Use of Mid-Upper Arm Circumference by Novel Community Platforms to Detect, Diagnose, and Treat Severe Acute Malnutrition in Children: A Systematic Review.

BACKGROUND: A stubborn persistence of child severe acute malnutrition (SAM) and continued gaps in program coverage have made identifying methods for expanding detection, diagnosis, and treatment of SAM an urgent public health need. There is growing consensus that making mid-upper arm circumference (MUAC) use more widely accessible among caregivers and community health workers (CHWs) is an important next step in further decentralizing SAM care and increasing program coverage, including the ability of CHWs to treat uncomplicated SAM in community settings. METHODS: We conducted a systematic review to summarize published and operational evidence published since 2000 describing the use of MUAC for detection and diagnosis of SAM in children aged 6-59 months by caregivers and CHWs, and of management of uncomplicated SAM by CHWs, all outside of formal health care settings. We screened 1,072 records, selected 43 records for full-text screening, and identified 22 studies that met our eligibility criteria. We extracted data on a number of items, including study design, strengths, and weaknesses; intervention and control; and key findings and operational lessons. We then synthesized the qualitative findings to inform our conclusions. The issue of treating children classified as SAM based on low weight-for-height, rather than MUAC, at household level, is not addressed in this review. FINDINGS: We found evidence that caregivers are able to use MUAC to detect SAM in their children with minimal risk and many potential benefits to early case detection and coverage. We also found evidence that CHWs are able to correctly use MUAC for SAM detection and diagnosis and to provide a high quality of care in the treatment of uncomplicated SAM when training, supervision, and motivation are adequate. However, the number of published research studies was small, their geographic scope was narrow, and most described intensive, small-scale interventions; thus, findings are not currently generalizable to public-sector health care systems. CONCLUSIONS: Scaling up the use of MUAC by caregivers and CHWs to detect SAM in household and community settings is a promising step toward improving the coverage of SAM detection, diagnosis, and treatment. Further research on scalability, applicability across a wider range of contexts, coverage impact, and cost is needed. The primary use of MUAC for SAM detection should also be explored where appropriate

Phase 1 study of fianlimab, a human lymphocyte activation gene-3 (LAG-3) monoclonal antibody, plus cemiplimab in advanced melanoma

Background: Concurrent LAG-3 blockade may enhance efficacy of anti-program cell death-1 (PD-1) therapies such as cemiplimab. We present updated safety and clinical activity data from patients with advanced melanoma treated concurrently with cemiplimab and fianlimab (NCT03005782). Methods: Patients were included with unresectable or metastatic melanoma (excluding uveal melanoma) who were anti-PD-ligand (L) 1 treatment naive (expansion cohort [EC] 6) or anti-PD-(L)1 experienced within 3 months of screening (EC7). Patients received fianlimab 1600 mg + cemiplimab 350 mg intravenously every 3 weeks for 12 months (optional extra 12 months if clinically indicated). Tumours were measured every 6 weeks for 24 weeks, then every 9 weeks. In EC6 (n = 40) and EC7 (n = 15), respectively (data cutoff 9th February 2022), median age was 69.5 and 59.0 years, and median treatment duration was 37.1 and 9.0 weeks. Results: In EC6 and EC7, respectively, incidence of Grade ≥3 treatment-emergent adverse events (TEAEs) were 38% and 47%, incidence of serious TEAEs was 33% and 33%, and 18% and 13% of patients discontinued treatment due to a TEAE. Adrenal insufficiency rate was 13% and 7% in EC6 and EC7, respectively; no instances led to treatment discontinuation. Investigator-assessed objective response rate was63%(six complete responses; 19 partial responses) in EC6 and 13% (two partial responses) in EC7. Kaplan-Meier estimate of median progression-free survival was 14.2 (95% CI: 5.6-not estimated) months in EC6 and 1.4 (95% CI: 1.3-7.7) months in EC7. Median duration of response was not reached in EC6 or EC7. Conclusion: Fianlimab plus cemiplimab in advanced melanoma had a similar safety profile to anti-PD-1 monotherapies. Clinical activity in anti-PD-(L)1-naive patients appeared higher than previously reported for anti-PD-1monotherapy or anti-LAG-3 plus anti-PD-1. A Phase 3 trial (NCT05352672) investigating fianlimab plus cemiplimab in advanced melanoma is ongoing

Molecular profiling of melanoma brain metastases compared to primary cutaneous melanoma and to extracranial metastases.

BACKGROUND: Brain metastases are a significant cause of mortality and morbidity for patients with melanoma. We hypothesize that the development of brain metastases may be explained by molecular heterogeneity between primary cutaneous melanoma (PCM) or extracranial (ECM) and brain (MBM) melanoma metastases. MATERIALS AND METHODS: We compared next-generation sequencing, tumor mutational burden (TMB), and immunohistochemical staining for PD-L1 expression, among 132 MBM, 745 PCM, and 1190 ECM. RESULTS: The most common genetic alterations among MBM included: BRAF (52.4%), NRAS (26.6%), CDKN2A (23.3%), NF1 (18.9%), TP53 (18%), ARID2 (13.8%), SETD2 (11.9%), and PBRM1 (7.5%). Four genes were found with higher frequency among MBM compared to PCM or ECM: BRAF (52.4% v 40.4% v 40.9%), SETD2 (11.9% v 1.9% v 3.9%), PBRM1 (7.5% v 1.6% v 2.6%), and DICER1 (4.4% v 0.6% v 0.4%). MBM showed higher TMB ( CONCLUSIONS: Our findings suggest a unique molecular profile for MBM, including higher rates of BRAF mutations, higher TMB and higher PD-L1 expression, and also implicate chromatin remodeling in the pathogenesis of MBM

Anti-PD-1 monoclonal antibody MEDI0680 in a phase I study of patients with advanced solid malignancies.

BACKGROUND: The safety, efficacy, pharmacokinetics, and pharmacodynamics of the anti-programmed cell death-1 antibody MEDI0680 were evaluated in a phase I, multicenter, dose-escalation study in advanced solid malignancies. METHODS: MEDI0680 was administered intravenously once every 2 weeks (Q2W) or once every 3 weeks at 0.1, 0.5, 2.5, 10 or 20 mg/kg. Two cohorts received 20 mg/kg once a week for 2 or 4 weeks, then 20 mg/kg Q2W. All were treated for 12 months or until progression. The primary endpoint was safety. Secondary endpoints were efficacy and pharmacokinetics. Exploratory endpoints included pharmacodynamics. RESULTS: Fifty-eight patients were treated. Median age was 62.5 years and 81% were male. Most had kidney cancer (n = 36) or melanoma (n = 9). There were no dose-limiting toxicities. Treatment-related adverse events occurred in 83% and were grade ≥ 3 in 21%. Objective clinical responses occurred in 8/58 patients (14%): 5 with kidney cancer, including 1 with a complete response, and 3 with melanoma. The relationship between dose and serum levels was predictable and linear, with apparent receptor saturation at 10 mg/kg Q2W and all 20 mg/kg cohorts. CONCLUSIONS: MEDI0680 induced peripheral T-cell proliferation and increased plasma IFNγ and associated chemokines regardless of clinical response. CD8+ T-cell tumor infiltration and tumoral gene expression of IFNG, CD8A, CXCL9, and granzyme K (GZMK) were also increased following MEDI0680 administration. TRIAL REGISTRATION: NCT02013804 ; date of registration December 12, 2013

Phase I study combining the aurora kinase A (AURKA) inhibitor alisertib (Ali) with mFOLFOX in gastrointestinal (GI) cancer

2593 Background: Overexpression and cellular mis-localization of AURKA in GI cancers results in chromosomal instability, activation of several oncogenic pathways, and inhibition of pro-apoptotic signaling. Inhibition of AURKA causes mitotic delays, severe chromosome congression, and activation of p53/p73 causing cell death. Our preclinical data showed synergy of Ali and platinum agents in GI cells and xenografts, and suggested an optimal timing window of the combination. The purpose of this study was to assess safety of Ali + mFOLFOX, as this is a standard platinum-based therapy for GI cancers. Methods: This CTEP-sponsored, investigator-initiated, study (NCT02319018) used standard 3+3 dose escalation to determine the maximum tolerated dose (MTD) of Ali + mFOLFOX. Eligible patients (pts) had metastatic or unresectable GI cancer where standard therapies did not exist or were no longer effective, or for whom FOLFOX was appropriate. Pts received escalating doses of Ali starting at 10 mg twice daily (D1-3), with leucovorin + oxaliplatin (85 mg/m 2 ) on D2 followed by continuous 5FU (2400 mg/m 2 ) infusion on D2-4 in 14-day cycles. Dose-limiting toxicity (DLT) was any treatment-related non-hematologic ≥Gr3 toxicity (except diarrhea or nausea, vomiting, controllable with meds) or ≥Gr4 hematologic toxicity observed during the first 28 days. Results: 13 pts were enrolled and 2 dose levels explored; 2 pts were not evaluable for DLT and replaced. Zero DLTs observed in first 3 pts. Ali was escalated to 20 mg where 2/6 had a DLT [Gr3 fatigue (n = 2); Gr3 nausea, vomiting, dehydration with hospitalization (n = 1)]. Ali was de-escalated and 2 of 3 pts have been enrolled; 0 DLTs observed thus far. Most frequent toxicities (%) were nausea (54), fatigue (46), neuropathy (46), anorexia (38), and anemia (38), most ≤Gr2. One of 10 evaluable pts had a partial response, and 6 had stable disease for a 70% disease control rate. Conclusions: The MTD will be 10 mg Ali (D1-3) + oxaliplatin (D2, 85 mg/m 2 ) + continuous 5FU (D2-4, 2400 mg/m 2 ). The combination was tolerable, and preliminary clinical activity was seen in a majority of pts. Correlative biomarker studies to evaluate AURKA target inhibition are ongoing and will be reported. Clinical trial information: NCT02319018

790MO Phase I study of fianlimab, a human lymphocyte activation gene-3 (LAG-3) monoclonal antibody, in combination with cemiplimab in advanced melanoma (mel)

Background: Concurrent blockade of LAG-3 may enhance efficacy of anti-programmed cell death-1 (PD-1) therapies. We present updated safety and clinical activity data from patients (pts) with advanced mel treated with concurrent anti-LAG-3 (fianlimab) and anti-PD-1 (cemiplimab). Methods: This phase 1 study included pts with unresectable or metastatic mel (excluding uveal mel) who were anti–PD-(L)1 treatment naïve (expansion cohort [EC] 6) or anti–PD-(L) 1 experienced within 3 months of screening (EC7). Pts received fianlimab 1600 mg + cemiplimab 350 mg intravenously every 3 weeks for 12 months (optional additional 12 months if clinically indicated). Tumour measurements were performed every 6 weeks for 24 weeks, then every 9 weeks. Results: As of the 9 Feb 2022 data cutoff date, 40 EC6 and 15 EC7 pts were enrolled and treated with fianlimab + cemiplimab. For EC6 and EC7 cohorts respectively, median age was 69.5 and 59.0 years, 62.5% and 46.7% were male, 90.0% and 60.0% were White. Median treatment duration was 37.1 weeks (EC6) and 9.0 weeks (EC7). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 37.5% (EC6) and 46.7% (EC7) of pts; serious TEAEs occurred in 32.5% (EC6) and 33.3% (EC7) of pts; 17.5% (EC6) and 13.3% (EC7) of pts discontinued treatment due to a TEAE. Rate of adrenal insufficiency (AI) was 12.5% (EC6) and 6.7% (EC7); none led to treatment discontinuation. Investigator-assessed objective response rate was 62.5% (6 complete responses; 19 partial responses [PRs]) in EC6 and 13.3% (2 PRs) in EC7 pts. Kaplan-Meier estimation of median progression-free survival was 14.2 (95% CI: 5.6–not estimated) months in EC6 and 1.4 (95% CI: 1.3–7.7) months in EC7 pts. Median duration of response had not been reached in both cohorts. LAG-3 and PD-L1 correlative biomarkers analysis will be included in the presentation. Conclusions: Fianlimab + cemiplimab in advanced mel pts had a similar safety profile to anti–PD-1 agents; clinical activity in anti-PD-(L)1-naïve patients appears higher than previously reported for anti-PD-1 monotherapy or anti–LAG-3 + anti–PD-1. A phase 3 trial (NCT05352672) investigating fianlimab + cemiplimab in advanced mel pts is ongoing

Correction to: Phase I study combining the aurora kinase a inhibitor alisertib with mFOLFOX in gastrointestinal cancer

The authors would like to note that the investigator affiliations have been corrected to reflect the actual affiliations of each author. The authors would also like to note an amendment to the first name of the second author. Nilo Azad was changed to reflect the full name of the author, which is Nilofer S. Azad as shown above. The original article has been corrected

Phase I study combining the aurora kinase a inhibitor alisertib with mFOLFOX in gastrointestinal cancer

Overexpression and cellular mis-localization of aurora kinase A (AURKA) in gastrointestinal cancers results in chromosomal instability, activation of multiple oncogenic pathways, and inhibition of pro-apoptotic signaling. Inhibition of AURKA causes mitotic delays, severe chromosome congression, and activation of p53/p73 leading to cell death. Our preclinical data showed cooperative activity with the AURKA inhibitor alisertib and platinum agents in cell lines and xenografts, and suggested an optimal treatment window. Therefore, this study was designed to determine the maximum-tolerated dose (MTD) of alisertib in combination with modified FOLFOX (mFOLFOX), as this is a standard platinum-based therapy for gastrointestinal cancers. Standard 3 + 3 dose escalation was used, where the starting dose of alisertib was 10 mg twice daily (Days 1-3), with leucovorin (400 mg/m ) and oxaliplatin (85 mg/m ) on Day 2 followed by continuous 46-h 5-FU (2400 mg/m ) infusion on Days 2-4 in 14-day cycles. Fourteen patients with advanced gastrointestinal cancers were enrolled and two doses explored; two patients were not evaluable for dose-limiting toxicity (DLT) and replaced. Two patients experienced DLTs at 20 mg of alisertib (Grade 3 fatigue (n = 2); Grade 3 nausea, vomiting, dehydration with hospitalization (n = 1)). MTD was 10 mg alisertib with 85 mg/m oxaliplatin and 2400 mg/m 5-FU. Most frequent toxicities were nausea (57%), diarrhea, fatigue, neuropathy, and vomiting (43%), and anorexia and anemia (36%); most were Grade 1-2. One patient with colorectal cancer had a partial response of 12 evaluable patients, and four patients had stable disease. Alisertib in combination with mFOLFOX did not demonstrate unexpected side effects, but the regimen was only tolerable at the lowest dose investigated

A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors

Objective Cobimetinib, a MEK1/2 inhibitor, was administered to patients with advanced solid tumors to assess safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity. Methods For dose-escalation, a 3 + 3 design was used. Oral cobimetinib was administered once daily on a 21-day on/7-day off (21/7) or a 14-day on/14-day off (14/14) schedule. Serial plasma samples were collected for pharmacokinetic (PK) analysis on Day 1 and at steady state. In expansion stages, patients with RAS or RAF mutant tumors were treated at the maximum tolerated dose (MTD) of the 21/7 or 14/14 schedule. Results Ninety-seven patients received cobimetinib. In the 21/7 dose escalation, 36 patients enrolled in 8 cohorts (0.05 mg/kg-80 mg). Dose-limiting toxicities (DLTs) were Grade 4 hepatic encephalopathy, Grade 3 diarrhea, and Grade 3 rash. In the 14/14 dose escalation, 20 patients enrolled in 4 cohorts (60-125 mg). DLTs were Grade 3 rash and Grade 3 blurred vision associated with presence of reversible subretinal fluid. The MTD was 60 mg on 21/7 schedule and 100 mg on 14/14 schedule. Cobimetinib PK showed dose-proportional increases in exposure. The most frequent adverse events attributed to cobimetinib were diarrhea, rash, fatigue, edema, nausea, and vomiting. In patients treated at the 60-mg (21/7) or 100-mg (14/14) dose, one unconfirmed complete response and 6 confirmed partial responses were observed. All responses occurred in melanoma patients; 6 harbored the BRAF(V600E) mutation. Conclusions Cobimetinib is generally well tolerated and durable responses were observed in BRAF(V600E) mutant melanoma patients. Evaluation of cobimetinib in combination with other therapies is ongoing