A phase II study of the safety of olanzapine for oxaliplatin based chemotherapy in coloraectal patients

Olanzapine has exhibited efficacy as an antiemetic agent when used with 5-HT3 receptor antagonists, dexamethasone, and NK1 receptor antagonists for patients receiving highly emetogenic chemotherapy. In addition, several studies have reported the efficacy or safety of olanzapine in patients receiving moderately emetogenic chemotherapy, including carboplatin, irinotecan, and oxaliplatin. However, no reports of olanzapine use have focused on patients receiving oxaliplatin-based chemotherapy. Therefore, we analyzed the safety of antiemetic therapy using olanzapine, palonosetron, aprepitant, and dexamethasone in colorectal cancer patients undergoing oxaliplatin-based chemotherapy. This study was a prospective phase II single-institution study of 40 patients (median age 60 years, 23 patients were male). The primary endpoint was the incidence of adverse events, and the exploratory endpoints were the rate of chemotherapy-induced nausea and vomiting. Almost all patients (90%) had a performance status of 0. All patients received the scheduled antiemetic therapy. The most common adverse event was somnolence (n = 7 patients, 17.5%). All adverse events were grade 1. Thirty-six patients were included in the exploratory analysis of efficacy. No patients experienced vomiting during the first 120 h after chemotherapy, and complete response and complete control were both 86.1%. The rate of total control was 55.6% during the same time period. Olanzapine use with 5-HT3 receptor antagonists, dexamethasone, and NK1 receptor antagonists was safe for colorectal cancer patients receiving oxaliplatin-based chemotherapy.

For moderately emetogenic chemotherapy (MEC), a small randomized control trial has reported the effects of olanzapine as an antiemetic agent in addition to 5-HT 3 receptor antagonists, dexamethasone, and NK 1 receptor antagonists. They could not confirm the efficacy of olanzapine at the acute phase of emesis because of a small sample size and did not focus on a regimen including oxaliplatin 5 . In this phase 2 study, we assessed the safety of antiemetic treatment using olanzapine, 5-HT 3 receptor antagonists, dexamethasone, and NK 1 receptor antagonists. We also explored the rate of CINV in patients receiving oxaliplatin-based chemotherapy.

Patients and methods
Eligibility criteria. This study is registered at UMIN Clinical Trials Registry (number UMIN 000032591).
The study included oxaliplatin-naïve patients with colorectal cancer who were 20 years of age or older and received FOLFOX (oxaliplatin 85 mg/m 2 , levo-leucovorin 200 mg/m 2 , and fluorouracil 400 mg/m 2 bolus and 2400 mg/m 2 continuous infusion) or XELOX (capecitabine 2000 mg/m 2 orally on days 1-14 and oxaliplatin 130 mg/m 2 via intravenous infusion on day 1). Molecular targeted therapy was allowed. Neoadjuvant chemotherapy, recurrent/unresectable chemotherapy, and adjuvant chemotherapy were included in this study. Institutional review boards approved the study protocol, and written informed consent was obtained from all participants before enrollment.
Exclusion criteria. Patients were excluded if they had nausea or vomiting within 24 h prior to enrollment, were treated with antiemetics within 24 h prior to treatment, had any factors causing nausea or vomiting (e.g., gastrointestinal obstruction or symptomatic brain metastasis), had uncontrollable diabetes, were pregnant or lactating or planning on becoming pregnant, or were currently receiving pimozide. Treatment protocol. All patients received oral aprepitant (125 mg) plus an intravenous 5-HT 3 receptor antagonist (palonosetron hydrochloride) and dexamethasone (6.6 mg) on day 1, and aprepitant (80 mg) and oral dexamethasone (2 mg) twice daily on days 2 and 3. Olanzapine (5 mg) was administered after dinner for 4 days from the first day of oxaliplatin administration. Patient evaluation. The study period was only the first cycle of oxaliplatin-based chemotherapy. Patients recorded their response in a diary daily for 5 days. The use of rescue therapy, defined as any medication taken to treat nausea and vomiting, was also recorded. The severity of nausea was classified into four grades: 0, none; 1, mild; 2, moderate; or 3, severe. No nausea and mild nausea were considered as no significant nausea. For vomiting, patients recorded the frequency. Retches were also included as vomiting 1 . An emetic episode was defined as single or multiple emetic vomiting experiences occurring within an interval of 5 min. It was also subjectively assessed by each patient. Statistical analysis. The primary endpoint was the incidence of grade 3 or 4 adverse events. Thirty-two patients were required to achieve 80% statistical power with a one-sided α error of 0.05 assuming an expected adverse event rate of 1% and a threshold of 10%. An arc-sine transformation was performed with the binomial test for the required sample sizes calculation 9 . The planned sample size was 40 patients for enrollment after taking dropouts into consideration. The exploratory endpoint was the rate of no vomiting, no nausea, no significant nausea (defined as none or mild nausea), complete response (defined as no vomiting episode and no rescue therapy), complete control (defined as no vomiting, no rescue therapy, and no significant nausea), and total control (no vomiting, no rescue therapy, and no nausea) in the acute (first 24 h after chemotherapy), delayed (24-120 h after chemotherapy), and overall phases (0-120 h after chemotherapy). We calculated 95% confidence intervals (CIs) for the proportion of patient characteristics and CINV. Adverse events were graded using Common Toxicity Criteria for Adverse Events, version 4.0. Alcohol use was divided into two groups: drinker, patient has drinking habit every day, and light/non-drinker for others. Statistical analyses were performed using JMP software version 13 (SAS Institute, Cary, NC, USA). The estimation of sample size was carried out in R version 4.0.2.
Ethical approval. All procedures involving human participants were performed 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 standards. This study was approved by the Institutional Review Board of Osaka International Cancer Center (approval no. 18015) and was registered at UMIN Clinical Trials Registry (number UMIN000032591) on 15/05/2018.

Results
Forty patients (age range 36-80 years; 23 males) were enrolled in this study between March 2018 and April 2019. Patient characteristics are provided in Table 1. The median age was 60 years ranged 36 to 80 years. The male was 23 (58%). Most patients had a performance status of 0. Twelve patients (30%) received FOLFOX regimen, and 28 patients (70%) received the CAPOX regimen. The use of molecular target drug was in 13 patients (33%). The previous colon resecton surgery was done in 30 patients (83%). Ileostomy was underwent in 4 patients (11%), and colostomy in 3 patients (8% Adverse events. All patients received the scheduled antiemetic treatment. The adverse events are given in Table 2. The most common adverse events were anorexia (35%) and somnolence (17.5%). All adverse events were grade 1 and were tolerated. We did not observe any adverse hematological events, and no treatment-related deaths were reported during this study.    Table 3). None of the patients experienced vomiting in the acute, delayed, or overall phases (Table 4). Five patients (14%) used rescue antiemetic therapy. Only 2 patients (6%) who had significant nausea used rescue antiemetic therapy. The proportions of patients with each outcome in each phase are given in Table 3. No nausea in the acute, delayed, and overall phase was noted in 97.2%, 61.1%, and 61.1% of patients, respectively.

Discussion
In this study, we analyzed the safety of olanzapine as an antiemetic agent with 5-HT 3 receptor antagonists, dexamethasone, and NK 1 receptor antagonists for colorectal cancer patients undergoing oxaliplatin-based chemotherapy. The incidence of somnolence was 17.5%, and the patients suffered no grade 2 or greater adverse events. We also analyzed the rate of CINV. None of the patients experienced vomiting, and a complete response occurred in 86.1% of patients in the delayed and overall phases. To the best of our knowledge, this report is the first to analyze the safety and efficacy of adding olanzapine to triple antiemetic therapy in oxaliplatin-based chemotherapy.  www.nature.com/scientificreports/ In HEC regimens, several studies have shown the efficacy of olanzapine. Navari et al. first reported the efficacy of adding olanzapine to dexamethasone and granisetron 4 . They also reported the efficacy of olanzapine combined with an NK 1 receptor antagonist, a 5-HT 3 receptor antagonist, and dexamethasone 10 . The FOND-O trial reported the efficacy of adding olanzapine to fosaprepitant, ondansetron, and dexamethasone in patients undergoing HEC and hematopoietic transplantation 11 . Recently, Hashimoto et al. assessed adding olanzapine to aprepitant, palonosetron, and dexamethasone in patients receiving cisplatin-based chemotherapy 6 .
For MEC regimens, only one small randomized trial has evaluated the efficacy of olanzapine with palonosetron and dexamethasone, without NK 1 receptor antagonist. Their study did not meet the primary endpoint of complete response, but the rate of significant nausea was significantly reduced in the olanzapine-treated group. Tanaka et al. reported a phase II study of the addition of olanzapine to antiemetic therapy with aprepitant, a 5-HT3 receptor antagonist, and dexamethasone in patients receiving chemotherapy including carboplatin 12 . In their study, the complete response rate in the overall phase was 93.9%, compared to 86.1% in the present study. In the SENRI trial, which was a non-blinded randomized trial, the complete response rate of patients treated with NK 1 receptor antagonist, a 5-HT 3 receptor antagonist, and dexamethasone was 85.0%. It was not possible to unconditionally compare the SENRI trial to this study; the number was small, evaluation was difficult, and we could not confirm the effectiveness of adding olanzapine determined by the complete response. Adding olanzapine may increase the complete response rate, which must be proven in a future phase III trial.
Several studies have investigated the efficacy and safety of 5 mg olanzapine with an NK 1 receptor antagonist, 5-HT 3 receptor antagonist, and dexamethasone in Japanese patients undergoing HEC [13][14][15] . A double-blind randomized phase II study suggested a recommended dose of 5 mg olanzapine as an antiemetic agent 15 . Therefore, we administered 5 mg olanzapine, not 10 mg, in this study. We did not note any severe adverse events, including somnolence. Thus, administration of 5 mg olanzapine to NK 1 receptor antagonist, palonosetron, and dexamethasone is a safe alternative to antiemetics for colorectal cancer patients treated with oxaliplatin-based chemotherapy.
In this study, we administered palonosetron, a second generation 5-HT 3 receptor antagonist characterized by a long plasma elimination half-life (~ 40 h) and a high selective binding affinity for the 5-HT 3 receptor. Several studies have shown a superior antiemetic effect of palonosetron compared to other 5-HT 3 receptor antagonists [16][17][18][19] . The efficacy of palonosetron relative to other 5-HT 3 receptor antagonists has been evaluated in a meta-analysis 20 , and the efficacy of the combination of NK 1 receptor antagonist, palonosetron, and dexamethasone compared to other antiemetic regimens was evaluated recently in a meta-analysis 21 . The combination antiemetic therapy of NK 1 receptor antagonist, palonosetron, and dexamethasone was superior in the delayed phase with MEC regimen, and the overall phase for HEC and MEC regimens. The TRIPLE study, a randomized, double-blind, phase III trial, revealed that the complete response in the delayed period was higher in patients using palonosetron than patients using granisetron 22 .
The present study has some limitations. First, it was a single-arm trial with limited sample size at a single institution. Second, we assessed the safety of olanzapine in patients receiving oxaliplatin-based chemotherapy, but the efficacy of this antiemetic regimen was unclear. Further comparative studies are needed to determine the efficacy.
In conclusion, administration of olanzapine with NK1 receptor antagonist, palonosetron, and dexamethasone is a safe alternative to antiemetics for colorectal cancer patients treated with oxaliplatin-based chemotherapy.