Geundoo Jang; Hun Ho Song; Keon Uk Park; Hyeong Su Kim; Dae Ro Choi; Jung Hye Kwon; Ho Young Kim; Boram Han; Jung Han Kim; Joo Young Jung; Hyo Jung Kim; Dae Young Zang

doi:10.4143/crt.2013.45.3.172

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Original Article A Phase II Study to Evaluate the Efficacy of Ramosetron, Aprepitant, and Dexamethasone in Preventing Cisplatin-Induced Nausea and Vomiting in Chemotherapy-Naive Cancer Patients: Geundoo Jang, MD, PhD¹, Hun Ho Song, MD, PhD¹, Keon Uk Park, MD, PhD², Hyeong Su Kim, MD³, Dae Ro Choi, MD⁴, Jung Hye Kwon, MD, PhD¹, Ho Young Kim, MD, PhD⁵, Boram Han, MD⁵, Jung Han Kim, MD, PhD³, Joo Young Jung, MD, PhD⁶, Hyo Jung Kim, MD, PhD⁵, Dae Young Zang, MD, PhD⁵; Cancer Research and Treatment : Official Journal of Korean Cancer Association 2013;45(3):172-177.
DOI: https://doi.org/10.4143/crt.2013.45.3.172
Published online: September 30, 2013

¹Department of Internal Medicine, Hallym University Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea.

²Department of Internal Medicine, Keimyung University Dongsan Medical Center, Keimyung University School of Medicine, Daegu, Korea.

³Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea.

⁴Department of Internal Medicine, Hallym University Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon, Korea.

⁵Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea.

⁶Department of Internal Medicine, Hallym University Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Dongtan, Korea.

Correspondence: Hyo Jung Kim, MD, PhD. Division of Hematology/Oncology, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, 22 Gwanpyeong-ro 170 beon-gil, Dongan-gu, Anyang 431-796, Korea.
Tel: 82-31-380-3704, Fax: 82-31-386-2269, hemonc@hallym.or.kr

*Geundoo Jang and Hun Ho Song contributed equally to this work.

• Received: April 25, 2013 • Accepted: June 4, 2013

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract

Purpose
Combination therapy with aprepitant, serotonin receptor antagonist, and steroids improves the complete response rate of both acute and delayed chemotherapy-induced nausea and vomiting (CINV). However, it is not known whether ramosetron is suitable for administration in combination with aprepitant. Therefore, we conducted a multicenter, open-label, prospective, phase II study in order to assess the efficacy and tolerability of combination therapy with ramosetron, aprepitant, and dexamethasone (RAD) for prevention of cisplatin-based CINV in chemotherapy-naïve patients with solid cancers.
Materials and Methods
Forty-one patients with various solid cancers (31 male and 10 female; median age, 59 years) who received treatment with highly emetogenic chemotherapy (median cisplatin dose, 70 mg/m²; range 50 to 75 mg/m²) were enrolled in this study. Oral aprepitant (125 mg on day 1; 80 mg on days 2 and 3), intravenous ramosetron (0.6 mg on day 1), and oral dexamethasone (12 mg on day 1; 8 mg on days 2-4) were administered for prevention of CINV.
Results
The complete response (no emesisand retching and no rescue medication) rate was 94.9% in the acute period (24 hours post-chemotherapy), 92.3% in the delayed period (24-120 hours post-chemotherapy), and 92.3% in the overall period (0-120 hours). The absolute complete response (complete response plus no nausea) rate was 74.4% in the acute period, 51.3% in the delayed period, and 46.2% in the overall period. There were no grade 3 or 4 toxicities related to these antiemetic combinations.
Conclusion
RAD regimen is a safe and effective antiemetic treatment for prevention of CINV in patients receiving highly emetogenic chemotherapy.
Key words: Aprepitant, Dexamethasone, Ramosetron, Chemotherapy-induced nausea and vomiting

Introduction

Chemotherapy-induced nausea and vomiting (CINV) is one of the most unpleasant side effects for patients receiving chemotherapy. It can have a significant effect on a patient's qualify of lifeand prevent continuation of chemotherapy. The incidence and severity of CINV are affected by diverse factors, including the specific chemotherapeutic agents, the dosage of the agents, the schedule and route of administration of the agents, and individual patient variability [1-3]. Cisplatin is one of the most effective chemotherapeutic agents available for treatment of many solid tumors. However, it is also highly emetogenic, resulting in poor compliance with chemotherapy. Therefore, control of CINV by selection of a relevant antiemetic regimen is as important as the efficacy of the chemotherapy regimen.

Development of newer antiemetic agents, such as serotonin (5-HT₃) receptor antagonists and neurokinin-1 (NK-1) receptor antagonists, has resulted in substantially reduced incidence and risk of CINV in patients receiving chemotherapy. In particular, a triple combination regimen consisting of a NK-1 antagonist, a 5-HT₃ antagonist, and dexamethasone is recommended by key clinical guidelines groups, including the National Comprehensive Cancer Network, the European Society of Medical Oncology, and the American Society of Clinical Oncology, for prevention of acute and delayed emesis in patients receiving highly emetic intravenous chemotherapy such as cisplatin [4-6]. The excellent efficacy of this triple-drug regimen with various 5-HT₃ antagonists, including ondansetron, granisetron, and palonosetron, has been reported [7-9]. However, the most effective 5-HT₃ antagonist for this combination has not yet been identified.

Ramosetron, a 5-HT₃ receptor antagonist developed in Japan (Yamanouchi Pharmaceutical Ltd., Tokyo, Japan), has been used widely in Asian countries for prevention of CINV. In several clinical trials, it showed equivalent efficacy and a similar safety profile when compared with ondansetron and granisetron [10-13]. However, there is currently no information with regard to whether ramosetron is as effective as other 5-HT₃ receptor antagonists for the triple combination regimen. In this study, we evaluated the clinical efficacy and tolerability of a combination regimen comprising ramosetron, aprepitant (NK-1 antagonist), and dexamethasone (RAD) for prevention of CINV in chemotherapy-naïve patients with solid cancers.

Materials and Methods

1. Patient selection

This study was a multicenter, open-label, prospective, phase II clinical trial conducted for investigation of the effects of RAD on prevention of CINV. Chemotherapy-naïve patients between the ages of 15 and 75 years with any solid cancer who were scheduled to receive single day chemotherapy with 50 mg/m² or more of cisplatin were eligible. Patients from five hospitals of Hallym University Medical Center and Keimyung University Dongsan Hospital in Korea were enrolled in this study. All patients had an Eastern Cooperative Oncology Group performance status of 0-2, adequate renal function (serum creatinine level<2.5 mg/dL or calculated creatinine clearance≥50 mL/min), adequate hepatic function (serum total bilirubin level<2 mg/dL, aspartate aminotransferase/alanine aminotransferase level of<3 times the upper normal limit, and alkaline phosphatase level<5 times the upper normal limit), and adequate marrow function (absolute neutrophil count≥1,500/µL and platelets≥100,000/µL). The primary exclusion criteria were as follows: receipt of medication (antiemetics, steroids, and benzodiazepines, etc.) that might affect study results within one week before the start of chemotherapy; symptomatic brain metastasis; gastro-intestinal obstruction or other disease that could provoke nausea and vomiting; administration of radiotherapy to the brain, abdomen, or pelvis within two weeks before the start of chemotherapy; and known allergy or severe side effects to the study drugs. All patients provided written informed consent, and the study protocol was approved by the Institutional Review Board of each institution and was registered with ClinicalTrials.gov (identifier, NCT01046461).

2. Study treatment

On day 1, all eligible patients received intravenous administration of 0.6 mg ramosetron 30 minutes before administration of chemotherapy, 125 mg aprepitant orally 1 hour before administration of chemotherapy, and 12 mg dexamethasone orally 30 minutes before administration of chemotherapy. For the next two days, the patients received 80 mg aprepitant and 8 mg dexamethasone orally in the morning. Dexamethasone was continued on day 4. Rescue antiemetics were administered at any time during the study period for vomiting or severe nausea at the request of the patients or as recommended by the attending physicians. The type of antiemetic agent was determined by the attending physicians.

3. Assessment

The primary efficacy endpoint was complete response (CR), which was defined as no vomiting, including retching, and no administration of rescue anti-emetic treatment, to the RAD regimen from the start of chemotherapy (0 hour) until-day 5 (defined as the overall phase). The overall phase was classified into an acute phase (0-24 hours) and a delayed phase (24-120 hours). The secondary endpoints were CR in the acute phase and delayed phase, absolute CR (defined as CR plus no nausea), and severity of nauseain both phases. The severity of nausea was determined using the visual analog scale of the Multinational Association Supportive Care Cancer antiemesis tool [14]. Tolerability was assessed on the basis of clinical and laboratory adverse events that occurred after the start of treatment and within 14 days after treatment ended and were evaluated according to the Common Toxicity Criteria for Adverse Events (CTCAE) v.3.0. During the overall phase, patients were asked to record daily episodes of vomiting or retching, the degree of nausea, and the use of rescue medication in a diary.

4. Statistics

Calculation of patient sample size was based on the following assumption. The CR rate of high dose cisplatin-induced overall phase CINV is known to be approximately 55% (p0) for patients receiving ramosetron and dexamethasone [15,16]. Assuming that the addition of aprepitant to ramosetron and dexamethasone improves the CR rate by up to 75% (p1), the sample size should be 37 according to the "exact single-stage phase II designs" procedure (5% α-error and 80% power) [17]. Considering a possible dropout rate of 5%, a target sample size of 39 would be needed. Descriptive examination of demographic data and patients' characteristics was performed and the percentage of patients achieving CR was calculated.

Results

A total of 41 patients were enrolled in this study between November 2010 and February 2012. Baseline clinical characteristics of the patients are summarized in Table 1. The median age of patients was 59 years. Male patients accounted for 76% of the patient population. The most common primary tumor site was the lung (49%), followed by the stomach (15%) and genitourinary tract (10%). All patients received cisplatin and other chemotherapeutic agents, including pemetrexed, taxanes, and gemcitabine. The median dose of a single administration of cisplatin was 70 mg/m² of the body surface area (range, 50 to 75 mg/m²).

1. Antiemetic efficacy

Of the 41 patients, analysis for antiemetic efficacy was performed for 39 patients. Two patients were excluded from the analysis because of major study violations. One patient was not a chemotherapy-naïve patient and the other received a low dose of ramosetron. The CR rate was 92.3% in the overall phase, 94.9% in the acute phase, and 92.3% in the delayed phase (Table 2). The absolute CR rate was 46.2% in the overall phase (74.4% in the acute phase and 51.3% in the delayed phase).

Median nausea scores during the overall, acute, and delayed phases were 2 (interquartile range [IQR], 0-4), 0 (IQR, 0-1), and 0 (IQR, 0-4), respectively. Mild nausea (score of 1-3 on the visual analogue scale) was observed in 10% of patients in the acute phase and in 13% of patients in the delayed phase (Table 3). Moderate-to-severe nausea (score of 4-10 on the visual analogue scale) was observed in 15% and 36% of patients in the acute and delayed phases, respectively.

2. Adverse events

There was no occurrence of additional serious adverse events associated with ramosetron. Overall adverse events according to CTCAE v.3.0 during chemotherapy are shown in Table 4. The most common grade 3/4 hematologic toxicity was neutropenia, with an incidence of 12%, followed by thrombocytopenia (10%). Regarding non-hematologic toxicities, 5% of patients experienced grade 3/4 diarrhea.

Discussion

In the current study, the RAD regimen showed significant efficacy for prevention ofcisplatin-induced CINV in chemonaïve cancer patients. Ninety-two percent of patients did not experience vomiting episodes, nor did they receive rescue medication for CINV during the overall phase. This CR rate is considerably high compared with that reported in other studies. The CR rates of a two-drug regimen with ramosetron plus dexamethasone for prevention of cisplatin-induced CINV were reported to range from 68% to 85% in the acute periodand from 58% to 75% in the delayed period [15,16,18]. In their study with ondansetron, Hesketh et al. [19] reported that CR rates for a triple-drug regimen of aprepitant, dexamethasone, and the 5-HT₃ antagonist were 89%, 75%, and 73% in acute, delayed, and overall phases, respectively. Longo et al. [20] conducted a study evaluating a three-drug regimen with palonosetron for prevention of CINV in patients receiving highly emetogenic chemotherapy. The CR rates in the acute, delayed, and overall periods were 98%, 73%, and 70%, respectively. In another triple regimen study with palonosetron, Herrington et al. [9] reported CR rates in the acute, delayed, and overall phases of 96%, 93%, and 93%, respectively, which was comparable to our results. In our trial, the CR rate was 95% in the acute period. Only two patients experienced episodes of vomiting during the first 24 hours after initiation of chemotherapy: one was a 58-year-old male with bladder cancer receiving cisplatin plus gemcitabine chemotherapy and the other was a 54-year-old male with small cell lung cancer receiving cisplatin plus irinotecan. The CR rate in the delayed period was 92%. However, in the trial conducted by Herrington et al. [9], the proportion of patients receiving cisplatin-based chemotherapy was 55%, which was different from that observed in our study. However, in this trial, the proportion of female patients considered vulnerable to CINV was relatively low when compared with other studies.

Ramosetron belongs to a new class of selective 5-HT₃ receptor antagonists. It is a tetrahydrobenzimidazole derivative, which is structurally different from ondansetron and granisetron, with more potent 5-HT₃ receptor antagonizing effects than the reference compounds used in animal experiments [21,22]. In addition, because its half-life is known to be longer than that of ondansetron and granisetron [23], it can be administered once per day. Its known side effects include an elevation of hepatic transaminases, headache, diarrhea, and febrile sensation with a frequency of less than 1%. In this study, there was no occurrence of ramosetron-related serious adverse events. Although two patients (5% of cases) experienced grade 3 diarrhea, it could be considered a side effect of chemotherapeutic agents. Most adverse events were also acceptable toxicities which could be related to chemotherapy and were similar in comparison with other studies [11-13].

Aprepitant, the first NK-1 receptor antagonist to be developed, prevents binding of substance P to the NK-1 receptor forimprovement of CINV. Although the RAD regimen, ramosetron combined with aprepitant and dexamethasone, has been widely used in clinical practice in Asian countries for prevention of CINV, there are not yet any published data on this triple-drug combination.

Despite advances in control of vomiting by development of effective antiemetic agents, many patients still suffer from chemotherapy-induced nausea. In particular, delayed nausea tends to show resistance to treatment. In our study, the absolute CR rate, defined as CR plus no nausea, was 46% during the overall period. While 15% of patients experienced moderate-to-severe nausea during the acute period, 36% developed moderate-to-severe nausea during the delayed period. This result was similar to those reported byother studies. In the trial conducted by Hesketh et al. [19], 48% of patients had no nausea in the overall phase, and 9% and 25% of patients were reported to have significant nausea in the acute and delayed phases, respectively. In a recent study, Roscoe et al. [24] reported that delayed nausea could be improved by addition of dexamethasone on days 2 and 3, but not by the 5-HT₃ receptor antagonist.

This study has some limitations. The patient sample size was relatively small, and the proportion of male patients was high. The effect of individual variable factors, such as alcohol consumption, chemotherapeutic agents administered in combination, and the impact of the cisplatin dose was not considered. However, to the best of our knowledge, this is the first prospectively conducted study on the efficacy of a three-drug regimen with ramosetron for prevention of CINV.

Conclusion

The results of this study showed that the RAD combination regimen is a very safe and effective antiemetic therapy for prevention of CINV in patients receiving highly emetogenic chemotherapy, although chemotherapy-induced nausea is still not completely overcome by use of this regimen. Based on the results of this study, we are currently conducting a prospective multicenter, randomized, single-blind phase III trial for comparison of RAD with ondansetron, aprepitant, and dexamethasone (NCT01536691).

Acknowledgements

Acknowledgments

This trial was supported in part by a research grant from the Investigator-Initiated Studies Program of the Merck Sharp & Dohme Corp. The opinions expressed in this paper are those of the authors and do not necessarily represent those of the Merck Sharp & Dohme Corp.

NOTES

Conflict of interest relevant to this article was not reported.

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Table 1

Patients' clinical characteristics

Characteristic	No. (%) (n=41)
Median age (range, yr)	59 (43-74)
Gender
Male	31 (75.6)
Female	10 (24.4)
ECOG PS
0	6 (14.6)
1	29 (70.7)
2	6 (14.6)
Primary tumor site
Lung	20 (48.8)
Stomach	6 (14.6)
Genitourinary	4 (9.8)
Esophagus	3 (7.3)
Head and neck	2 (4.9)
Pancreato-biliary	2 (4.9)
Others	4 (9.8)
Type of chemotherapy
Adjuvant	3 (7.3)
Palliative	38 (92.7)
Chemotherapy regimen
Cisplatin/pemetrexed	10 (24.4)
Cisplatin/paclitaxel	9 (22.0)
Cisplatin/docetaxel	8 (19.5)
Cisplatin/gemcitabine	7 (17.1)
Cisplatin/irinotecan	3 (7.3)
Cisplatin/vinorelbine	2 (4.9)
Cisplatin/others	2 (4.9)
Median cisplatin dose (range, mg/m²)	70 (50-75)

ECOG, Eastern Cooperative Oncology Group; PS, performance scale.

Table 2

Antiemetic efficacy (n=39)

Period	Complete response^a)	Absolute complete response^b)
Acute phase (day 1)	37 (94.9)	29 (74.4)
Delayed phase (day 2-5)	36 (92.3)	20 (51.3)
Overall phase (day 1-5)	36 (92.3)	18 (46.2)

Values are presented as number (%). ^a)Defined as no emesis and no rescue medication, ^b)Defined as complete response plus no nausea

Table 3

Nausea visual analogue scale (n=39)

Grade (score)	Acute phase	Delayed phase
None (0)	29 (74.4)	20 (51.3)
Mild (1-3)	4 (10.3)	5 (12.8)
Moderate (4-6)	5 (12.8)	10 (25.6)
Severe (7-10)	1 (2.6)	4 (10.3)

Values are presented as number (%).

Table 4

Adverse events according to CTCAE version 3 (n=41)

Event	Grade 1/2	Grade 3/4
Neutropenia	4 (9.8)	5 (12.2)
Anemia	13 (31.7)	1 (2.4)
Thrombocytopenia	5 (12.2)	4 (9.8)
Increased ALT	3 (7.3)	0
Anorexia	7 (17.3)	1 (2.4)
Diarrhea	2 (4.9)	2 (4.9)
Stomatitis	3 (7.3)	0
Alopecia	5 (12.2)	0 (0.0)
Asthenia	3 (7.3)	0
Fever	5 (12.2)	1 (2.4)
Febrile neutropenia	0	4 (9.8)
Pneumonia	3 (7.3)	0

Values are presented as number (%). CTCAE, Common Toxicity Criteria for Adverse Events; ALT, alanine aminotransferase.

Figure & Data

REFERENCES

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A Phase II Study to Evaluate the Efficacy of Ramosetron, Aprepitant, and Dexamethasone in Preventing Cisplatin-Induced Nausea and Vomiting in Chemotherapy-Naive Cancer Patients

Cancer Res Treat. 2013;45(3):172-177. Published online September 30, 2013

DOI: https://doi.org/10.4143/crt.2013.45.3.172

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Abstract
Introduction
Materials and Methods
Results
Discussion
Conclusion
Acknowledgments
NOTES
REFERENCES

A Phase II Study to Evaluate the Efficacy of Bortezomib in Combination with Thalidomide in Treatment-Naïve Waldenstrom Macroglobulinemia Patients

A Phase II Study to Evaluate the Efficacy of Ramosetron, Aprepitant, and Dexamethasone in Preventing Cisplatin-Induced Nausea and Vomiting in Chemotherapy-Naive Cancer Patients

Characteristic	No. (%) (n=41)
Median age (range, yr)	59 (43-74)
Gender
Male	31 (75.6)
Female	10 (24.4)
ECOG PS
0	6 (14.6)
1	29 (70.7)
2	6 (14.6)
Primary tumor site
Lung	20 (48.8)
Stomach	6 (14.6)
Genitourinary	4 (9.8)
Esophagus	3 (7.3)
Head and neck	2 (4.9)
Pancreato-biliary	2 (4.9)
Others	4 (9.8)
Type of chemotherapy
Adjuvant	3 (7.3)
Palliative	38 (92.7)
Chemotherapy regimen
Cisplatin/pemetrexed	10 (24.4)
Cisplatin/paclitaxel	9 (22.0)
Cisplatin/docetaxel	8 (19.5)
Cisplatin/gemcitabine	7 (17.1)
Cisplatin/irinotecan	3 (7.3)
Cisplatin/vinorelbine	2 (4.9)
Cisplatin/others	2 (4.9)
Median cisplatin dose (range, mg/m²)	70 (50-75)

Period	Complete response^a)	Absolute complete response^b)
Acute phase (day 1)	37 (94.9)	29 (74.4)
Delayed phase (day 2-5)	36 (92.3)	20 (51.3)
Overall phase (day 1-5)	36 (92.3)	18 (46.2)

Grade (score)	Acute phase	Delayed phase
None (0)	29 (74.4)	20 (51.3)
Mild (1-3)	4 (10.3)	5 (12.8)
Moderate (4-6)	5 (12.8)	10 (25.6)
Severe (7-10)	1 (2.6)	4 (10.3)

Event	Grade 1/2	Grade 3/4
Neutropenia	4 (9.8)	5 (12.2)
Anemia	13 (31.7)	1 (2.4)
Thrombocytopenia	5 (12.2)	4 (9.8)
Increased ALT	3 (7.3)	0
Anorexia	7 (17.3)	1 (2.4)
Diarrhea	2 (4.9)	2 (4.9)
Stomatitis	3 (7.3)	0
Alopecia	5 (12.2)	0 (0.0)
Asthenia	3 (7.3)	0
Fever	5 (12.2)	1 (2.4)
Febrile neutropenia	0	4 (9.8)
Pneumonia	3 (7.3)	0

Table 1 Patients' clinical characteristics

ECOG, Eastern Cooperative Oncology Group; PS, performance scale.

Table 2 Antiemetic efficacy (n=39)

Values are presented as number (%). ^a)Defined as no emesis and no rescue medication, ^b)Defined as complete response plus no nausea

Table 3 Nausea visual analogue scale (n=39)

Values are presented as number (%).

Table 4 Adverse events according to CTCAE version 3 (n=41)

Values are presented as number (%). CTCAE, Common Toxicity Criteria for Adverse Events; ALT, alanine aminotransferase.