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Purpose: To report the results of OPAL (ClinicalTrials.gov identifier: NCT03574779) cohort A, a single-arm substudy of niraparib plus dostarlimab and bevacizumab for the treatment of advanced, platinum-resistant ovarian cancer (PROC)., Methods: Participants with PROC who received 1-2 previous lines of therapy were treated with niraparib (200 or 300 mg once daily), dostarlimab (500 mg once every 3 weeks for four 21-day cycles, followed by 1,000 mg once every 6 weeks), and bevacizumab (15 mg/kg once every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR) per RECIST v1.1. Safety was also assessed. Exploratory biomarker end points included evaluation of changes in the tumor molecular profile and microenvironment using baseline and on-treatment tumor samples., Results: Of 41 enrolled participants (median age, 66.0 years [range, 37-83 years]), 9.8% had tumors that were BRCA -mutated, 19.5% were homologous recombination (HR)-deficient, and 17.1% were HR repair (HRR)-mutated. As of the cutoff date, all participants discontinued treatment. The ORR was 17.1% (80% CI, 9.8 to 27.0), including one complete response (2.4%); the disease control rate was 73.2% (80% CI, 62.3 to 82.2). Two participants withdrew before first postbaseline scan because of adverse events (AEs). Grade ≥3 treatment-emergent AEs were reported in 92.7% of participants, with the most common being hypertension (26.8%). Response was not correlated with BRCA , HRR, HR deficiency (HRD), or PD-L1 status. Changes suggesting immune activation were observed in on-treatment samples after triplet therapy., Conclusion: Results demonstrated modest activity of niraparib, dostarlimab, and bevacizumab in participants with PROC, many of whom had prognostic factors for poor treatment response. Most participants with response were bevacizumab-naïve. No association was found with HRD, BRCA , or PD-L1 status. AEs were consistent with previous monotherapy reports, except that hypertension was reported more frequently.

Objective: This study assessed the efficacy, safety, and health-related quality of life (HRQoL) of the treatment regimen of dostarlimab, a programmed death-1 inhibitor, combined with niraparib, a poly (ADP-ribose) polymerase inhibitor, in patients with BRCA wild type (BRCAwt) recurrent platinum-resistant ovarian cancer (PROC) who had previously received bevacizumab treatment., Methods: This Phase II, open-label, single-arm, multicenter study, conducted in the USA, enrolled patients with recurrent PROC to receive niraparib and dostarlimab until disease progression or unacceptable toxicity (up to 3 years). A preplanned interim futility analysis was performed after the first 41 patients had undergone ≥1 radiographic evaluation (approximately 9 weeks from the first treatment)., Results: The prespecified interim futility criterion was met and the study was therefore terminated. For the 41 patients assessed, the objective response rate (ORR) was 7.3% (95% confidence interval: 1.5-19.9); no patients achieved a complete response, 3 patients (7.3%) achieved a partial response (duration of response; 3.0, 3.8, and 9.2 months, respectively), and 9 patients (22.0%) had stable disease. In total, 39 patients (95.1%) experienced a treatment-related adverse event, but no new safety issues were observed. HRQoL, assessed using FOSI, or Functional Assessment of Cancer Therapy - Ovarian Symptom Index scores, worsened over time compared with baseline scores., Conclusions: The study was terminated due to the observed ORR at the interim futility analysis. This highlights a need for effective therapies in treating patients with recurrent BRCAwt PROC., Competing Interests: Declaration of Competing Interest LMR reports personal fees from GSK/TESARO for consultancy unrelated to this study; research grant (to institution): Seagen, Genmab, Merck, Akeso, Mersana, Incyte, GOG Foundation, Genentech; consulting fees: Agenus, Akeso, AstraZeneca, Clovis Oncology, Eisai, Elevar, EMD Serono/Merck, Genmab, Seagen, GOG Foundation, Hengrui, ImmunoGen, Iovance, Merck, Mersana, Myriad, Novocure, Pfizer, Regeneron, Roche/Genentech, GSK/Tesaro, Zentalis; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AstraZeneca, Eisai, Myriad, Roche/Genentech, GSK/Tesaro. DMO reports grant funding (to the institution) from AbbVie; personal fees for an advisory board from AbbVie; support for manuscript preparation from GSK/TESARO. BJM reports consulting/advisory role and honoraria for AbbVie, ChemoCare, ChemoID, Eisai, Geistlich Pharma, Incyte, Mateon Therapeutics, Merck, Myriad Pharmaceuticals, Perthera, Precision Oncology, Samumed, Takeda, and VBL Therapeutics; consulting/advisory role, honoraria, and research funding (to the institution) from Advaxis, Amgen, Immunogen, NuCana BioMed and Pfizer; consulting/advisory role, speakers bureau, honoraria, and research funding (to the institution) from AstraZeneca, Roche/Genentech and TESARO; consulting/advisory role, speakers bureau and honoraria from Clovis Oncology; speakers bureau, honoraria and research funding (to the institution) from Janssen; consulting/advisory role for Cerulean Pharma, OncoMed, and OncoSec; a leadership role for US Oncology; honoraria from Agenus, Conjupro Biotherapeutics, Genmab, Immunomedics, OncoQuest, and PumaBiotechnology; research funding (to the institution) from Array BioPharma, Lilly, Morphotek, Novartis, and Regeneron. RLC reports consulting, grant and honoraria/reimbursement from AstraZeneca, Clovis Oncology, Janssen, Merck, and Roche/Genentech; consulting and honoraria/reimbursement from Arrivive, Eisai, Novocure, Oncomed/Mateo, and TESARO/GSK; consulting and grant from AbbVie, grant from Genmab. SG reports a consulting/advisory role for AstraZeneca, Immunogen, Rigel, and Sermonix Pharmaceuticals; research funding (to the institution) from AbbVie, AstraZeneca, Genentech/Roche, Iovance Biotherapeutics, Pfizer, PharmaMar, and GSK/TESARO; hold patents, royalties or other intellectual property with Sermonix Pharmaceuticals. SA reports research funding from AstraZeneca. LRD reports consulting/advisory role for Genentech/Roche, Merck, Inovio Pharmaceuticals, CUE Biopharma; institutional research funding from GSK, Millennium, Bristol-Myers Squibb, Aeterna Zentaris, Novartis, Abbvie, GSK/TESARO, Cerulean Pharma, Aduro Biotech, Advaxis, Syndax, Pfizer, Merck, Genentech/Roche, Cerulean Pharma, Morab, Morphotek, Syndax, Ludwig Institute for Cancer Research, Leap Therapeutics. HD reports a consulting/advisory role for Eisai and Merck. RWH reports speaker's bureau from AstraZeneca, Clovis, and GSK. MH reports advisory board participation for Clovis Oncology, Janssen, Immunogen, Eisai, Seagen, and Tesaro; grant funding from Merck. HSC has nothing to disclose. NGC reports participation in advisory boards from AstraZeneca, GSK, Toray, Tarveda Therapeutics, Aadi. ACE is an employee and stockholder in Natera Inc. REO is funded in part by the NIH/NCI Cancer Center Support Grant P30 CA008748, reports personal fees for advisory boards from TESARO/GSK, Bayer, Regeneron, SeaGen, Fresenius Kabi, R-Pharm, Miltenyi, 2seventybio and Immunogen; reports personal fees from MJH Life Sciences, Onclive/PER and Curio; and reports non-compensated membership of steering committees for the PRIMA and DUO-O studies. SW reports a consulting/advisory role for Regeneron. AT, AS, LMN, AB and VS are employees of and hold stocks/shares in GSK. PAK reports personal fees from GSK/TESARO for consultancy unrelated to this study and personal fees for advisory board participation from AstraZeneca, Merck, and Pfizer., (Copyright © 2023. Published by Elsevier Inc.)

The purpose of this study was to assess the effect of pevonedistat, a neural precursor cell expressed, developmentally down-regulated protein 8 (NEDD8)-activating enzyme inhibitor, on the heart rate-corrected QT (QTc) interval in cancer patients. Patients were randomized 1:1 to receive pevonedistat 25 or 50 mg/m 2 on day 1 and the alternate dose on day 8. Triplicate electrocardiograms were collected at intervals over 0-11 hours and at 24 hours via Holter recorders on days -1 (baseline), 1, and 8. Changes from time-matched baseline values were calculated for QTc by Fridericia (QTcF), PR, and QRS intervals. Serial time-matched blood samples for analysis of pevonedistat plasma pharmacokinetics were collected and a concentration-QTc analysis conducted. Safety was assessed by monitoring vital signs, physical examinations, and clinical laboratory tests. Forty-four patients were included in the QTc analysis. Maximum least square (LS) mean increase from time-matched baseline in QTcF was 3.2 milliseconds at 1 hour postdose for pevonedistat at 25 mg/m 2 , while the LSs mean change from baseline in QTcF was -1.7 milliseconds 1 hour postdose at 50 mg/m 2 . The maximum 2-sided 90% upper confidence bound was 6.7 and 2.9 milliseconds for pevonedistat at 25 and 50 mg/m 2 , respectively. Pevonedistat did not result in clinically relevant effects on heart rate, nor on PR or QRS intervals. Results from pevonedistat concentration-QTc analysis were consistent with these findings. Administration of pevonedistat to cancer patients at a dose of up to 50 mg/m 2 showed no evidence of QT prolongation, indicative of the lack of clinically meaningful effects on cardiac repolarization. ClinicalTrials.gov identifier: NCT03330106 (first registered on November 6, 2017)., (© 2022 Takeda Pharmaceutical and The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

The failure rate for phase III trials in oncology is high; quantitative predictive approaches are needed. We developed a model-based meta-analysis (MBMA) framework to predict progression-free survival (PFS) from overall response rates (ORR) in relapsed/refractory multiple myeloma (RRMM), using data from seven phase III trials. A Bayesian analysis was used to predict the probability of technical success (PTS) for achieving desired phase III PFS targets based on phase II ORR data. The model demonstrated a strongly correlated (R 2 = 0.84) linear relationship between ORR and median PFS. As a representative application of the framework, MBMA predicted that an ORR of ∼66% would be needed in a phase II study of 50 patients to achieve a target median PFS of 13.5 months in a phase III study. This model can be used to help estimate PTS to achieve gold-standard targets in a target product profile, thereby enabling objectively informed decision-making., (© 2017 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Summary: Two male first cousins with mild haemophilia A had baseline factor VIII levels of 12-15% and experienced bleeding requiring coagulation factor infusion therapy with trauma and surgical procedures. Both the patients with haemophilia A also had electrocardiographically documented symptomatic paroxysmal atrial fibrillation (PAF) for several years that had become resistant to pharmacological suppression. Radiofrequency ablation was considered in both the cases but deferred considering refusal of consent by the patients to undergo the procedure. Remission of arrhythmias has been reported in patients with iron-overload syndromes. Body iron stores assessed by serum ferritin levels were elevated in both men but neither had the C282Y or H63D genes for haemochromatosis. Calibrated reduction of iron stores by serial phlebotomy, avoiding iron deficiency, was followed by remission of symptomatic PAF in both cases. Iron reduction may be an effective treatment for arrhythmias apart from the classic iron-overload syndromes and deserves further study particularly in patients with bleeding disorders who might be at risk for arrhythmias and other diseases of ageing.

Using a standard radio-receptor assay, we have demonstrated that [125I]insulin can bind specifically to each of two types of purified enveloped viruses, influenza A virus and Rous sarcoma virus. A non-enveloped icosahedral virus (echovirus 11) and herpes simplex virus type 2, which acquires its envelope from the nuclear membrane of the cell, did not possess insulin receptor activity. Displacement of specifically bound radiolabelled insulin from the viral surface was achieved by addition of an excess of unlabelled insulin but not by addition of another unrelated protein, cytochrome C. We conclude that certain types of enveloped viruses may acquire insulin binding sites from the plasma membrane of their host cell.