Phase 1 first-in-human dose-escalation study of ANV419 in patients with relapsed/refractory advanced solid tumors.

BACKGROUND: ANV419 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 ßγ 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. METHODS: ANV419-001 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). RESULTS: Forty 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). CONCLUSIONS: ANV419 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 NUMBER: NCT04855929.

Sleep architecture in neonatal and infantile onset epilepsies in the first six months of life: A scoping review.

AIM: 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. METHOD: 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. RESULTS: 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. INTERPRETATION: 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.

Development of the SMA independence scale-upper limb module (SMAIS-ULM): A novel scale for individuals with Type 2 and non-ambulant Type 3 SMA.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival.

PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Targeted therapies in the management of renal cell carcinoma: role of bevacizumab.

Bevacizumab (10 mg/kg every 2 weeks), in combination with interferon alpha-2a (IFN), is an effective option for first-line therapy for advanced and/or metastatic renal cell carcinoma (RCC). Two phase III trials clearly show significant improvements in progression-free survival and response rate in patients with treatment-naïve metastatic RCC receiving bevacizumab combined with IFN compared with IFN. The dose of IFN, which was initiated at 9 MIU 3 times a week in these trials, can be reduced to effectively manage IFN-related side effects without compromising the efficacy of bevacizumab plus IFN. Bevacizumab has good tolerability with manageable side effects, both alone and in combination with other agents; the tolerability profile of bevacizumab in combination with IFN is consistent with the well-characterized and well-established profiles of these therapies. The tolerability of bevacizumab combined with IFN and the flexibility to manage IFN-related side effects are important considerations when selecting first-line therapy. With a number of options now available for RCC therapy, optimizing their use is a key consideration in improving patient benefit.