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Multicenter, placebo-controlled, double-blind, randomized study of fosnetupitant in combination with palonosetron for the prevention of chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy.

ABSTRACT: BACKGROUND:The current randomized, double-blind, phase 2 study assessed the efficacy and safety profile of a single intravenous administration of fosnetupitant, a neurokinin 1 receptor antagonist prodrug, for the prevention of chemotherapy-induced nausea and vomiting in Japanese patients receiving cisplatin-based chemotherapy. METHODS:Patients scheduled to receive cisplatin (at a dose of ?70 mg/m2 )-based regimens were randomly assigned to receive fosnetupitant at a dose of 81 mg or 235 mg or placebo in combination with palonosetron at a dose of 0.75 mg and dexamethasone. The primary endpoint was complete response (CR; no vomiting and no rescue medication) during the overall phase (0-120 hours). The overall CR rate was compared between each dose of fosnetupitant and the placebo group adjusting for the stratification factors of sex and age class (age <55 years vs age ?55 years). Safety was assessed, with special attention given to events that potentially were suggestive of infusion site reactions. RESULTS:A total of 594 patients were randomized. Of these, 194 patients, 195 patients, and 195 patients, respectively, in the placebo and fosnetupitant 81-mg and 235-mg dose groups were evaluable for efficacy. The overall CR rate was 54.7% for the placebo group, 63.8% for the fosnetupitant 81-mg dose group (adjusted difference, 9.1%; 95% CI, -0.4% to 18.6% [P = .061]), and 76.8% for the fosnetupitant 235-mg dose group (adjusted difference, 22.0%; 97.5% CI, 11.7% to 32.3% [P < .001]). Safety profiles were comparable between the 3 groups. The incidence of infusion site reactions related to fosnetupitant was ?1% in each dose group. CONCLUSIONS:Fosnetupitant at a dose of 235 mg provided superior prevention of chemotherapy-induced nausea and vomiting among patients receiving cisplatin-based chemotherapy compared with the control group, and with a satisfactory safety profile.

SUBMITTER: Sugawara S

PROVIDER: S-EPMC6900104 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Multicenter, placebo-controlled, double-blind, randomized study of fosnetupitant in combination with palonosetron for the prevention of chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy.

Sugawara Shunichi S Inui Naoki N Kanehara Masashi M Morise Masahiro M Yoshimori Kozo K Kumagai Toru T Fukui Tomoya T Minato Koichi K Iwashima Akira A Takeda Yuichiro Y Kubota Kaoru K Saeki Toshiaki T Tamura Tomohide T

Cancer 20190805 22

<h4>Background</h4>The current randomized, double-blind, phase 2 study assessed the efficacy and safety profile of a single intravenous administration of fosnetupitant, a neurokinin 1 receptor antagonist prodrug, for the prevention of chemotherapy-induced nausea and vomiting in Japanese patients receiving cisplatin-based chemotherapy.<h4>Methods</h4>Patients scheduled to receive cisplatin (at a dose of ≥70 mg/m<sup>2</sup> )-based regimens were randomly assigned to receive fosnetupitant at a dos ...[more]

PMID: 31381152

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Project description:BackgroundFor the prevention of chemotherapy-induced nausea and vomiting (CINV) during the delayed phase (24-120 hours) after moderately emetogenic chemotherapy (MEC), the use of 3-day dexamethasone (DEX) is often recommended. This study compared the efficacy and safety of two DEX-sparing regimens with 3-day DEX, focusing on delayed nausea.Patients and methodsThis open-label, randomized, phase III study was designed to demonstrate noninferiority of two DEX-sparing regimens: ondansetron + DEX on day 1 + metoclopramide on days 2-3 (MCP arm), and palonosetron + DEX on day 1 (PAL arm) versus ondansetron on day 1 + DEX on days 1-3 (DEX arm) in chemotherapy-naïve patients receiving MEC. Primary efficacy endpoint was total control (TC; no emetic episodes, no use of rescue medication, no nausea) in the delayed phase. Noninferiority was defined as a lower 95% CI greater than the noninferiority margin set at -20%. Secondary endpoints included no vomiting, no rescue medication, no (significant) nausea, impact of CINV on quality of life, and antiemetics-associated side effects.ResultsTreatment arms were comparable for 189 patients analyzed: predominantly male (55.7%), median age 65.0?years, colorectal cancer (85.7%), and oxaliplatin-based chemotherapy (81.5%). MCP demonstrated noninferiority to DEX for delayed TC (MCP 56.1% vs. DEX 50.0%; 95% CI, -11.3%, 23.5%). PAL also demonstrated noninferiority to DEX (PAL 55.6% vs. DEX 50.0%; 95% CI, -12.0%, 23.2%). There were no statistically significant differences for all secondary endpoints between treatment arms.ConclusionThis study showed that DEX-sparing regimens are noninferior to multiple-day DEX in terms of delayed TC rate in patients undergoing MEC. ClinicalTrials.gov identifier. NCT02135510.Implications for practiceChemotherapy-induced nausea and vomiting (CINV) in the delayed phase (24-120 hours after chemotherapy) remains one of the most troublesome adverse effects associated with cancer treatment. In particular, delayed nausea is often poorly controlled. The role of dexamethasone (DEX) in the prevention of delayed nausea after moderately emetogenic chemotherapy (MEC) is controversial. This study is the first to include nausea assessment as a part of the primary study outcome to better gauge the effectiveness of CINV control and patients' experience. Results show that a DEX-sparing strategy does not result in any significant loss of overall antiemetic control: DEX-sparing strategies incorporating palonosetron or multiple-day metoclopramide are safe and at least as effective as standard treatment with a 3-day DEX regimen with ondansetron in controlling delayed CINV-and nausea in particular-following MEC.

Project description:BackgroundNeurokinin (NK) 1 receptor antagonists (RAs), administered in combination with a 5-hydroxytryptamine-3 (5-HT3 ) RA and dexamethasone (DEX), have demonstrated clear improvements in chemotherapy-induced nausea and vomiting (CINV) prevention over a 5-HT3 RA plus DEX. However, studies comparing the NK1 RAs in the class are lacking. A fixed combination of a highly selective NK1 RA, netupitant, and the 5-HT3 RA, palonosetron (NEPA), simultaneously targets two critical antiemetic pathways, thereby offering a simple convenient antiemetic with long-lasting protection from CINV. This study is the first head-to-head NK1 RA comparative study in patients receiving anthracycline cyclophosphamide (AC) and non-AC moderately emetogenic chemotherapy (MEC).Materials and methodsThis was a pragmatic, multicenter, randomized, single-cycle, open-label, prospective study designed to demonstrate noninferiority of single-dose NEPA to a 3-day aprepitant regimen in preventing CINV in chemotherapy-naive patients receiving AC/non-AC MEC in a real-life setting. The primary efficacy endpoint was complete response (no emesis/no rescue) during the overall (0-120 hour) phase. Noninferiority was achieved if the lower limit of the 95% confidence interval (CI) of the difference between NEPA and the aprepitant group was greater than the noninferiority margin set at -10%.ResultsNoninferiority of NEPA versus aprepitant was demonstrated (risk difference 9.2%; 95% CI, -2.3% to 20.7%); the overall complete response rate was numerically higher for NEPA (64.9%) than aprepitant (54.1%). Secondary endpoints also revealed numerically higher rates for NEPA than aprepitant.ConclusionThis pragmatic study in patients with cancer receiving AC and non-AC MEC revealed that a single dose of oral NEPA plus DEX was at least as effective as a 3-day aprepitant regimen, with indication of a potential efficacy benefit for NEPA.Implications for practiceIn the absence of comparative neurokinin 1 (NK1 ) receptor antagonist (RA) studies, guideline committees and clinicians consider NK1 RA agents to be interchangeable and equivalent. This is the first head-to-head study comparing one NK1 RA (oral netupitant/palonosetron [NEPA]) versus another (aprepitant) in patients receiving anthracycline cyclophosphamide (AC) and non-AC moderately emetogenic chemotherapy. Noninferiority of NEPA versus the aprepitant regimen was demonstrated; the overall complete response (no emesis and no rescue use) rate was numerically higher for NEPA (65%) than aprepitant (54%). As a single-dose combination antiemetic, NEPA not only simplifies dosing but may offer a potential efficacy benefit over the current standard-of-care.

Dataset Information

Multicenter, placebo-controlled, double-blind, randomized study of fosnetupitant in combination with palonosetron for the prevention of chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy.

Publications

Multicenter, placebo-controlled, double-blind, randomized study of fosnetupitant in combination with palonosetron for the prevention of chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy.

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