, personal fees from Nanobiotix Advisory and Consultancy Work, personal fees from Novartis Advisory and Consultancy Work, personal fees from Pfizer Advisory and Consultancy Work, personal fees from Pharmamar Advisory and Consultancy Work, personal fees from Roche Advisory and Consultancy Work, personal fees from Takeda Advisory and Consultancy Work, personal fees from Bayer Advisory and Consultancy Work, outside the submitted work., (© IGCS and ESGO 2021. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Introduction: The National Comprehensive Cancer Network guidelines recommend re-challenge with the first-line treatment for relapsed small cell lung cancer (SCLC) with chemotherapy-free interval (CTFI)≥180 days. A phase II study (NCT02454972) showed remarkable antitumor activity in SCLC patients treated with lurbinectedin 3.2 mg/m 2 1 -h intravenous infusion every 3 weeks as second-line therapy. We report results for the pre-planned subset of patients with CTFI ≥ 180 days., Material and Methods: Twenty patients aged ≥18 years with pathologically proven SCLC diagnosis, pretreated with only one prior platinum-containing line, no CNS metastases, and with CTFI ≥ 180 days were evaluated. The primary efficacy endpoint was the overall response rate (ORR) assessed by the Investigators according to RECIST v1.1., Results: ORR was 60.0 % (95 %CI, 36.1-86.9), with a median duration of response of 5.5 months (95 %CI, 2.9-11.2) and disease control rate of 95.0 % (95 %CI, 75.1-99.9). Median progression-free survival was 4.6 months (95 %CI, 2.6-7.3). With a censoring of 55.0 %, the median overall survival was 16.2 months (95 %CI, 9.6-upper level not reached). Of note, 60.9 % and 27.1 % of patients were alive at 1 and 2 years, respectively. The most common grade 3/4 adverse events and laboratory abnormalities were hematological disorders (neutropenia, 55.0 %; anemia; 10.0 % thrombocytopenia, 10.0 %), fatigue (10.0 %) and increased liver function tests (GGT, 10 %; ALT and AP, 5.0 % each). No febrile neutropenia was reported., Conclusion: Lurbinectedin is an effective treatment for platinum-sensitive relapsed SCLC, especially in patients with CTFI ≥ 180 days, with acceptable safety and tolerability. These encouraging results suggest that lurbinectedin can be another valuable therapeutic option rather than platinum re-challenge., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Trabectedin is an FDA-approved DNA minor groove binder that has activity against translocation-associated sarcomas. Lurbinectedin is a next-generation minor groove binder with preclinical activity against myeloid leukemia cells. A dose-finding phase 1 clinical trial was performed in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with further assessment of safety and tolerability. Forty-two patients with relapsed/refractory AML/MDS received lurbinectedin administered as a 1-hour intravenous infusion in a 3 + 3 study design. Two dosing schedules were used: 3.5, 5, 7, or 6 mg on days 1 and 8 or 2, 3, 1, or 1.5 mg for 3 consecutive days on days 1 to 3. Three patients experienced dose-limiting toxicities of rhabdomyolysis (grade 4), hyperbilirubinemia (grade 3), and oral herpes (grade 3) with the day 1 and 8 schedule. Otherwise, adverse events mainly consisted of gastrointestinal manifestations (n = 11), febrile neutropenia/infections (n = 4), pulmonary toxicity (n = 2), and renal failure (n = 2). The most common laboratory abnormalities observed were an increase in creatinine (93%) and anemia, neutropenia, and thrombocytopenia (100%). Overall, 33 of 42 patients (79%) had reduction in blasts in peripheral blood or bone marrow. One patient achieved a partial response and 2 patients a morphologic leukemia-free state. Most (n = 30, 71%) were discontinued due to progressive disease. Early deaths occurred from disease-related causes that were not attributable to lurbinectedin. Four patients with a chromosome 11q21-23 abnormality had significantly greater bone marrow blast reduction than those without such abnormality, with decrease of 31 ± 14% (n = 4) vs 8 ± 8% (n = 16), respectively (P = .04). Overall, lurbinectedin was safe and tolerated using the schedules and dose levels tested. While no sustained remissions were observed, single-agent lurbinectedin was transiently leukemia suppressive for some patients., (© 2018 John Wiley & Sons, Ltd.)

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., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background To determine the recommended dose (RD) of a combination of PM01183 and gemcitabine in patients with advanced solid tumors. Methods Forty-five patients received escalating doses of PM01183/gemcitabine on Days 1 and 8 every 3 weeks (d1,8 q3wk) following a standard 3 + 3 design. Results PM01183 3.5 mg flat dose (FD)/gemcitabine 1000 mg/m 2 was the highest dose level tested. Dose-limiting toxicities (DLTs) were mostly hematological and resulted in the expansion of a lower dose level (PM01183 3.5 mg FD/gemcitabine 800 mg/m 2 ); 19 patients at this dose level were evaluable but >30% had DLT and >20% had febrile neutropenia. No DLT was observed in 11 patients treated at PM01183 3.0 mg FD/gemcitabine 800 mg/m 2 , which was defined as the RD. This regimen was feasible and tolerable with manageable toxicity; mainly grade 3/4 myelosuppression. Non-hematological toxicity comprised fatigue, nausea, vomiting, and transaminases increases. Fifteen (33%) patients received ≥6 cycles with no cumulative hematological toxicity. Pharmacokinetic analysis showed no evidence of drug-drug interaction. Nine of 38 patients had response as per RECIST (complete [3%] and partial [21%]), for an overall response rate (ORR) of 24% (95% Confidence Interval [CI] 12-40%). Eleven patients (29%) had disease stabilization ≥4 months. Responses were durable (median of 8.5 months): overall median progression-free survival (PFS) was 4.2 months (95% CI, 2.7-6.5 months). Conclusions The RD for this combination is PM01183 3.0 mg FD (or 1.6 mg/m 2 )/gemcitabine 800 mg/m 2 d1,8 q3wk. This schedule is well tolerated and has antitumor activity in several advanced solid tumor types.

This phase I trial determined the recommended dose for phase II trials (RD) of carboplatin 1-h intravenous (i.v.) infusion followed by PM00104 1-h i.v. infusion on Day 1 every 3 weeks (q3wk) in adult patients with advanced solid tumors. A toxicity-guided, dose-escalation design was used. Patients were stratified and divided into heavily (n = 6) or mildly pretreated (n = 14) groups. Transient grade 4 thrombocytopenia (in one heavily and three mildly pretreated patients) was the only dose-limiting toxicity (DLT) observed. Carboplatin AUC3-PM00104 2.0 mg/m(2) was the RD in both groups. At this RD, the carboplatin AUC was equal to ~60 % the target AUC used in other combinations, and the PM00104 dose intensity was 56-67 % of the value achieved at the RD for single-agent PM00104 given as 1-h infusion q3wk. Most treatment-related adverse events were grade 1/2. They mainly consisted of gastrointestinal and general symptoms, such as fatigue, anorexia, mucosal inflammation or nausea. Transient neutropenia (50 % of patients) and thrombocytopenia (33-38 %) were the most common severe hematological abnormalities; their incidence was higher than with single-agent PM00104. No pharmacokinetic drug-drug alterations occurred. Partial response was found in one patient with triple negative breast cancer pretreated with paclitaxel/bevacizumab. Three patients with colorectal cancer, head and neck cancer, and tumor of unknown origin had disease stabilization for ≥3 months. In conclusion, no optimal dose was reached due to overlapping myelosuppression despite stratification according to prior treatment. Therefore, this carboplatin plus PM00104 combination was not selected for further clinical research.

Purpose: Lurbinectedin (PM01183) binds covalently to DNA and has broad activity against tumor cell lines. This first-in-human phase I study evaluated dose-limiting toxicities (DLT) and defined a phase II recommended dose for PM01183 as a 1-hour intravenous infusion every three weeks (q3wk)., Experimental Design: Thirty-one patients with advanced solid tumors received escalating doses of PM01183 following an accelerated titration design., Results: PM01183 was safely escalated over 200-fold, from 0.02 to 5.0 mg/m(2). Dose doubling was utilized, requiring 15 patients and nine dose levels to identify DLT. The recommended dose was 4.0 mg/m(2), with one of 15 patients having DLT (grade 4 thrombocytopenia). Clearance was independent of body surface area; thus, a flat dose of 7.0 mg was used during expansion. Myelosuppression, mostly grade 4 neutropenia, occurred in 40% of patients but was transient and manageable, and none was febrile. All other toxicity was mild and fatigue, nausea and vomiting were the most common at the recommended dose. Pharmacokinetic parameters showed high interindividual variation, though linearity was observed. At or above the recommended dose, the myelosuppressive effect was significantly associated with the area under the concentration-time curve from time zero to infinity (white blood cells, P = 0.0007; absolute neutrophil count, P = 0.016). A partial response was observed in one patient with pancreatic adenocarcinoma at the recommended dose., Conclusion: A flat dose of 7.0 mg is the recommended dose for PM01183 as a 1-hour infusion q3wk. This dose is tolerated and active. Severe neutropenia occurred at this dose, although it was transient and with no clinical consequences in this study., (©2014 AACR.)

Purpose: This exploratory phase II clinical trial evaluated the antitumor activity, safety profile and pharmacokinetics of PM00104 (Zalypsis(®)) 3 mg/m(2) 1 h every 3-week intravenous infusion in patients with advanced and/or metastatic urothelial carcinoma progressing after first-line platinum-based chemotherapy., Methods: The primary efficacy end point was the disease control rate (DCR), defined as the percentage of patients with confirmed objective response or progression-free at 3 months, according to the response evaluation criteria in solid tumors., Results: In a first stage (n = 19 patients evaluable for efficacy), only one patient achieved DCR (stable disease as best response and progression-free survival of 3.1 months). According to the 2-stage design used, the primary efficacy objective was unmet, and therefore, the trial was finalized without opening the second stage. The most common adverse events related to PM00104 were fatigue, anorexia, nausea, troponin I increase and neutropenia, which were transient and manageable with dose modifications or administration delays. Mean PK results (Cmax = 48.57 μg/l and area under the curve (AUC) = 154.97 h μg/l) were similar to those observed in a previous phase I trial evaluating the same dose and schedule. Few troponin I concentrations were higher than 0.10 ng/ml, and none of them were related to parameters of PM00104 exposure such as AUC or Cmax., Conclusions: No recommendation is given for further evaluation of PM00104 as single-agent treatment of patients with pretreated advanced and/or metastatic urothelial carcinoma. No new safety signals were observed.

Ewing sarcoma is a rare connective tissue tumor characterized by the translocation of the EWS gene, mainly between chromosome 11 and 22, giving rise to gene re-arrangements between the EWS gene and various members of the ETS gene family. Multi-agent chemotherapy has improved the outcome for patients with localized Ewing sarcoma, but survival of patients with recurrent/metastatic disease remains poor. An exploratory two-stage, single-arm Phase II multicenter trial of the synthetic alkaloid, PM00104, was conducted in patients with recurrent Ewing sarcoma. The primary end point of the trial was objective response rate. PM00104 was administered at a dose of 2 mg/m(2) on Days 1, 8 and 15 of a 4 week cycle. Seventeen patients were recruited. No objective responses were reported in the 16 patients evaluable for efficacy. Recruitment was closed without proceeding to the second stage of the trial. Four patients achieved stable disease as best response, and in two of these patients the stabilization was longer than 4 months. The median progression-free survival was 1.8 months (95 % CI, 0.9-3.5 months) and median overall survival was not reached (95%CI, 56.2 % at censored data). Pharmacokinetics in patients with Ewing sarcoma was similar to that previously reported in other patient populations. PM00104 showed modest activity in Ewing sarcoma at 2 mg/m(2) on a weekly schedule. There remains an unmet need for effective therapies for patients with advanced/metastatic Ewing sarcoma.

PM00104 (Zalypsis®) is a new synthetic alkaloid with potent cytotoxic activity against tumor cell lines. This phase I clinical trial determined the maximal tolerated dose (MTD) and recommended dose (RD) for phase II trials of PM00104 administered as a 1-hour intravenous (i.v.) infusion weekly for three consecutive weeks resting every fourth week (d1,8,15 q4wk). Forty-nine patients with advanced solid malignancies received PM00104 following a toxicity-guided, accelerated, dose-escalation design. Doses evaluated ranged from 0.07 to 3.0 mg/m(2). Dose-limiting toxicities (DLTs) appeared at the highest doses tested and comprised grade 3 diarrhea and grade 4 lipase increase at 2.0 mg/m(2); grade 1 thrombocytopenia and grade 2 neutropenia with two infusion omissions, grade 3 fatigue and grade 4 febrile neutropenia at 2.5 mg/m(2); and grade 3/4 fatigue, grade 4 neutropenia lasting >5 days and grade 4 thrombocytopenia at 3.0 mg/m(2). RD was established at 2.0 mg/m(2). PM00104-related adverse events at the RD were mostly grade 1/2, with fatigue, nausea and vomiting as the most common. Transient and manageable myelosuppression and transaminase increases were also reported. Main pharmacokinetic parameters increased linearly with dose. Disease stabilization lasting ≥ 3 months was found in 4 patients with cervical carcinoma, colorectal adenocarcinoma, lachrymal adenoid carcinoma, and bladder carcinoma (n=1 each). In conclusion, PM00104 2.0 mg/m(2) 1-hour, d1,8,15 q4wk showed a positive risk-benefit ratio, which has supported its further evaluation in three ongoing 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: 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.