NEPA is a novel oral fixed-dose combination of netupitant (NETU), a new highly selective neurokinin-1 (NK1) receptor antagonist (RA) and palonosetron (PALO), a pharmacologically and clinically ...distinct 5-hydroxytryptamine type 3 (5-HT3) RA. This study was designed to determine the appropriate clinical dose of NETU to combine with PALO for evaluation in the phase 3 NEPA program.
This randomized, double-blind, parallel group study in 694 chemotherapy naïve patients undergoing cisplatin-based chemotherapy for solid tumors compared three different oral doses of NETU (100, 200, and 300mg) + PALO 0.50mg with oral PALO 0.50mg, all given on day 1. A standard 3-day aprepitant (APR) + IV ondansetron (OND) 32mg regimen was included as an exploratory arm. All patients received oral dexamethasone on days 1–4. The primary efficacy endpoint was complete response (CR: no emesis, no rescue medication) during the overall (0–120h) phase.
All NEPA doses showed superior overall CR rates compared with PALO (87.4%, 87.6%, and 89.6% for NEPA100, NEPA200, and NEPA300, respectively versus 76.5% PALO; P < 0.050) with the highest NEPA300 dose studied showing an incremental benefit over lower NEPA doses for all efficacy endpoints. NEPA300 was significantly more effective than PALO and numerically better than APR + OND for all secondary efficacy endpoints of no emesis, no significant nausea, and complete protection (CR plus no significant nausea) rates during the acute (0–24h), delayed (25–120h), and overall phases. Adverse events were comparable across groups with no dose response. The percent of patients developing electrocardiogram changes was also comparable.
Each NEPA dose provided superior prevention of chemotherapy-induced nausea and vomiting (CINV) compared with PALO following highly emetogenic chemotherapy; however, NEPA300 was the best dose studied, with an advantage over lower doses for all efficacy endpoints. The combination of NETU and PALO was well tolerated with a similar safety profile to PALO and APR + OND.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Safe, effective and convenient antiemetic regimens that preserve benefit over repeated cycles are needed for optimal supportive care during cancer treatment. NEPA, an oral fixed-dose combination of ...netupitant, a highly selective NK1 receptor antagonist (RA), and palonosetron (PALO), a distinct 5-HT3 RA, was shown to be superior to PALO in preventing chemotherapy-induced nausea and vomiting after a single cycle of highly (HEC) or moderately (MEC) emetogenic chemotherapy in recent trials. This study was designed primarily to assess the safety but also to evaluate the efficacy of NEPA over multiple cycles of HEC and MEC.
This multinational, double-blind, randomized phase III study (NCT01376297) in 413 chemotherapy-naïve patients evaluated a single oral dose of NEPA (NETU 300mg + PALO 0.50mg) given on day 1 with oral dexamethasone (DEX). An oral 3-day aprepitant (APR) regimen + PALO + DEX was included as a control (3:1 NEPA:APR randomization). In HEC, DEX was administered on days 1–4 and in MEC on day 1. Safety was assessed primarily by adverse events (AEs), including cardiac AEs; efficacy by complete response (CR: no emesis, no rescue).
Patients completed 1961 total chemotherapy cycles (76% MEC, 24% HEC) with 75% completing ≥4 cycles. The incidence/type of AEs was comparable for both groups. Most frequent NEPA-related AEs included constipation (3.6%) and headache (1.0%); there was no indication of increasing AEs over multiple cycles. The majority of AEs were mild/moderate and there were no cardiac safety concerns based on AEs and electrocardiograms. The overall (0–120h) CR rates in cycle 1 were 81% and 76% for NEPA and APR + PALO, respectively, and antiemetic efficacy was maintained over repeated cycles.
NEPA, a convenient single oral dose antiemetic targeting dual pathways, was safe, well tolerated and highly effective over multiple cycles of HEC/MEC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The advent of new cancer therapies, alongside expected growth and ageing of the population, better survival rates and associated costs of care, is uncovering a need to more clearly define and ...integrate supportive care services across the whole spectrum of the disease. The current focus of cancer care is on initial diagnosis and treatment, and end of life care. The Multinational Association of Supportive Care in Cancer defines supportive care as ‘the prevention and management of the adverse effects of cancer and its treatment’. This encompasses the entire cancer journey, and necessitates involvement and integration of most clinical specialties. Optimal supportive care can assist in accurate diagnosis and management, and ultimately improve outcomes. A national strategy to implement supportive care is needed to acknowledge evolving oncology practice, changing disease patterns and the changing patient demographic.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: Although all first-generation 5-HT3 receptor antagonists demonstrate efficacy in preventing acute chemotherapy-induced nausea and vomiting (CINV), effective prevention of delayed CINV has ...not yet been achieved. This study compared the efficacy and tolerability of palonosetron, a novel, second-generation 5-HT3 receptor antagonist, with ondansetron. Patients and methods: In this multicenter, randomized, double-blind, stratified, phase III study, 570 adult cancer patients were randomized to receive a single i.v. dose of palonosetron 0.25 mg, palonosetron 0.75 mg or ondansetron 32 mg, each administered 30 min before initiation of moderately emetogenic chemotherapy. The primary end point was the proportion of patients with no emetic episodes and no rescue medication complete response (CR) during the 24 h after chemotherapy administration (acute period). Secondary end points included efficacy in treatment of delayed CINV (≤5 days post-chemotherapy) and overall tolerability. Results: 563 patients were evaluable for efficacy. CR rates were significantly higher (P <0.01) for palonosetron 0.25 mg than ondansetron during the acute (0–24 h) (81.0% versus 68.6%, respectively), delayed (24–120 h) (74.1% versus 55.1%) and overall (0–120 h) (69.3% versus 50.3%) periods. CR rates achieved with palonosetron 0.75 mg were numerically higher but not statistically different from ondansetron during all three time intervals. Both treatments were well tolerated. Conclusions: A single i.v. dose of palonosetron 0.25 mg was significantly superior to i.v. ondansetron 32 mg in the prevention of acute and delayed CINV.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
NEPA, an oral fixed combination of the NK1RA netupitant (300mg) and clinically/pharmacologically distinct 5-HT3RA palonosetron (PALO, 0.50mg), is the first fixed antiemetic combination to have been ...approved. A single oral NEPA capsule plus dexamethasone (DEX) given before anthracycline–cyclophosphamide (AC) and non-AC highly emetogenic chemotherapy (HEC) showed superior prevention of chemotherapy-induced nausea and vomiting (CINV) over PALO plus DEX for 5days postchemotherapy. The safety of NEPA was well-established in the phase II/III clinical program in 1169 NEPA-treated patients. An intravenous (i.v.) formulation of the NEPA combination (fosnetupitant 235mg plus PALO 0.25mg) has been developed.
This randomized, multinational, double-blind, stratified (by sex and country) phase III study (NCT02517021) in chemotherapy-naïve patients with solid tumors assessed the safety of a single dose of i.v. NEPA infused over 30min before initial and repeated cycles of HEC. Patients received either i.v. NEPA or oral NEPA, both with oral DEX on days 1–4. Safety was assessed primarily by treatment-emergent adverse events (AEs) and electrocardiograms.
A total of 404 patients completed 1312 cycles. The incidence and type of treatment-emergent AEs were similar for both treatment groups with the majority of AEs as mild/moderate in intensity. There was no increased incidence of AEs in subsequent cycles in either group. The incidence of treatment-related AEs was similar and relatively low in both groups (12.8% i.v. NEPA and 11.4% oral NEPA during the entire study), with constipation being the most common (6.4% i.v. NEPA, 6.0% oral NEPA). No serious treatment-related AEs occurred in either group. No infusion site or anaphylactic reactions related to i.v. NEPA occurred. No clinically relevant changes in QTc and no cardiac safety concerns were observed.
Intravenous NEPA was well-tolerated with a similar safety profile to oral NEPA in patients with various solid tumors receiving HEC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
An attempt has been made to develop a new metallic glass (MG) that combines high hardness with wear resistance. Refractory metallic films of W33Ni32B35 (at.%) have been deposited on stainless steel ...and Si substrates by dc magnetron sputtering. The alloy films are glassy, have a high crystallization temperature of 873 °C and rank among the very hard metallic materials (∼24 GPa). Importantly, this MG also shows excellent wear resistance, approaching that of standard tribological materials like TiN and hence it represents one of the most wear-resistant known metallic materials. Based on its unique combination of high strength and low elastic modulus, other potential applications are also discussed.
•A new, refractory W–Ni–B metallic glass is developed.•Exceptionally wear-resistant alloy.•Very high resilience, suggesting applications in MEMS.•Much cheaper than other W-based metallic glasses.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
In the last 10 years, some regulatory authorities have consistently suggested that the design of randomized controlled trials testing treatments for cachexia should be aimed at demonstrating ...appropriate risk versus benefit, where benefit is defined as concomitant improvement in skeletal muscle mass (or lean mass) and relevant/meaningful physical function or improved survival. ...unlike areas such as hypertension where a given change in blood pressure is accepted as a surrogate for clinical events, it has to be recognized that in cachexia, the ‘relevance’ or ‘meaningfulness’ of a change in surrogates such as hand grip strength, stair‐climb power, leg extension strength or timed sit‐up‐and‐go is not known. For patients with heart failure, chronic kidney disease, stroke or ageing‐related frailty, such multimodal approaches are frequently considered, but evidence is so far weak compared with what has been achieved in COPD. F.S. reports unrestricted grants for clinical research from Celgene, Fresenius, and Helsinn, participation in Novartis lead clinical trial BYM338, and Punctual Advisorship (Boards, Expert meetings) Acacia, ACRAF, Amgen, Baxter, Celgene, Danone, Fresenius, GSK, Grünenthal, Helsinn, ISIS Global, Millennium/Takeda, Mundipharma, Novartis, Novelpharm, Nycomed, Obexia, Otsuka, Ono, Pharm‐Olam, Pfizer, Psioxus, PrIME, Santhera, Sunstone, Teva, Vifor.
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