Invest New Drugs (2018) 36:151–155
DOI 10.1007/s10637-017-0487-3
SHORT REPORT
Feasibility of olanzapine, multi acting receptor targeted
antipsychotic agent, for the prevention of emesis caused
by continuous cisplatin- or ifosfamide-based chemotherapy
Seiko Bun 1 & Kan Yonemori 2 & Toru Akagi 1 & Emi Noguchi 2 & Tatsunori Shimoi 2 &
Akihiko Shimomura 2 & Mayu Yunokawa 2 & Chikako Shimizu 2 & Yasuhiro Fujiwara 2 &
Yoshinori Makino 1 & Yoshikazu Hayashi 1 & Kenji Tamura 2
Received: 3 February 2017 / Accepted: 26 June 2017 / Published online: 21 July 2017
# Springer Science+Business Media, LLC 2017
Summary Background To determine the feasibility and effica-
cy of olanzapine, which is approved by the Pharmaceuticals and
Medical Devices Agency as multi acting receptor targeted anti-
psychotic agent of the thienobenzodiazepine class, for prevention
of chemotherapy-induced nausea and vomiting (CINV) in pa-
tients undergoing continuous five-day chemotherapy. Patients
and methods This study was a prospective dose escalation study
at a single center (UMIN ID: UMIN000015386). Patients re-
ceived a combination of adriamycin and ifosfamide (AI) or a
combination of bleomycin, etoposide, and cisplatin (BEP). On
days 1–5, all patients received intravenous granisetron (1 mg)
and intravenous dexamethasone sodium phosphate (24 mg).
Olanzapine was administrated on day-1 to day5 at bedtime.
The dose of olanzapine followed a dose-escalation scheme, with
monitoring of safety and tolerability at each dose. A 3 + 3 cohort
design was used, with three to six patients per cohort. Results
Nine patients were enrolled (three for each cohort). No patients
experienced dose-limiting toxicity (DLT). The most frequent ad-
verse events were dry mouth and constipation. In each cohort, the
maximum severity of nausea was Grade 2, and no patients ex-
perienced a vomiting episode. Conclusion A 2.5 mg/day dosage
of olanzapine is sufficient to prevent from CINV in Japanese
patients receiving continuous five-day chemotherapy. A dose of
10 mg/day, which is recommended by international CINV guide-
lines, is also tolerated. If CINV is not controlled by an initial dose
* Seiko Bun
sbun@ncc.go.jp
1
Department of Pharmacy, National Cancer Center Hospital, 5-1-1,
Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
2
Department of Breast and Medical oncology, National Cancer Center
Hospital, Tokyo, Japan
of 2.5 mg/day of olanzapine, dosage escalation is encouraged.
Future studies should compare olanzapine with aprepitant.
Keywords Olanzapine . Recommended dose . Emesis .
Five-day chemotherapy . BEP . Ai
Introduction
Chemotherapy-induced nausea and vomiting (CINV), a major
adverse effect of cancer treatment, is associated with a significant
deterioration in quality of life [1]. Single-day chemotherapy has
been developed to ameliorate CINV. In particular, a combination
of 5-hydroxytryptamine type 3 (5HT3) receptor antagonists [2],
dexamethasone, and neurokinin-1 (NK1) receptor antagonists [3]
protect against CINV, especially in the context of high-risk che-
motherapy [4]. However, as for multiple-day chemotherapy, such
as a 5-day continuous regimen, protection method of CINV has
not been developed so far.
Olanzapine, which is approved as an antipsychotic drug by
the Food and Drug Administration (FDA) and the
Pharmaceuticals and Medical Devices Agency (PMDA), is use-
ful for prevention of CINV. Several reports have been shown
olanzapine is useful and efficacy for CINV [5, 6]. Olanzapine
blocks multiple neurotransmitters in the central nervous system,
including dopamine at D1, D2, D3, and D4 receptors; serotonin at
5-HT type 2a, 5-HT type 2c (5-HT2c), 5-HT3, and 5-HT type 6
receptors; catecholamines at alpha1-adrenergic receptors; acetyl-
choline at muscarinic receptors; and histamine at H1 receptors
[7]. Also, in contrast to aprepitant and fosaprepitant which inter-
act with steroids or ifosphamide, olanzapine is known to have
fewer clinically important drug–drug interactions. Although in-
ternational CINV guidelines recommend administration of
olanzapine at a dose of 10 mg/day [8], patients often experience
152
uncomfortable adverse events at this dosage such as dry mouth,
somnolence, and dizziness. Olanzapine effectively prevents
CINV when used in a 1-day administration regimen, e.g., AC
(combination of adriamycin and cyclophosphamide therapy) for
breast cancer and CHOP (combination of adriamycin, cyclo-
phosphamide and vincristine therapy) for hematological cancer
[6, 9, 10]; however, there are currently no data indicating the
efficacy and prevention for CINV by a continuous administration
regimen, e.g., BEP (combination of bleomycin, etopocide and
cisplatin therapy) for germ cell tumor or AI (combination of
adriamycin and ifosphamide) for sarcoma. In this study, we in-
vestigated the feasibility and efficacy of olanzapine for preven-
tion of CINV in Japanese patients undergoing a 5-day continuous
regimen with cisplatin or ifosfamide.
Patients and methods
Patients
Eligible Japanese patients met the following criteria: 15 to
75 years old; with cancer; receiving a chemotherapy regimen
including cisplatin or ifosfamide for multiple days, e.g., BEP
(bleomycin, etoposide, and cisplatin) or AI (adriamycin and
ifosfamide); chemotherapy naïve; Eastern Cooperative
Oncology Group (ECOG) performance status 0–2; absolute neu-
trophil count ≥1500/mm3; platelet count ≥10,000/mm3; hemo-
globin count ≥9.0 g/dL; serum creatinine <1.5 mg/dL; bilirubin
<2 mg/dL; and GOT or GPT 3-fold above the upper limit of
normal. Exclusion criteria were as follows: lack of nausea and
vomiting before beginning protocol therapy; brain metastasis;
hypersensitivity to olanzapine; treatment with a contra-indicated
drug for olanzapine; and uncontrolled diabetes mellitus.
All patients gave written informed consent, and the study was
approved by the National Cancer Center Institutional Review
Board (No.2013–346) in accordance with guidelines on medical
and epidemiological research in an epidemiologic study.
Study design
This study was a prospective dose escalation study at a single
center (UMIN ID: UMIN000015386). Patients who received
AI (doxorubicin, 30 mg/m2 on days 1 and 2; ifosfamide, 2 mg/
m2 on days 1–5), BEP (bleomycin, 30 mg/body on days 1, 8,
and 15; etoposide, 100 mg/m2 on days 1–5; cisplatin, 20 mg/
m2 on days 1–5) were assigned to this protocol. During the
study period, all patient demographics (age, gender, height,
weight, body surface area) and medical data (disease, ECOG
PS, laboratory data, medications) were recorded.
All patients received intravenous granisetron (1 mg) and in-
travenous dexamethasone (19.8 mg; 24 mg as dexamethasone
sodium phosphate) on days 1–5. All anti-emetics were adminis-
tered approximately 1 h before administration of chemotherapy.
Invest New Drugs (2018) 36:151–155
Olanzapine was administrated on day-1 to day5 at bedtime (the
day before the start of chemotherapy to the day of the last
chemotherapy).
Rescue doses, such as prochlorperazine and other phenothia-
zines, were permitted for all cohorts of patients who experienced
nausea and vomiting. However, we did not permit the use of
neurokinin-1 (NK1) antagonist and olanzapine for rescue therapy.
The dose of olanzapine followed a dose-escalation scheme,
with monitoring of safety and tolerability at each dose. A 3 + 3
cohort design was used, with three to six patients per cohort. The
starting dose (cohort 1) was 2.5 mg at bedtime (hs), and if this
was considered tolerable, the dose was escalated to 5 mg hs
(cohort 2). In addition, if the regimen in cohort 2 was considered
tolerable, the dose was escalated to 10 mg hs (cohort 3). A dose
was considered intolerable if two out of six patients in the cohort
experienced dose-limiting toxicity (DLT). If the dose in cohort 3
was not tolerable, cohort 2 could be investigated to identify the
recommended dose (RD). If all cohorts were tolerable, we could
determine the RD that did not cause severe symptoms in patients
undergoing who receive olanzapine. Dose-limiting toxicity was
defined as dry mouth, somnolence, or dizziness above grade 3;
these were the primary reasons that patients rejected olanzapine
in the previous reports by our group [11, 12].
Assessments
The primary objective was to investigate the tolerability of esca-
lating doses of olanzapine in Japanese patients undergoing
multiple-day chemotherapy with AI or BEP. The secondary ob-
jectives were to determine the RD and to evaluate the safety and
antiemetic effect. Antiemetic effect was defined as follows: no
nausea, no vomiting, and no rescue drugs. The overall assess-
ment period was 0–240 h, the early assessment period was 0–
120 h, and the delayed assessment period was 120–240 h.
Safety and tolerability were assessed by recording adverse
events (AEs), physical examination, laboratory findings, and
M.D. Anderson Symptom Inventory (MDASI) [13, 14].
Patients recorded their symptoms using MDASI for cohorts
2 and 3, starting on the day before the chemotherapy and
continuing through day 10. AEs were graded using the
National Cancer Institute’s Common Terminology Criteria
for Adverse Events (NCI CTCAE) v4.0 [15] and summarized
from the first dose through 10 days.
Results
Patient characteristics
A total of nine patients were enrolled in this study from
August 2014 to March 2016, and were divided into three
cohorts of three patients each. Median ages were as follows:
cohort 1, 35 years (range, 25–43); cohort 2, 48 years (range,
Invest New Drugs (2018) 36:151–155 153

Table 1 Patients characteristics

Cohort 1 2.5 mg hs (n = 3) Cohort 2 5 mg hs (n = 3) Cohort 3 10 mg hs (n = 3)

Median age, years 35 (25–43) 48 (34–56) 34 (22–53)

(range)
Gender, n
Male 2 3 2
Female 1 0 1
ECOG performance status, n
0 3 3 3
Disease, n
Germ cell tumor 3 1 2
Synovial sarcoma 0 2 0
Spindle cell sarcoma 0 0 1
Chemotherapy, n
BEP 3 1 2
AI 0 2 1

hs: before bedtime

ECOG: Eastern Cooperative Oncology Group
BEP: bleomycin, 30 mg/body on days 1, 8, and 15; etoposide, 100 mg/m2 on days 1–5; cisplatin, 20 mg/m2 on
days 1–5
AI: doxorubicin, 30 mg/m2 on days 1 and 2; ifosfamide, 2 mg/m2 on days 1–5

34–56); and cohort 3, 34 years (22–53). All patients had 1 constipation (cohort 1, two patients; cohort 2, one patient;
European Cooperative Oncology Group Performance status cohort 3, one patient) (Table 3).
(PS) 0. Seven of the patients were male. Six patients received
BEP and three patients received AI (Table 1).
Efficacy

Tolerability
Olanzapine-related toxicity was grade 1, which was similar in
each cohort (Table 2). No patients exhibited DLT: dry mouth of
grade 1 was observed in some patients (cohort 1, no patients;
cohort 2, 3 patients; cohort 3, one patient), but no patients exhib-
ited somnolence and dizziness. Other non-hematological toxic-
ities included grade 1 fatigue (cohort 1, one patient; cohort 2, one
patient; cohort 3, no patients), grade 1 malaise (cohort 1, no
patients; cohort 2, one patient; cohort 3, one patient), and grade
In each cohort, the maximum severity of nausea was grade 2, and
no patients experienced a vomiting episode. Some patients need-
ed rescue medication on days 3–5 (the early assessment period),
but there was no significant difference between the two groups
(Table 3). The number of rescue medication on days 6–10 (the
delayed assessment period) was fewer than that on days 1–5 (the
early assessment period). MDASI tended to improve with in-
creasing doses of olanzapine (Fig. 1). The common symptoms
in MDASI were Black of appetite^, Bsleepy^, Bfatigue^ and Bdry
mouth^ (data not shown).

Table 2 Grading of nausea and

vomiting for each cohort, and Grade (worst) Days after chemotherapy
time until use of rescue medicine.
M: Use of metoclopramide (5 mg Case Nausea Vomiting 1 2 3 4 5 6 7 8 9 10
po). P: Use of prochlorperazine Cohort 1 2.5 mg hs 1 Grade 1 None M M P M
(5 mg po) 2 Grade 1 None
3 Grade 1 None M
Cohort 2 5 mg hs 4 Grade 2 None M M
5 Grade 1 None
6 Grade 1 None
Cohort 3 10 mg hs 7 None None
8 Grade1 None P
9 Grade1 None M M M M
154 Invest New Drugs (2018) 36:151–155

Table 3 AEs of all grades

occurring in this study Cohort 1 2.5 mg hs (n = 3) Cohort 2 5 mg hs (n = 3) Cohort 3 10 mg hs (n = 3)

Dry mouth 0/3 3/3 1/3

Somnolence 0/3 0/3 0/3
Dizziness 0/3 0/3 0/3
Fatigue 1/3 1/3 0/3
Malaise 0/3 1/3 1/3
Constipation 2/3 1/3 1/3

Discussion higher dosage of olanzapine did not score the worse

This is the first report to demonstrate the suitability of
olanzapine for preventing CINV in Japanese patients receiving
continuous 5-day chemotherapy. Even though five-day chemo-
therapy regimen was usually used in patients with uncommon
cancers such as sarcoma or germ cell tumor, which our depart-
ment treat only a few new patients per year, we could recruit 9
patients in two years.
Patients who received any dosage of olanzapine experi-
enced reduced nausea and vomiting. In addition, all doses of
olanzapine were safe and efficacious. The lowest dosage,
2.5 mg/day, was tolerable for the purpose of preventing
CINV; similarly, the highest dosage of 10 mg/day was also
well tolerated. No dosage of olanzapine caused dose-limiting
toxicity, but we did observe individual differences in efficacy.
It is known that the side effects of olanzapine are more com-
mon at higher doses. In our study, patients who received
Fig. 1 Patient-reported outcomes for nausea. Patients in Cohort 2 (a) and
3 (b) according to self-reported MDASI. Patients recorded MDASI at
about 9 pm each day
MDASI, compared with lower dosage. Most of the symptoms
that patients experienced were similar to those in the previous
reports. The mechanism of olanzapine as antiemetics is main-
ly considered to be associated with dopamine receptor and
histamine receptor. The results of our study can be explained
by the past reports in psychiatric fields which analyzed the
occupancy of the receptors by olanzapine. There, even the
lower dosage of olanzapine, such as 2.5 mg/day, had a high
affinity for the receptors, e.g., serotonin receptor (70–80%)
and dopamine receptor (60%) [16]. These results suggest that
Japanese patients can begin with the lowest dosage of
olanzapine; if that dosage does not prevent CINV, then the
patients can receive the higher dose (10 mg/day) recommend-
ed by international CINV guidelines.
In addition, olanzapine exhibits fewer drug–drug inter-
actions than aprepitant and fosaprepitant. In particular,
previous reports suggested that ifosfamide interacts with
aprepitant and fosaprepitant, resulting in an increase in
blood concentration of the chemotherapeutic drug and a
concomitant increase in the incidence or severity of
ifosfamide-related encephalopathy [17, 18]. Our results
suggest means to improve safety for patients receiving
chemotherapy that includes ifosfamide.
A limitation of our study is that we evaluated a small num-
ber of patients and did not evaluate pharmacokinetic parame-
ters of drug–drug interactions.
In conclusion, a 2.5–10 mg/day dosage of olanzapine for
CINV was tolerable and safe in Japanese patients who re-
ceived continuous 5-day chemotherapy with ifosfamide or
cisplatin. We recommend a starting dosage of olanzapine at
2.5 mg/day, with escalation to 10 mg/day if the lower dose is
not efficacious.
Currently, the evidence of multiday chemotherapy is limit-
ed, and the international CINV guideline state Bantiemetics
appropriate for the emetogenic risk class of chemotherapy be
administrated for each day^ and recently guidelines have stat-
ed B5-day cisplatin regimens be treated with 5-HT3 antago-
nists in combination with corticosteroid and aprepitant^.
Future studies should compare olanzapine versus aprepitant.
In addition, we should assess the drug–drug interactions and
determine the optimal antiemetic method for patients who
receive ifosfamide or cisplatin in multi-day regimens.
Invest New Drugs (2018) 36:151–155
Acknowledgements The authors were responsible for all content and
editorial decisions and received no honoraria related to the development
of this publication. All authors contributed to the research, writing, and
reviewing of all drafts of this manuscript and approved the final draft.
Compliance with ethical standards
Conflict of interest Author Seiko Bun declares that she has no conflict
of interest. Kan Yonemori declares that he has no conflict of interest. Toru
Akagi declares that he has no conflict of interest. Emi Noguchi declares
that she has no conflict of interest. Tatsunori Shimoi declares that he has
no conflict of interest. Akihiko Shimomura declares that he has no con-
flict of interest. Mayu Yunokawa declares that she has no conflict of
interest. Chikako Shimizu declares that she has no conflict of interest.
Yasuhiro Fujiwara declares that he has no conflict of interest. Yoshinori
Makino declares that he has no conflict of interest. Yoshikazu Hayashi
declares that he has no conflict of interest. Kenji Tamura declares research
funding from The National Cancer Center Research and Development
Fund.
Funding This work was supported in part by The National Cancer
Center Research and Development Fund (26-A-23).
Ethical approval All procedures performed in studies involving hu-
man participants were in accordance with the ethical standards of the
institutional and/or national research committee and with the 1964
Helsinki declaration and its later amendments or comparable ethical stan-
dards. This article does not contain any studies with animals performed by
any of the authors.
Informed consent Informed consent was obtained from all individual
participants included in the study.
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