Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with moderately emetogenic chemotherapy: results of a randomized, double-blind phase III trial

C Weinstein, K Jordan, S A Green, E Camacho, S Khanani, E Beckford-Brathwaite, W Vallejos, L W Liang, S J Noga, B L Rapoport, C Weinstein, K Jordan, S A Green, E Camacho, S Khanani, E Beckford-Brathwaite, W Vallejos, L W Liang, S J Noga, B L Rapoport

Abstract

Background: To establish the role of antiemetic therapy with neurokinin-1 (NK1) receptor antagonists (RAs) in nonanthracycline and cyclophosphamide (AC)-based moderately emetogenic chemotherapy (MEC) regimens, this study evaluated single-dose intravenous (i.v.) fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) associated with non-AC MEC.

Patients and methods: In this international, phase III, double-blind trial, adult cancer subjects scheduled to receive ≥1 non-AC MEC on day 1 were randomized to a regimen comprising single-dose i.v. fosaprepitant 150 mg or placebo along with ondansetron and dexamethasone on day 1; control regimen recipients received ondansetron on days 2 and 3. Primary end points were the proportion of subjects achieving a complete response (CR; no vomiting and no use of rescue medication) in the delayed phase (25-120 h after MEC initiation) and safety. Secondary end points included CR in the overall and acute phases (0-120 and 0-24 h after MEC initiation, respectively) and no vomiting in the overall phase. Nausea and the Functional Living Index-Emesis were assessed as exploratory end points.

Results: The fosaprepitant regimen improved CR significantly in the delayed (78.9% versus 68.5%; P < 0.001) and overall (77.1% versus 66.9%; P < 0.001) phases, but not in the acute phase (93.2% versus 91.0%; P = 0.184), versus control. In the overall phase, the proportion of subjects with no vomiting (82.7% versus 72.9%; P < 0.001) and no significant nausea (83.2% versus 77.9%; P = 0.030) was also significantly improved with the fosaprepitant regimen. The fosaprepitant regimen was generally well tolerated.

Conclusion: Single-dose fosaprepitant added to a 5-HT3 RA and dexamethasone was well tolerated and demonstrated superior control of CINV (primary end point achieved) associated with non-AC MEC. This is the first study to evaluate NK1 RA therapy as an i.v. formulation in a well-defined non-AC MEC population.

Clinicaltrialsgov: NCT01594749 (https://ichgcp.net/clinical-trials-registry/NCT01594749).

Keywords: fosaprepitant dimeglumine; moderately emetogenic chemotherapy; nausea; neurokinin-1 receptor antagonists; vomiting.

© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Figures

Figure 1.
Figure 1.
CONSORT diagram. ASaT, all subjects as treated; ITT, intent-to-treat.
Figure 2.
Figure 2.
Proportion of subjects with (A) complete response (CR) and (B) no vomiting in the acute (0–24 h), delayed (25–120 h), and overall (0–120 h) phases following initiation of a first dose of moderately emetogenic chemotherapy.

References

    1. Roila F, Herrstedt J, Aapro M et al. . Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol 2010; 21(suppl 5): v232–v243.
    1. National Comprehensive Cancer Network, Inc. NCCN Clinical Practice Guidelines in Oncology. Antiemesis. Version 1.2014. National Comprehensive Cancer Network Web site; 2014.
    1. Gralla RJ, Roila F, Tonato M, Herrstedt J. MASCC/ESMO antiemetic guideline 2013. Hillerød, Denmark: Multinational Association of Supportive Care in Cancer; 2014.
    1. Jordan K, Gralla R, Jahn F, Molassiotis A. International antiemetic guidelines on chemotherapy induced nausea and vomiting (CINV): content and implementation in daily routine practice. Eur J Pharmacol 2014; 722: 197–202.
    1. Basch E, Prestrud AA, Hesketh PJ et al. . Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2011; 29: 4189–4198.
    1. Hickok JT, Roscoe JA, Morrow GR et al. . 5-Hydroxytryptamine-receptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial. Lancet Oncol 2005; 6: 765–772.
    1. Geling O, Eichler HG. Should 5-hydroxytryptamine-3 receptor antagonists be administered beyond 24 hours after chemotherapy to prevent delayed emesis? Systematic re-evaluation of clinical evidence and drug cost implications. J Clin Oncol 2005; 23: 1289–1294.
    1. Hesketh PJ, Grunberg SM, Gralla RJ et al. . The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin—the Aprepitant Protocol 052 Study Group. J Clin Oncol 2003; 21: 4112–4119.
    1. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD et al. . Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America. Cancer 2003; 97: 3090–3098.
    1. Warr DG, Hesketh PJ, Gralla RJ et al. . Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy. J Clin Oncol 2005; 23: 2822–2830.
    1. Prescribing information. Emend (Aprepitant) Capsules, for Oral use. Whitehouse Station, NJ: Merck Sharp & Dohme Corp. 2013.
    1. Prescribing information. Emend (Fosaprepitant Dimeglumine) for Injection, for Intravenous use. Whitehouse Station, NJ: Merck Sharp & Dohme Corp. 2013.
    1. Jordan K, Jahn F, Aapro M. Recent developments in the prevention of chemotherapy-induced nausea and vomiting (CINV): a comprehensive review. Ann Oncol 2015; 26: 1081–1090.
    1. Hesketh PJ, Kris MG, Grunberg SM et al. . Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol 1997; 15: 103–109.
    1. Saito H, Yoshizawa H, Yoshimori K et al. . Efficacy and safety of single-dose fosaprepitant in the prevention of chemotherapy-induced nausea and vomiting in patients receiving high-dose cisplatin: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial. Ann Oncol 2013; 24: 1067–1073.
    1. Gralla RJ, de Wit R, Herrstedt J et al. . Antiemetic efficacy of the neurokinin-1 antagonist, aprepitant, plus a 5HT3 antagonist and a corticosteroid in patients receiving anthracyclines or cyclophosphamide in addition to high-dose cisplatin: analysis of combined data from two phase III randomized clinical trials. Cancer 2005; 104: 864–868.
    1. Rapoport BL, Jordan K, Boice JA et al. . Aprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with a broad range of moderately emetogenic chemotherapies and tumor types: a randomized, double-blind study. Support Care Cancer 2010; 18: 423–431.
    1. Aapro M, Rugo H, Rossi G et al. . A randomized phase 3 study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy. Ann Oncol 2014; 25: 1328–1333.
    1. Schnadig ID, Modiano MR, Poma A et al. . Phase 3 trial results for rolapitant, a novel NK-1 receptor antagonist, in the prevention of chemotherapy-induced nausea and vomiting (CINV) in subjects receiving moderately emetogenic chemotherapy (MEC). J Clin Oncol 2014; 32(5 suppl): abstr 9633.
    1. Grunberg S, Chua D, Maru A et al. . Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol—EASE. J Clin Oncol 2011; 29: 1495–1501.
    1. Gralla RJ, Bosnjak SM, Hontsa A et al. . A phase III study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting over repeated cycles of chemotherapy. Ann Oncol 2014; 25: 1333–1349.
    1. Leal AD, Kadakia KC, Looker S et al. . Fosaprepitant-induced phlebitis: a focus on patients receiving doxorubicin/cyclophosphamide therapy. Support Care Cancer 2014; 22: 1313–1317.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit