A phase III trial of bevacizumab combined with interferon alfa-2a (IFN) showed significant improvements in progression-free survival (PFS) in metastatic renal cell carcinoma (mRCC). Here, we report ...overall survival (OS) data.
Six hundred forty-nine patients with previously untreated mRCC were randomly assigned to receive bevacizumab (10 mg/kg every 2 weeks) plus IFN (9 MIU subcutaneously three times a week; n = 327) or IFN plus placebo (n = 322) in a multicenter, randomized, double-blind, phase III trial. The primary end point was OS. Final analysis of the secondary end point (PFS) was reported earlier.
Median OS was 23.3 months with bevacizumab plus IFN and 21.3 months with IFN plus placebo (unstratified hazard ratio HR = 0.91; 95% CI, 0.76 to 1.10; P = .3360; stratified HR = 0.86; 95% CI, 0.72 to 1.04; P = .1291). Patients (> 55%) in both arms received at least one postprotocol antineoplastic therapy, possibly confounding the OS analysis. Patients receiving postprotocol therapy including a tyrosine kinase inhibitor had longer median OS (bevacizumab plus IFN arm: 38.6 months; IFN plus placebo arm: 33.6 months; HR = 0.80; 95% CI, 0.56 to 1.13). Tolerability was similar to that reported previously.
Bevacizumab plus IFN is active as first-line treatment in patients with mRCC. Most patients with mRCC receive multiple lines of therapy, so considering the overall sequence of therapy when selecting first-line therapy may optimize patient benefit.
BackgroundANV419 is a stable antibody–cytokine fusion protein consisting of interleukin-2 (IL-2) fused to an anti-IL-2 monoclonal antibody that sterically hinders binding of IL-2 to the α subunit of ...its receptor but has selective affinity for the receptor βγ subunits. Thus, ANV419 preferentially stimulates CD8+ effector T cells and natural killer cells which are associated with tumor killing, while minimizing the activation of immunosuppressive regulatory T cells.MethodsANV419-001 is an open-label, multicenter, phase 1 study to evaluate the safety, tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ANV419. Secondary objectives were to characterize the pharmacokinetics, pharmacodynamics and tumor response. Adult patients with advanced solid tumors and disease progression after ≥1 previous line of systemic therapy were enrolled. ANV419 was administered by intravenous infusion once every 2 weeks, with a planned treatment duration of 12 months. The dose escalation part of the study explored doses 3, 6 and 12 µg/kg as single patient cohorts followed by 24–364 µg/kg in a 3+3 design. Interim results are reported here (data cut-off: March 22, 2023).ResultsForty patients were enrolled and received at least one dose of ANV419. The MTD and RP2D were determined to be 243 µg/kg. The most common ANV419-related treatment-emergent adverse events were Grade 1 and 2 fever (31 (77.5%)), chills (23 (57.5%), vomiting (14 (35.0%)), cytokine release syndrome and nausea (12 (30.0%) each). Transient and self-limiting lymphopenia due to lymphocyte redistribution was observed in all patients. In the RP2D cohort, Grade ≥3 thrombocytopenia and fever were reported by one patient (12.5%) each. All events were manageable with standard supportive care. At doses of 243 µg/kg (RP2D/MTD), the estimated T1/2 was approximately 12 hours. At ANV419 doses ≥108 µg/kg, 64% of patients had a best response of at least SD (15 SD and 1 confirmed PR).ConclusionsANV419 at doses up to 243 µg/kg (the RP2D) was well tolerated and showed signs of antitumor activity in a heavily pretreated patient population with advanced solid tumors.Trial registration numberNCT04855929.
The amount of assistance required to perform daily activities for individuals with Type 2 and non-ambulant Type 3 spinal muscular atrophy (SMA) is often cited as meaningful for quality of life, and ...important to routinely assess.
The SMA Independence Scale (SMAIS), a patient-reported outcome measure for individuals with SMA aged ≥12 years, and an observer-reported outcome measure for caregivers of individuals aged ≥2 years, was developed and evaluated in two phases. In Phase 1, 30 draft items were developed following review of the literature. Semi-structured interviews were then conducted with individuals with SMA and caregivers to establish content validity, resulting in a 29-item measure. In Phase 2, classical test theory and Rasch measurement theory methods were used to examine the cross-sectional and longitudinal measurement performance of the SMAIS in two independent datasets.
Phase 1 qualitative findings supported the relevance, acceptability, and comprehensibility of 29 items. In Phase 2, psychometric analyses indicated that the five response options were poorly discriminated and were thus collapsed to three options for subsequent analyses. Items showed statistical misfit, implying that the SMAIS was not assessing a single underlying construct. Based on conceptual evaluation of the items, and assessment of item performance, a more targeted 22-item upper limb score was derived. Reliability and validity analyses confirmed acceptable measurement properties of this score.
Qualitative and quantitative analyses support the use of the 22-item SMAIS–Upper Limb Module in individuals with Type 2 and non-ambulant Type 3 SMA, aged ≥2 years.
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•Maintaining independence is critical for non-ambulant individuals with Type 2/3 SMA.•Psychometric analyses supported the development of the 22-item SMAIS–ULM.•The SMAIS–ULM measures the level of assistance required to complete upper limb ADLs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Reviews the development of bevacizumab and clinical trials of its use for treating patients with renal cell carcinoma (RCC). Backgrounds the disease and its historical management options. Considers ...future strategies for providing additional benefit to RCC patients. Source: National Library of New Zealand Te Puna Matauranga o Aotearoa, licensed by the Department of Internal Affairs for re-use under the Creative Commons Attribution 3.0 New Zealand Licence.
Epilepsy occurs in approximately 80 per 100,000 infants in the first year of life, ranging in severity from self-limited and likely to spontaneously resolve, to severe developmental and epileptic ...encephalopathies. Sleep plays a key role in early brain development and the reciprocal relationship between sleep and seizures is not yet fully understood, particularly in young children. We conducted a Scoping Review to synthesise current knowledge of sleep architecture in neonates and infants with epilepsy.
Peer-reviewed publications from 2005 to 2022 describing sleep architecture in infants up to six months of age with unprovoked seizures were included. The analysis set was derived from EMBASE, Web of Science and PubMED using key terms “sleep, epilepsy and infant” and related descriptors. Inclusion criteria were prospectively described in a Scoping Review protocol. Sleep architecture was assessed as macro- and micro-structural elements.
21 publications were included in the qualitative analysis. In self-limited familial and genetic epilepsy, sleep macrostructure was generally preserved. In DEEs and in epileptic encephalopathies of genetic or structural aetiology, sleep architecture was significantly disrupted.
Early identification of infants with epilepsy is important to ensure early and effective treatment. In the DEE spectrum, sleep architecture is significantly impacted, and abnormal sleep architecture may be associated with compromised developmental outcome. Further research is needed to identify the sequence of events in abnormal brain development, epilepsy and sleep disruption and potentially help to predict the course of epilepsy towards a self-limited epilepsy versus a DEE.
•Sleep is critical for brain development.•Complex relationship exists between sleep and epilepsy.•Scoping review of sleep architecture in infants with unprovoked seizures.•In self-limited epilepsy, sleep macrostructure was preserved.•In developmental and epileptic encephalopathies, sleep architecture was significantly disrupted.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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Background: ANV419 is a potent, selective IL-2Rβγ targeted antibody IL-2 fusion protein, designed to enable the delivery of high dose interleukin-2 (IL-2) to patients, in order to stimulate ...anti-tumour response and minimise toxicities. The ANV419-001 first-in-human study (NCT 04855929) demonstrated that ANV419 preferentially stimulates cytotoxic CD8+ T and natural killer (NK) cells over immunosuppressive regulatory T cells, with a significantly longer half-life than that of conventional IL-2. The safety and tolerability data from this study confirmed that ANV419 delivers high molar equivalents of IL-2 in a tolerable and convenient way. In patients with multiple myeloma, the critical role of NK cells has been well described. ANV419 is expected to promote antitumor response via the preferential stimulation of cytotoxic CD8+ T and NK cells. Methods: The OMNIA-2 study (ANV419-102; NCT 05641324) will evaluate safety and preliminary efficacy of ANV419 as monotherapy and in combination with daratumumab (dara), or lenalidomide with low dose dexamethasone (lena/dex), in patients with relapsed or refractory multiple myeloma. OMNIA-2 is a Phase I open-label, multi-center study in adult patients (n = 52) with symptomatic multiple myeloma who responded to previous treatment and received autologous stem cell transplant, or at least 2 lines of therapy including an immunomodulator, proteasome inhibitor, and/or dara. The study is conducted in 2 stages using a Bayesian Optimal Phase 2 approach. Stage 1 consists of a run-in phase with subsequent randomization to ANV419 243mcg/kg or ANV419 108mcg/kg for 8 weeks, followed by a second randomisation to ANV419 108mcg/kg in combination with lena/dex or dara for a further 8 weeks. Stage 2 follows a similar design as stage 1 and consists of a monotherapy run-in phase with either high or low dose ANV419, with a second randomisation to ANV419 108mcg/kg in combination with either lena/dex or dara, according to the safety and efficacy observed in Stage 1. ANV419 is administered intravenously over 15 to 20 minutes every two weeks. Lena, dex and dara are administered at their respective approved dosing regimens. Tumour response is determined using IMWG (2016) response criteria. AEs are assessed according to CTCAE V5.0. OMNIA-2 is being conducted in Denmark, France, Germany, Spain, Switzerland, UK and enrolment began in January 2023 and preliminary data are expected in Q1 2024. Clinical trial information: NCT05641324 .
BackgroundANV419 is a fusion protein of an anti-IL-2 antibody and human-IL-2 with selective signaling through IL-2Rβ/γ thus limiting the side effects of activating the IL-2Rα/β/γ ANV419 is ...investigated in a phase I dose finding study in patients with advanced solid tumors (ANV419-001).MethodsThe primary objective of ANV419-001 is safety and tolerability of ANV419. Secondary objectives include response rate (RECISTv1.1), pharmacokinetic and pharmacodynamic evaluation. ANV419 is administered as a 15 minutes intravenous infusion Q2W. As of 29th June 2022, 26 patients with Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 and a range of primary tumor types with multiple previous lines of therapy have been enrolled and dosed in 9 cohorts up to 243μg/kg.ResultsANV419 was generally well tolerated across multiple cycles, with no dose-limiting toxicities (DLTs) up to and including 243µg/kg. The most frequent ANV419 related adverse events (AEs), reported in at least 10% of patients, were chills, fever, fatigue, nausea, vomiting, cytokine release syndrome (CRS) and increased liver function tests, mainly Grade 1 and Grade 2. All drug related events were responsive to supportive care therapy and reversible.A dose proportional increase in ANV419 plasma concentration results in an increased estimated half-life up to 28 hours at higher doses.In this study, IL-6, IL-8, TNF-α, and IFN-γ levels (10-Plex Panel) were transiently increased at high doses (108 and 243µg/kg), 4 hours after infusion.Pharmacodynamic evaluation of ANV419 on day 4 post-dosing (cycle 1 and 2) showed a selective and dose dependent proliferation of CD8+ T and NK cells, with a lower increase of proliferating Tregs. As typical for IL-2 related lymphocyte sequestration, a transient dose dependent lymphopenia was observed in all patients lasting up to at least 72 hours after ANV419 infusion, followed by a dose dependent increasing lymphocyte counts up to 5.4-fold of baseline. Lymphocyte numbers keep increasing over multiple cycles up to 3.8-fold after 2 cycles (243µg/kg). In 21 patients with at least one post-baseline tumor response assessment, 52% of patients (n=11) achieved a response of SD or PR, with 10 SD, 1 PR and 10 PD.ConclusionsANV419 maintains a favorable safety profile, while inducing a systemic inflammatory response in cancer patients with preferential proliferation of effector cells compared to high dose of IL-2. Dose escalation is ongoing. The preliminary efficacy data shows a potential for ANV419 as therapeutic option for patients with progressing/relapsing cancer. Updated data will be shared at the meeting.Trial RegistrationNCT04855929Ethics ApprovalThe study ANV419-001 has been approved by the following Ethics committee:- HM Hospitals Drug Research Ethics Committee (CEIm) (ID: 20.12.1736-GHM)- EKNZ – Ethikkommission Nordwest und Zentralschweiz ( ID 2021-00911)- London – Surrey Borders Research Ethics Committee (ID: 21/LO/0213)Written consent was obtained from all patients prior taking part into this study.ConsentWritten informed consent was obtained from the patient for publication of this abstract.
Abstract
Developing a safe and effective non-alpha IL-2R agonist to enhance the numbers and activation status of immune effector cells for the treatment of cancer has remained an elusive goal since ...the initial approval of Interleukin-2 (IL-2). ANV419 comprises an antibody specific for the IL-2Rα-binding domain of IL-2 fused to native hIL-2 and functions as a potent, highly selective, IL-2Rβγ binding agonist. ANV419 has shown high effector selectivity and a favorable safety profile in preclinical testing, including in non-human primates, and is currently being investigated in an ongoing phase I/II dose finding study in multiple tumor types (ANV419-001). Here we present data from the single patient cohort and the initial 3+3 cohort dose escalation. Data cut-off was December 22nd, 2021. Ten patients in five dose cohorts. Patients had progressed melanoma (cutaneous (n=3), uveal (n=2), mucosal (n=1), choroidal (n=1)), renal cell carcinoma(n=1), hepatocellular carcinoma (n=1) and colorectal cancer(n=1) received Q2W doses of ANV419 of 3mcg/kg (n=1), 6mcg/kg (n=1), 12mcg/kg (n=1), 24mcg/kg (n=4) and 48mcg/kg (n=3) body weight without immunosuppressive premedication as a 15-minute intravenous infusion. Patients received a mean of 4 cycles. Minimal follow up of patients completing the dose limiting toxicity (DLT) period is 2 cycles. All patients experienced mild chills (Grade 1) with or without low-grade fever (Grade 1) hours after drug administration. These resolved with antipyretic treatment within hours. There were two grade 2 AEs in two patients related to ANV419. One patient developed Grade 2 CRS (hypotension grade 2 with fever (Grade 1) and chills (Grade 1) that resolved with 500ml intravenous fluid. One patient experienced transient, self-limiting Grade 2 CRS. No drug related Adverse Events >Grade 2 and no DLTs were observed. One patient in the 24 mcg/kg cohort was non evaluable and was subsequently replaced. Pharmacodynamic evaluation on day 4 post-dosing, showed a dose dependent increase of Ki-67 positivity in CD8 T cells (2%, 14%, 37%, 62%, 62% vs. baseline mean (BLM) 2%)) and NK cells (30%, 62%, 75%, 85%, 80% vs BLM 6%) but not CD4 regulatory T cells (4%, 13%, 25%, 16%, 19% vs. BLM 5%) at 3, 6, 12, 24 and 48 mcg/kg doses respectively. Pharmacokinetic data show a dose proportional increase of serum concentration of ANV419. Both PK and PD were conserved over multiple cycles. Four patients continue to receive ANV419. Four patients underwent more than one follow-up imaging, all of which showed stable disease. Updated patient data will be presented during the meeting. ANV419 is very well tolerated and induces a high degree of proliferation in CD8 T cells and NK cells but not Tregs. ANV419-001 will further evaluate the safety and efficacy of ANV419 alone and in combination with other immunotherapy drugs.
Citation Format: Elena Garralda, Alonso Guzman, Juanita Lopez, Vicky Sanchez-Perez, Heinz Läubli, Emiliano Calvo, Christoph Huber, Nicole Egli, Aswathy Nair, Julie Mouton, Kirsten Richter, Carlo Lanza, Sangeeta Jethwa, Silvio Costanzo, Christoph Bucher. ANV419, an IL-2R-beta-gamma targeted antibody-IL-2 fusion protein, induces selective effector cell proliferation in patients with progressed cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT140.
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Background: IL-2R agonists that are well tolerated and can selectively enhance immune activation may improve outcomes of patients with cancer. ANV419 is a potent and highly selective IL-2Rβγ ...binding agonist, consisting of an antibody specific for the IL-2Rα-binding domain of IL-2, fused to native hIL-2. It is currently being investigated in a phase I/II dose finding study in patients with relapsed/refractory advanced solid tumors (ANV419-001). The primary objective of ANV419-001 is to describe the safety and tolerability of ANV419. Methods: ANV419 is administered intravenously over 15 minutes every 2 weeks, without premedication. Thirteen patients with melanoma (cutaneous (n = 3), uveal (n = 2), mucosal (n = 2), choroidal (n = 1)), renal cell carcinoma (n = 1), hepatocellular carcinoma (n = 1), colorectal cancer (n = 1), esophageal adenocarcinoma (n = 1) and adenoid cystic carcinoma (n = 1) have been dosed in six cohorts. Patients received 3mcg/kg (n = 1), 6mcg/kg (n = 1), 12mcg/kg (n = 1), 24mcg/kg (n = 4), 48mcg/kg (n = 3) 72mcg/kg (n = 3) and 108 mcg/kg (ongoing) of ANV419. Results: ANV419 is well tolerated, all related AEs are Grade 1 or Grade 2 and no DLTs have been observed. Most patients experienced chills (G1), with or without low-grade fever (G1), 2-4 hours after post- infusion, which resolved with antipyretic treatment. Two G2 AEs related to ANV419 have been reported in two patients. One patient was reported to have G2 Cytokine Release Syndrome (hypotension (G2), fever (G1), chills (G1)) and one patient experienced transient, self-limiting G2 elevation of liver function tests. Four Serious Adverse Events were reported in three patients (urinary tract infection, lethargy, thoracic pain and abdominal pain), none of which were considered related to ANV419. Pharmacodynamic evaluation on day 4 post-dosing, showed an effector cell selective, dose dependent increase of Ki-67 positive CD8 T cells (2%, 14%, 37%, 62%, 62%, vs. baseline mean (BLM) 2%) and NK cells (30%, 62%, 75%, 85%, 80%, vs BLM 6%) with a dose independent frequency of Ki67+ Tregs ranging from 4% to 25% (BLM 7%) at 3, 6, 12, 24 and 48 mcg/kg doses respectively. At 72mcg/kg mean CD8 T cell and NK proliferation was 70% and 51% respectively, while the mean Treg proliferation increased to 48%. Pharmacokinetic data (including patients treated with up to 24 mcg/kg ANV419) show a dose proportional increase of the ANV419 plasma concentration. The estimated half-life at the 24mcg/kg dose is 17.6 hrs. Four patients continue to receive ANV419. Of the 11 patients who received at least two cycles of ANV419, 4 were assessed to have stable disease. One patient progressed after 24 weeks of confirmed stable disease. Conclusions: Overall, ANV419 is well tolerated and selectively induces expansion and proliferation of CD8 T cells and NK cells, but not Tregs up to a dose of at least 48mcg/kg. Updated data will be shared during the meeting. Clinical trial information: NCT04855929.
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