A double-blind randomized phase II dose-finding study of olanzapine 10 mg or 5 mg for the prophylaxis of emesis induced by highly emetogenic cisplatin-based chemotherapy

Abstract

Purpose

The aim of this phase II study was to evaluate the efficacy and safety of two doses (10 and 5 mg) of olanzapine in combination with standard antiemetic treatment (aprepitant, palonosetron, and dexamethasone) for patients receiving highly emetogenic chemotherapy (HEC).

Methods

A multi-institutional, double-blind, randomized phase II, dose-finding study of olanzapine was performed in patients with a malignant solid tumor who were receiving HEC with cisplatin (≥ 50 mg/m2). Patients were randomly assigned either olanzapine 10 or 5 mg orally on days 1–4, combined with standard antiemetic treatment. The primary endpoint was a complete response (CR; no emesis and no use of rescue medications) in the delayed phase (24–120 h after the start of cisplatin treatment).

Results

153 patients were randomized to the 10 mg group (n = 76) or the 5 mg group (n = 77). The CR rate in the delayed phase was 77.6% (80% CI: 70.3–83.8, P = 0.01) in the 10 mg group and 85.7% (80% CI: 79.2–90.7, P < 0.001) in the 5 mg group (P value for H 0: complete response rate ≤ 65%). The most common adverse event was somnolence, which had an incidence of 53.3 and 45.5% in the 10 and 5 mg olanzapine groups, respectively.

Conclusions

Both doses of 10 and 5 mg olanzapine provided a significant improvement in delayed emesis. A dose of 5 mg olanzapine was determined as the recommended dose for a further phase III study based on higher CR and lower somnolence rates.

Clinical Trial Information

UMIN000014214

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References

  1. 1.

    Basch E, Prestrud AA, Hesketh PJ et al (2011) Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 29:4189–4198. doi:10.1200/JCO.2010.34.4614

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    National Comprehensive Cancer Network (2014) Antiemesis. In: NCCN clinical practice guidelines in oncology version 1. 2014. Available via the National Comprehensive Cancer Network. https://www.nccn.org/. Accessed 13 Sep 2014

  3. 3.

    Suzuki K, Yamanaka T, Hashimoto H et al (2016) Randomized, double-blind, phase III trial of palonosetron versus granisetron in the triplet regimen for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy: TRIPLE study. Ann Oncol 27:1601–1606. doi:10.1093/annonc/mdw220

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Bymaster FP, Calligaro DO, Falcone JF et al (1996) Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 14:87–96. doi:10.1016/0893-133X(94)00129-N

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Schotte A, Janssen PF, Gommeren W et al (1996) Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl) 124:57–73

    CAS  Article  Google Scholar 

  6. 6.

    Bymaster FP, Nelson DL, DeLapp NW et al (1999) Antagonism by olanzapine of dopamine D1, serotonin2, muscarinic, histamine H1 and alpha 1-adrenergic receptors in vitro. Schizophr Res 37:107–122

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Navari RM, Einhorn LH, Passik SD et al (2005) A phase II trial of olanzapine for the prevention of chemotherapy-induced nausea and vomiting: a Hoosier Oncology Group study. Support Care Cancer 13:529–534. doi:10.1007/s00520-004-0755-6

    Article  PubMed  Google Scholar 

  8. 8.

    Navari RM, Einhorn LH, Loehrer PJ Sr et al (2007) A phase II trial of olanzapine, dexamethasone, and palonosetron for the prevention of chemotherapy-induced nausea and vomiting: a Hoosier oncology group study. Support Care Cancer 15:1285–1291. doi:10.1007/s00520-007-0248-5

    Article  PubMed  Google Scholar 

  9. 9.

    Tan L, Liu J, Liu X et al (2009) Clinical research of Olanzapine for prevention of chemotherapy-induced nausea and vomiting. J Exp Clin Cancer Res 28:131. doi:10.1186/1756-9966-28-131

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Navari RM, Gray SE, Kerr AC (2011) Olanzapine versus aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a randomized phase III trial. J Support Oncol 9:188–195. doi:10.1016/j.suponc.2011.05.002

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Navari RM, Nagy CK, Gray SE (2013) The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy. Support Care Cancer 21:1655–1663. doi:10.1007/s00520-012-1710-6

    Article  PubMed  Google Scholar 

  12. 12.

    Mizukami N, Yamauchi M, Koike K et al (2014) Olanzapine for the prevention of chemotherapy-induced nausea and vomiting in patients receiving highly or moderately emetogenic chemotherapy: a randomized, double-blind, placebo-controlled study. J Pain Symptom Manag 47:542–550. doi:10.1016/j.jpainsymman.2013.05.003

    Article  Google Scholar 

  13. 13.

    Abe M, Hirashima Y, Kasamatsu Y et al (2016) Efficacy and safety of olanzapine combined with aprepitant, palonosetron, and dexamethasone for preventing nausea and vomiting induced by cisplatin-based chemotherapy in gynecological cancer: KCOG-G1301 phase II trial. Support Care Cancer 24:675–682. doi:10.1007/s00520-015-2829-z

    Article  PubMed  Google Scholar 

  14. 14.

    Nagashima K, Iwasa S, Yanai T et al (2015) A double-blind randomized Phase II study of olanzapine 10 versus 5 mg for emesis induced by highly emetogenic chemotherapy. Jpn J Clin Oncol 45:229–231. doi:10.1093/jjco/hyu191

    Article  PubMed  Google Scholar 

  15. 15.

    Lecoutre B, Derzko G, Grouin JM (1995) Bayesian predictive approach for inference about proportions. Stat Med 14:1057–1063

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Passik SD, Navari RM, Jong SH (2004) A phase I trial of olanzapine (Zyprexa) for the prevention of delayed emesis in cancer patients: a Hoosier Oncology Group study. Cancer Invest 22:383–388

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Roila F, Molassiotis A, Herrstedt J et al (2016) 2016 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea and vomiting in advanced cancer patients. Ann Oncol 27(suppl 5):v119–v133. doi:10.1093/annonc/mdw270

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Navari RM, Qin R, Ruddy KJ et al (2016) Olanzapine for the prevention of chemotherapy-induced nausea and vomiting. N Engl J Med 375:134–142. doi:10.1056/NEJMoa1515725

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    National comprehensive cancer network (2017) Antiemesis. In: NCCN clinical practice guidelines in oncology version 1. 2017-February 22, 2017. Available via the National comprehensive cancer network. https://www.nccn.org/. Accessed 23 Mar 2017

  20. 20.

    Hashimoto H, Yanai T, Nagashima K et al (2016) A double-blind randomized phase II study of 10 versus 5 mg olanzapine for emesis induced by highly emetogenic chemotherapy with cisplatin. J Clin Oncol 34(15):10111. doi:10.1200/JCO.2016.34.15_suppl.10111

    Google Scholar 

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Acknowledgements

The authors thank the patients, clinical investigators, and site personnel who participated in the study. Additional participating institutions and investigators included Shikoku Cancer Center (Daijiro Harada, Yuki Kogure). This work was supported in part by the Foundation for Promotion of Cancer Research in Japan.

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Correspondence to Noboru Yamamoto.

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Conflict of interest

Satoru Iwasa, Koji Takeda, Yasuhiro Shimada and Noboru Yamamoto have received payment for lectures and research funding from Eli Lilly. All remaining authors have declared no conflicts of interest.

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Yanai, T., Iwasa, S., Hashimoto, H. et al. A double-blind randomized phase II dose-finding study of olanzapine 10 mg or 5 mg for the prophylaxis of emesis induced by highly emetogenic cisplatin-based chemotherapy. Int J Clin Oncol 23, 382–388 (2018). https://doi.org/10.1007/s10147-017-1200-4

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Keywords

  • Olanzapine
  • Chemotherapy-induced nausea and vomiting
  • Prophylaxis
  • Phase II study