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BACKGROUND: Pixantrone dimaleate (pixantrone)-a novel aza-anthracenedione-was synthesised to reduce anthracycline-related cardiotoxicity without compromising antitumour efficacy. We aimed to assess the efficacy and safety of pixantrone versus an investigator's choice of a single-agent therapy in heavily pretreated patients with relapsed or refractory aggressive non-Hodgkin lymphoma. METHODS: In this phase 3, multicentre, open-label, randomised trial at 66 hospitals in Europe, India, Russia, South America, the UK, and the USA, patients with histologically confirmed aggressive non-Hodgkin lymphoma who had relapsed after two or more previous chemotherapy regimens were randomly assigned (1:1) by an interactive voice response system to treatment with pixantrone dimaleate (85 mg/m(2) intravenously on days 1, 8, and 15 of a 28-day cycle, for up to six cycles) or to a comparator (vinorelbine, oxaliplatin, ifosfamide, etoposide, mitoxantrone, or gemcitabine) given at prespecified standard doses and schedules. Patients were stratified by region, International Prognostic Index score, and previous stem-cell transplantation. Patients and investigators were not masked to treatment assignment; however, an independent assessment panel was masked. The primary endpoint was the proportion of patients with a complete or unconfirmed complete response in the intention-to-treat (ITT) population at the end of treatment. Primary analyses of efficacy were based on the independent assessment panel's data review. The study is registered at ClinicalTrials.gov, number NCT00088530. FINDINGS: The ITT population comprised 70 patients randomly assigned to the pixantrone group and 70 to the comparator. Five patients (two in the pixantrone group and three in the comparator group) dropped out before receiving their study drug. 14 patients (20·0% [95% CI 11·4-31·3]) who received pixantrone achieved a complete or unconfirmed complete response at end of treatment compared with four patients (5·7% [1·6-14·0]) in the comparator group (p = 0·021). The most common grade 3 or 4 adverse events in patients given pixantrone were uncomplicated, non-cumulative neutropenia (28 [41·2%] of 68 patients vs 13 [19·4%] of 67 patients in the comparator group), leucopenia (16 [23·5%] vs five [7·5%]), and thrombocytopenia (eight [11·8%] vs seven [10·4%]). INTERPRETATION: Pixantrone, given as a single-agent salvage therapy in heavily pretreated patients with relapsed or refractory aggressive non-Hodgkin lymphoma, is efficacious and tolerable. It could be a treatment option for patients whose aggressive non-Hodgkin lymphoma has failed to respond to at least two previous chemotherapy regimens. FUNDING: Cell Therapeutics, Inc. [ABSTRACT FROM AUTHOR]

Phosphatidylinositol 3-kinase (PI3-K) signalling pathway is a crucial path in cancer for cell survival and thus represents an intriguing target for new paediatric anti-cancer drugs. However, the unique clinical toxicities of targeting this pathway (resulting in hyperglycaemia) difficulties combining with chemotherapy, rarity of mutations in childhood tumours and concomitant mutations have resulted in major barriers to clinical translation of these inhibitors in treating both adults and children. Mutations in PIK3CA predict response to PI3-K inhibitors in adult cancers. The same mutations occur in children as in adults, but they are significantly less frequent in paediatrics. In children, high-grade gliomas, especially diffuse midline gliomas (DMG), have the highest incidence of PIK3CA mutations. New mutation-specific PI3-K inhibitors reduce toxicity from on-target PI3-Kα wild-type activity. The mTOR inhibitor everolimus is approved for subependymal giant cell astrocytomas. In paediatric cancers, mTOR inhibitors have been predominantly evaluated by academia, without an overall strategy, in empiric, mutation-agnostic clinical trials with very low response rates to monotherapy. Therefore, future trials of single agent or combination strategies of mTOR inhibitors in childhood cancer should be supported by very strong biological rationale and preclinical data. Further preclinical evaluation of glycogen synthase kinase-3 beta inhibitors is required. Similarly, even where there is an AKT mutation (∼0.1 %), the role of AKT inhibitors in paediatric cancers remains unclear. Patient advocates strongly urged analysing and conserving data from every child participating in a clinical trial. A priority is to evaluate mutation-specific, central nervous system-penetrant PI3-K inhibitors in children with DMG in a rational biological combination. The choice of combination, should be based on the genomic landscape e.g. PTEN loss and resistance mechanisms supported by preclinical data. However, in view of the very rare populations involved, innovative regulatory approaches are needed to generate data for an indication., Competing Interests: Declaration of Competing Interest RB is an employee of Genentech, A Member of the Roche Group, South San Francisco, CA USA. JC is an employee of Bayer Healthcare Pharmaceuticals, Whippany, NJ, USA. SGD has received consulting fees for advisory board participation from Amgen, Bayer, InhibRx, and Jazz and travel funding from Loxo, Roche, and Salarius. JF is an employee of Kazia Therapeutics. IG an employee of Celcuity. HK is an employee of Loxo Oncology at Lilly. DL is an employee of Merck Sharp & Dohme. AM is an employee of Actuate. MEM has receiving consulting fees for advisory board participation from Ymabs Therapeutics, Recordati and travel funding from Bayer. KN has received consulting fees for advisory board participation from Y-mAbs, EUSA Pharma and Bayer, fees for teaching from Bayer and serving on a data monitoring committee from Lilly. ADJP has consulted for Lilly, Norgine and Developmental Therapeutics Consortium Limited and been an advisor for Amgen. All remaining authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The PI3K-mTOR pathway is frequently dysregulated in breast cancer. Combining an inhibitor targeting all class I PI3K isoforms and mTOR complex 1 (mTORC1)-mTOR complex 2 (mTORC2) with endocrine therapy and a CDK4/6 inhibitor might provide more effective tumour control than standard-of-care therapy. To evaluate this hypothesis, gedatolisib, a pan-PI3K-mTOR inhibitor, was assessed in a phase 1b trial combined with palbociclib and endocrine therapy in patients with hormone receptor-positive, HER2-negative, advanced breast cancer. Results from the dose expansion portion of this trial are reported herein., Methods: This multicentre, open-label, phase 1b study recruited female patients aged at least 18 years from 17 sites across the USA with hormone-receptor-positive, HER2-negative, advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0-1. Four patient groups were studied in the dose expansion portion of the study: treatment-naive in the advanced setting (first line; group A), progression on 1-2 lines of endocrine therapy but CDK4/6 inhibitor-naive (group B); and one or more previous lines (second-line and higher) of therapy, including a CDK4/6 inhibitor (groups C and D). Gedatolisib 180 mg was administered intravenously weekly in 28-day treatment cycles for groups A-C, and on days 1, 8, and 15 for group D. Letrozole (group A), fulvestrant (groups B-D), and palbociclib (all groups) were administered at standard doses and schedules. The primary endpoint was investigator-assessed objective response rate per RECIST version 1.1 in the evaluable analysis set. This trial is completed and registered with ClinicalTrials.gov, NCT02684032., Findings: Between Dec 19, 2017, and June 19, 2019, 103 female participants were enrolled in the dose expansion groups A (n=31), B (n=13), C (n=32), and D (n=27). Median follow-up was 16·6 months (IQR 5·7-48·4) for group A, 11·0 months (7·6-16·9) for group B, 3·6 months (1·8-7·5) for group C, and 9·4 months (5·3-16·7) for group D for the primary endpoint. Gedatolisib, palbociclib, and endocrine therapy induced an objective response in 23 (85·2%; 90% CI 69·2-94·8) of 27 evaluable first-line participants (group A). In the second-line and higher setting, an objective response was observed in eight (61·5%; 90% CI 35·5-83·4) of 13 evaluable group B participants, seven (25·0%; 12·4-41·9) of 28 evaluable group C participants, and 15 (55·6%; 38·2-72·0) of 27 evaluable group D participants; this included participants with both wild-type and mutated PIK3CA tumours. The most common grade 3-4 treatment-related adverse events were neutropenia (65 [63%] of 103), stomatitis (28 [27%]), and rash (21 [20%]). Grade 3-4 hyperglycaemia was reported in six (6%) participants. 23 (22%) of 103 participants had a treatment-related serious adverse event, and there were no treatment-related deaths. Nine (9%) participants discontinued treatment because of a treatment-emergent adverse event., Interpretation: Gedatolisib plus palbociclib and endocrine therapy showed a promising objective response rate compared with the published results for standard-of-care therapies and had an acceptable safety profile., Funding: Pfizer and Celcuity., Competing Interests: Declaration of interests RML received medical writing support and institutional research funding from Celcuity and Pfizer; institutional research funding from Novartis, Eli Lilly, Puma, Zentalis, Arvinas, and Accutar Biotechnology; and consulting fees from or participation on advisory boards for Celcuity, Pfizer, Novartis, Eli Lilly, Gilead, and Biotheryx. HSH received institutional research funding from Abbvie, Arvinas, Celcuity, Department of Defense, G1 Therapeutics, GlaxoSmith Kline, Horizon Oncology Research, Marker Therapeutics, Mersana, Novartis, Pfizer, Phoenix Pharmaceuticals, Pyonr, QuantumLeap Health, and Seagen, Zymeworks; consulting fees from or participation on advisory boards for Daiichi Sankyo–Astra Zeneca, Immunomedics–Gilead, and Novartis; and Speaker's Bureau fees for Eli Lilly. HSR received institutional research funding from Astellas Pharma, AstraZeneca, Daiichi Sankyo, F Hoffmann-La Roche–Genentech, Gilead Sciences, GlaxoSmithKline, Lilly, Merck, Novartis Pharmaceuticals Corporation, OBI Pharma, Pfizer, Pionyr; consulting fees from or participation on advisory boards for Napo Pharmaceutical, Puma Biotechnology, Blueprint, Scorpion Therapeutics, and Daiichi Sankyo; and honoraria from Blueprint, Mylan, and Puma Biotechnology. EMS-R received research funding from Susan G Komen, V Foundation, NIH, and Breast Cancer Research Foundation; consulting fees from or participation on advisory boards for Lilly, SeaGen, Immunomedics, Tersera, AstraZeneca, Merck, Novartis, and Mylan; other payments or honoraria from the American Society of Clinical Oncology, the National Comprehensive Cancer Network, American Association for Cancer Research–Bristol Myers Squibb–Winn Clinical Trials Workshop. JMS received institutional research funding from Celcuity, Pfizer, Merck, Seagen, Seattle Genetics, Minerva, Myriad Pharmaceuticals, Novartis, Genentech, Cascadian Therapeutics, Abbvie, and Nektar; consulting fees from Volastra and GE Healthcare; royalties or licenses from UW Comotion as a donation to the UW Breast Program; honoraria from Binaytara Foundation, Washington State Medical Oncology Society, and Hong Kong International Oncology Symposium; meeting or travel support from ECOG ACRIN, A2 Biotherapeutics, IwCAR-T, the Society of Nuclear Medicine and Molecular Imaging, and Translational Breast Cancer Research Consortium; and is a member of data safety monitoring or advisory boards for GE Healthcare, Sensei Biotherapeutics, and GlaxoSmithKline. ECD received institutional research funding from Merck, Novartis, Meryx, H3 Biomedicine, and G1 Therapeutics and participated on the data safety monitoring board for Sanofi. PK received institutional research funding from AstraZeneca, Hibercell, Sanofi, Eli Lilly, Zymeworks, and Genentech. SS is a full-time employee of Celcuity receiving a salary and holding shares in Celcuity; and received consulting fees from Celcuity (before employment), Artiva Biotherapeutics, Elevation Oncology, Kartos Therapeutics, Tellios Pharma, and Direct Biologics. SCM, BFS, and IG are full-time employees of Celcuity receiving a salary and holding shares in Celcuity. RW received institutional research funding from Celcuity and Pfizer, is a member of advisory boards for Celcuity and Seagen, and is a member of the investigational steering committee for this study., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) have adverse outcomes. We evaluated the efficacy and safety of the phosphatidylinositol 3-kinase inhibitor copanlisib in patients with relapsed/refractory DLBCL and assessed the relationship between efficacy and DLBCL cell of origin (COO; activated B-cell like [ABC] and germinal center B-cell like [GCB]) and other biomarkers. The primary endpoint was objective response rate (ORR) in DLBCL COO subgroups (ABC, GCB, and unclassifiable) and by CD79B mutational status (NCT02391116). Sixty-seven patients received copanlisib (ABC DLBCL, n = 19; GCB DLBCL, n = 30; unclassifiable, n = 3; missing, n = 15). The ORR was 19.4%; 31.6% and 13.3% in ABC and GCB DLBCL patients, respectively. ORR was 22.2%/20.0% for patients with/without CD79B mutations (wild type, n = 45; mutant, n = 9; missing, n = 13). Overall median progression-free survival and duration of response were 1.8 and 4.3 months, respectively. Adverse events included hypertension (40.3%), diarrhea (37.3%), and hyperglycemia (32.8%). Aberrations were detected in 338 genes, including BCL2 (53.7%) and MLL2 (53.7%). A 16-gene signature separating responders from nonresponders was identified. Copanlisib treatment demonstrated a manageable safety profile in patients with relapsed/refractory DLBCL and a numerically higher response rate in ABC vs. GCB DLBCL patients.