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Randomized Phase II Study of the Neurokinin 1 Receptor Antagonist CJ-11,974 in the Control of Cisplatin-Induced Emesis

From the St. Elizabeth's Medical Center, Boston, MA; Ochsner Cancer Center, New Orleans, LA; Central Arkansas Hematology and Oncology Clinic, Hot Springs, AR; Fairfax/Prince William Hematology-Oncology, PC, Alexandria, VA; Bennett Cancer Center, Stamford, CT; and Pfizer Central Research, Pfizer, Inc, Groton, CT.

Address reprint requests to Paul J. Hesketh, MD, Section of Medical Oncology, St. Elizabeth's Medical Center, 736 Cambridge St, Boston, MA 02135; Email phesketh{at}aol.com

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To determine the efficacy and safety of the neurokinin type 1 receptor antagonist CJ-11,974 for the control of high-dose cisplatin-induced emesis.

PATIENTS AND METHODS: A double-blind, randomized, phase II design with a group sequential stopping rule was used in this study. Sixty-one patients with cancer who were receiving cisplatin at a dose of at least 100 mg/m² for the first time were enrolled. All patients received granisetron 10 µg/kg and dexamethasone 20 mg intravenously 30 minutes before they were given cisplatin. Patients were randomly assigned to two groups: group 1 received CJ-11,974 100 mg, and group 2 received placebo orally 30 minutes before and 12 hours after cisplatin and then twice daily on days 2 through 5 after cisplatin. The primary end point was the percentage of patients who developed delayed emesis (emesis on the second to fifth days after cisplatin).

RESULTS: Thirty patients were enrolled in group 1, and 31 patients were enrolled in group 2. Fifty-eight patients were assessable for efficacy. Complete control of emesis (expressed as the percentage of patients who had no emesis) was as follows: day 1, 85.7% (group 1) and 66.7% (group 2) (P = .090); days 2 through 5, 67.8% (group 1) and 36.6% (group 2) (P = .0425, adjusted); days 1 through 5, 64.3% (group 1) and 30% (group 2) (P = .009). Patients in group 1 experienced significantly less nausea than patients in group 2 on day 1 (P = .024). Treatment was well tolerated in both groups.

CONCLUSION: We conclude from this exploratory phase II trial that CJ-11,974 is superior to placebo in controlling cisplatin-induced delayed emesis and may provide additive benefit in acute emesis and nausea control when combined with a 5-hydroxytryptamine-3 receptor antagonist and dexamethasone. Additional larger trials are indicated to confirm the clinical value of CJ-11,974.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
THE INTRODUCTION OF SELECTIVE inhibitors of the 5-hydroxytryptamine type 3 (5-HT₃) receptor represented a major advance in efforts to control chemotherapy-induced nausea and vomiting.¹ A number of these agents are now available in oral and intravenous formulations for clinical use. Despite several preclinical differences, they all seem to have comparable efficacy and minimal adverse effects.^2,3 At present, the combination of a selective 5-HT₃ receptor antagonist and a corticosteroid represents the antiemetic treatment of choice with chemotherapy regimens with moderate to high emetogenic potential.⁴ Despite the significant progress realized over the past decade, chemotherapy-induced emesis remains a substantial problem in a number of clinical situations, including cisplatin-induced delayed emesis, multicycle chemotherapy, and very-high-dose chemotherapy, in which at least one of every three patients continues to have emesis.^5-7 Further progress is dependent on innovative approaches.

Substance P is an 11-amino acid neuropeptide of the tachykinin family of peptides, originally named for their vasorelaxant properties.⁸ Substance P is found in the gut and central nervous system and can produce vomiting when injected into ferrets.⁹ Substance P exerts its effects by binding to a specific neuroreceptor, neurokinin 1 (NK₁). A number of nonpeptide compounds that selectively block the NK₁ receptor have been identified.^9-12 A unique feature of the NK₁ receptor antagonists has been their broad spectrum of activity in preclinical models. The NK₁ receptor antagonist CP-99,994 has been demonstrated to prevent emesis induced by a wide range of emetic stimuli, such as apomorphine, morphine, nicotine, copper sulfate, ipecacuanha, radiation, cyclophosphamide, cisplatin, and motion in the ferret and dog.^13-15 This wide spectrum of antiemetic activity is not shared by serotonin and dopamine receptor antagonists and suggests that substance P may exert a critical role in the emetic reflex pathway and may be an appropriate target for therapeutic intervention.

The potential utility of the NK₁ receptor antagonists may not be limited to acute (24 hours after chemotherapy) chemotherapy-induced emesis. Two reports suggest potential activity in delayed emesis as well. Rudd et al¹¹ demonstrated that CP-99,994 could abolish both acute and delayed emesis after cisplatin administration in the ferret. In addition, Kris et al¹⁶ recently reported the first clinical experience evaluating the potential antiemetic efficacy of an NK₁ receptor antagonist in cancer patients. In a small, dose-ranging, open-label trial with the NK₁ receptor antagonist CP-122,721, control of delayed emesis improved from 17% without the NK₁ receptor antagonist to 83% with the addition of a single dose of CP-122,721 before cisplatin.

CJ-11,974 is another highly selective (K_i = 0.4 nmol/L) antagonist of the NK₁ receptor that has recently been identified (Fig 1). At a dose of 3 mg/kg, it can completely block cisplatin-induced emesis in the ferret (manuscripts in preparation). The present study was undertaken to determine the potential efficacy and safety of CJ-11,974 in controlling cisplatin-induced nausea and vomiting.

View larger version (11K): [in this window] [in a new window]   Fig 1. Structure of CJ-11,974-1 (molecular weight, 527.6). The suffix "1" in the code number denotes that the compound is a dihydrochloride salt. CJ-11,974 (molecular weight, 454.7) refers to the free-base form.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
Sixty-one patients scheduled to receive cisplatin chemotherapy were enrolled by the 10 participating institutions. Eligibility criteria included pathologically confirmed cancer, age at least 18 years, Karnofsky performance status at least 60%, chemotherapy to include cisplatin at a dose of at least 100 mg/m² administered over a period of 3 hours or less, normal screening electrocardiogram with stable heart rhythm, WBC count of at least 3,500/µL, platelet count of at least 75,000/µL, bilirubin level less than 1.8 mg/dL, AST and ALT levels less than 2 times the upper limit of normal, and creatinine clearance at least 55 mL/min. Patients with any of the following were excluded from participation: primary CNS malignancy or untreated brain metastases, prior treatment with cisplatin, multiple-day therapy with highly emetogenic chemotherapy, known seizure disorder, clinically significant neuromuscular disorder or a degenerative disorder of the nervous system, clinically significant gastrointestinal disease, clinically significant endocrine abnormalities not controlled with current therapy, congestive heart failure or active angina, significant arrhythmia or myocardial infarction within the past 6 months, history of significant hypersensitivity to multiple drugs, use of any medications with potential antiemetic action within 24 hours of cisplatin, radiation therapy to the abdominal or pelvic areas within 48 hours before the study period, and pregnancy or lactation. Written informed consent was obtained from all patients, and the study was approved by the institutional review board of each institution.

Study Drug
CJ-11,974 was supplied by the sponsor as 100-mg capsules. Granisetron and dexamethasone were supplied by the study sites. The latter two antiemetics were prepared by study pharmacists using saline dilution to a total volume of 50 mL at the time of dosing.

Study Design
A phase II, double-blind, randomized, group sequential design was used. All patients were undergoing their first course of cisplatin chemotherapy. All patients received granisetron 10 µg/kg and dexamethasone 20 mg intravenously 30 minutes before cisplatin. In addition, patients were randomly assigned to two groups: group 1 received CJ-11,974 100 mg orally 30 minutes before and 12 hours after cisplatin, and twice daily on days 2 through 5 after cisplatin; group 2 received identical-appearing placebo capsules orally 30 minutes before and 12 hours after cisplatin, and twice daily on days 2 through 5 after cisplatin.

Evaluation Methods and Measurement
Pretreatment evaluations included a complete medical history, physical examination, ECG, and clinical laboratory profile within 72 hours of the start of chemotherapy. Assessment of the effectiveness of antiemetic therapy during the first 24 hours (acute period) and second through fifth days (delayed period) after cisplatin was measured using the number and time to onset of emetic episodes. An emetic episode was defined as a single vomit (productive emesis) or up to five or more retches (unproductive emesis) occurring within a 5-minute interval. Nausea was assessed by patient self-assessment using a numerical scale from 0 to 10 (0 = no nausea; 10 = nausea as bad as it could be). Time to onset of nausea and the use and time of administration of any rescue antiemetic medication was also recorded by patients.

Patient self-assessments were recorded at least 5 minutes before and 15 minutes after CJ-11,974 administration and at 6 to 8 hours after dosing for all patients. This information was recorded in workbooks provided to the patients. Patients were directly observed by the investigator or study staff for at least 6 to 8 hours after chemotherapy, and observations regarding emesis or adverse events were recorded. After the latter period, patients were asked to record symptoms at the time of any significant symptomatic change as well as before the initiation of any antiemetic rescue medication during the 5-day study period. Patients were called on a daily basis by a study coordinator to inquire about the control of emesis and the use of any rescue medication.

Postdosing safety evaluations included the following: ECG 2 hours after the initial CJ-11,974 dosing, vital signs and a brief cardiopulmonary physical examination before discharge from the clinic, and a brief physical examination and laboratory safety tests 7 to 14 days after cisplatin. Patients were provided with antiemetic rescue medication at the investigator's discretion and were instructed to take rescue medication at any time if significant nausea or emesis developed.

Efficacy Parameters
The group of patients receiving CJ-11,974 was compared with the placebo group over the 5-day study period with regard to emetic episodes and requirement for rescue antiemetic medications. The primary efficacy end point was the proportion of patients with complete control (no emetic episodes) during days 2 to 5 after cisplatin administration (delayed emesis period). Secondary efficacy comparisons between the two treatment groups included complete control of emesis during the acute period (24 hours) after chemotherapy, control of nausea, time to administration of rescue therapy, and total number of emetic episodes.

Statistical Methods
The primary efficacy end point was the control of delayed emesis, defined as the proportion of patients reporting no emetic episodes 24 to 120 hours after the start of chemotherapy. A sequential design was chosen because of the large variation in the published rates of control of delayed emesis after other antiemetics, which created difficulty when calculating a sample size for this study.¹⁷ The randomized design of this study is consistent with the study designs used to study chemotherapy-induced emesis and should not be confused with any of the randomized designs used for studying multiple experimental antitumor agents.

Under the sequential design of the trial, the primary end point was monitored after 24 patients had completed the 5-day study period and then after every 12 additional completed patients. Despite these interim checks, the overall 5% type 1 error was preserved by using a modified triangular test¹⁸ with calculation of initial boundaries based on 80% power to detect a 40-percentage-point minimum difference in the rate of delayed emesis between the two treatments, control and treated success rates set at 40% and 80%, respectively, and an estimated inspection interval of 17.

After each monitoring time point, the score function, a measure of the observed advantage of CJ-11,974 over placebo, was evaluated at 0 using accumulated information and plotted against its variance. If the outer test boundary was crossed, the trial was to be stopped with sufficient evidence of a treatment difference. If, on the other hand, the lower test boundary was crossed, the trial was to be stopped with sufficient evidence of no treatment difference. In the absence of either occurrence, the trial was to continue until a total of 84 patients were enrolled. All interim analyses were conducted using PEST3 software for sequential trials.¹⁹

Once the study had ended, the median unbiased estimate of the log-odds ratio and 95% confidence interval and median unbiased estimates of the success rates in the two treatment groups were calculated.²⁰ In addition to the primary end point of occurrence of delayed emesis, other efficacy end points were summarized upon completion of the trial. Secondary emesis and nausea control rates were compared by using Pearson's ² test. The time to first postcisplatin use of an antiemetic rescue medication was calculated for each rescued subject by finding the minimum of all times of rescue in hours after the start of cisplatin therapy. Subjects with no rescue were assumed to be censored at 120 hours postcisplatin. Using time to rescue, survival functions were estimated in the two treatment groups using the product-limit method (Kaplan-Meier) and compared using a log-rank test. Any P values associated with comparisons of such secondary end points are unadjusted.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
Sixty-one patients from 10 sites were enrolled onto the study and received the study drug and their initial course of cisplatin-containing chemotherapy. Three (two from group 1 and one from group 2) of the 61 total patients who received the study drug were not included in efficacy analyses because assessments were not recorded (one patient did not return the self-assessment workbook, and one patient withdrew before efficacy evaluations) or because of overdose (one patient mistakenly took the total 5-day quantity of study drug on day 1).

The two treatment groups were well matched with regard to sex, primary cancer diagnosis, and history of alcohol consumption. Although the mean ages of the groups were similar, 40% of patients receiving CJ-11,974 (group 1) were 71 years of age or older, as compared with 16% of patients receiving placebo (group 2) (P = .05). Mean baseline creatinine clearances (milliliters/minute) for the two groups were 76.5 and 89.0 for the CJ-11,974 and placebo groups, respectively. Demographic characteristics of the treatment groups are listed in Table 1. The mean cisplatin dose was 102 mg/m² in group 1 and 96 mg/m² in group 2.

Efficacy
Interim analyses were performed on three cohorts, after 24, 36, and 58 patients had completed the study. At the second analysis, results of the modified triangular test indicated a statistically significant treatment difference in the proportion of patients experiencing delayed emesis. Given that this was the first study of CJ-11,974 in this patient population, it was decided to continue after the second interim analysis to gain further efficacy and safety experience with this experimental drug in this group of patients.

Patients receiving CJ-11,974 experienced significantly less delayed emesis than patients receiving placebo (Table 2). The percentages of patients with no emesis during days 2 to 5 were 67.8% and 36.6% in groups 1 and 2, respectively (P = .042, adjusted). The estimated odds ratio was 3.5 (95% confidence interval, 1.1 to 11.8). Patients receiving CJ-11,974 also experienced less acute emesis and emesis throughout the 5-day study period, compared with patients receiving placebo, although the acute comparison did not reach statistical significance (Table 2). The proportions of patients with no emesis during the first 24 hours after cisplatin were 85.7% and 66.7% in groups 1 and 2, respectively (P = .090). During days 1 to 5, control of emesis was observed in 64% of patients receiving CJ-11,974 and 30% of patients receiving placebo (P = .009).

Patients receiving CJ-11,974 also noted less nausea during the study, although the only significant differences were seen in the first 24 hours after cisplatin (Table 3). The proportions of patients with no nausea during the first 24 hours of the study were 79% and 50% in groups 1 and 2, respectively (P = .024). Forty-three percent of patients receiving CJ-11,974 reported no nausea during the day 2 to 5 study period, compared with 30% of patients receiving placebo (P = .309). During the entire 5-day study period, 39% of the patients in group 1 had no nausea, compared with 27% of patients in group 2 (P = .306), and the proportions of patients with no emesis, no nausea, and no rescue medication were 39% in group 1 and 17% in group 2 (P = .098). The distribution of time to first rescue for nausea or emesis differed between the two treatment groups, although not significantly (P = .17). Patients receiving placebo were rescued sooner than patients receiving CJ-11,974, with the median time to first rescue 52.9 hours in group 1 and 28 hours in group 2.

Safety
All 61 patients treated on the study were considered assessable for adverse events. Safety results are listed in Table 4. Significant treatment-related adverse events were uncommon in the CJ-11,974 and placebo groups. With respect to laboratory parameters, no differences were noted between the groups in changes in bilirubin, AST, ALT, alkaline phosphatase, or hematologic parameters. More patients receiving CJ-11,974 had elevations of blood urea nitrogen (BUN) of more than 1.3 times the upper limit of normal (54%), compared with patients receiving placebo (23%). Among the latter two groups, the mean changes from baseline in BUN for the placebo and CJ-11,974 patients at the final determination (9 to 10 days posttreatment) were 21.6 and 29.5, respectively.

When this apparent imbalance was examined further, it was observed that the occurrence of clinically significant BUN abnormalities in the two treatment groups was confounded by age. When a linear logistic model was fitted to the probability of a clinically significant BUN abnormality, only the term for age (up to 60, 61 to 70, 71 or more) was significant at the .05 level. Providing further support for this, when the (calculated) creatinine clearance abnormalities were analyzed similarly, age was again the only significant model term.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Significant progress has been made over the past 15 years in the development of more effective and better tolerated means to prevent chemotherapy-induced nausea and vomiting.²¹ The majority of patients receiving moderately to highly emetogenic chemotherapy will not experience acute emesis with the current antiemetic standard of a 5-HT₃ receptor antagonist and dexamethasone. Further clinical progress seems to have plateaued over the past 5 years, however, despite the introduction of additional 5-HT₃ receptor antagonists. The problem of cisplatin-induced emesis illustrates the current dilemma quite well. Cisplatin has traditionally served as the standard emetogenic challenge for new antiemetic approaches, given its high intrinsic emetogenicity and predictable pattern of acute and delayed emesis. The clinical utility of the 5-HT₃ receptor antagonists was first demonstrated in the setting of acute cisplatin-induced emesis.^1,4 Nevertheless, optimal control of acute and delayed cisplatin-induced emesis remains elusive. In the first 24 hours after high-dose cisplatin, up to one third of patients still experience emesis with current treatment approaches.⁴ Delayed emesis (> 24 hours) is even more problematic. The 5-HT₃ receptor antagonists have had a much more modest impact in the delayed as compared with acute emetic setting, suggesting that serotonin-independent mechanisms may be operative.^22-24 With the current best antiemetic approaches, which include a corticosteroid combined with metoclopramide or a 5-HT₃ receptor antagonist, up to 50% of patients still experience delayed emesis after high-dose cisplatin.²⁴

Further progress will rely on the introduction of agents with mechanisms of action not dependent on dopamine or 5-hydroxytryptamine. Selective antagonists of the neurokinin 1 receptor appear to represent a good candidate group. Compelling preclinical data suggest antiemetic efficacy for these agents in the same animal model in which 5-HT₃ receptor antagonists demonstrated antiemetic activity.^10,13

The current report represents the first phase II study evaluating a selective NK₁ receptor antagonist for the prevention of chemotherapy-induced emesis in cancer patients. CJ-11,974 was statistically superior to placebo in the prevention of delayed (days 2 to 5) emesis, acute (day 1) nausea, and emesis throughout the study period (days 1 to 5) after high-dose cisplatin. In addition, patients receiving CJ-11,974 had better control of acute emesis and delayed nausea than patients receiving placebo, although these differences did not reach statistical significance. Treatment with CJ-11,974 was well tolerated, with no clear-cut significant drug-related toxicity noted. A greater number of patients on the CJ-11,974 arm did experience clinically significant elevations of BUN. However, because of the disproportionate number of patients age 71 years or older on the CJ-11,974 arm with lower pretreatment creatinine clearances, the role of CJ-11,974 in the clinically significant BUN abnormalities remains unclear. Of note, a clinical trial evaluating the safety of CJ-11,974 in a group of healthy elderly volunteers (mean age, 69 years) has recently been completed (data on file). None of the 23 subjects receiving CJ-11,974 at loading doses up to 200 mg followed by 100 mg twice per day over 2 weeks had any clinically significant elevations in either BUN or creatinine levels.

Age has previously been identified as a potentially important prognostic factor for emesis, and an inverse relationship between age and frequency of emesis has been reported.²⁵ Given the unequal distribution of older patients between the two study arms, it is reasonable to ask whether the age imbalance could have accounted for some of the therapeutic benefits attributed to CJ-11,974. However, unlike the BUN and creatinine clearance abnormalities, when emesis rates were adjusted for age level using Cochran-Mantel-Haenszel tests (data not shown), the conclusions with regard to efficacy were unchanged and consistent with those from the unadjusted analyses.

The findings from the current study should be considered preliminary and exploratory in nature. Nevertheless, these results strongly suggest that NK₁ receptor antagonists may represent a useful new class of agents for preventing chemotherapy-induced emesis. In addition, this trial provides a sound rationale to proceed with additional studies to clarify the potential value of these agents. These future studies should address a number of critical issues, including (1) corroboration that the addition of CJ-11,974 to a 5-HT₃ receptor antagonist and dexamethasone significantly improves the control of acute emesis; (2) comparison of CJ-11,974 to conventional agents such as dexamethasone and metoclopramide in cisplatin-induced delayed emesis; (3) assessment of the value of adding CJ-11,974 to standard agents for cisplatin-induced delayed emesis; (4) appropriate schedule, minimally effective dose, and timing of CJ-11,974 administration; (5) assessment of the safety and efficacy of CJ-11,974 in a population of elderly cancer patients; and (6) evaluation of the antiemetic efficacy of CJ-11,974 with noncisplatin chemotherapy. Only with the completion of well-designed trials to address these issues will sufficient information be available to define accurately the true utility of these agents.

	ACKNOWLEDGMENTS

 
Supported by Pfizer Central Research, Pfizer, Inc, Groton, CT.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Hesketh PJ, Gandara DR: Serotonin antagonists: A new class of antiemetic agents. J Natl Cancer Inst 83:613-620, 1991[Abstract/Free Full Text]

2. Perez EA: Review of the preclinical pharmacology and comparative efficacy of 5-hydroxytryptamine-3 receptor antagonists for chemotherapy-induced emesis. J Clin Oncol 13:1036-1043, 1995[Abstract]

3. Morrow GR, Hickok JT, Rosenthal SN: Progress in reducing nausea and emesis: Comparisons of ondansetron (Zofran), granisetron (Kytril) and tropisetron (Navoban). Cancer 76:343-357, 1996

4. Hesketh PJ: Treatment of chemotherapy-induced emesis in the 1990s: Impact of the 5-HT₃ receptor antagonists. Support Care Cancer 2:286-292, 1994[Medline]

5. Hesketh PJ, Harvey WH, Beck TM, et al: A randomized, double-blind comparison of intravenous ondansetron alone and in combination with intravenous dexamethasone in the prevention of high-dose cisplatin-induced emesis. J Clin Oncol 12:596-600, 1994[Abstract]

6. Roila F: Control of acute cisplatin-induced emesis over repeat courses of chemotherapy. Oncology 53:65-72, 1996 (suppl 1)

7. Frakes LA, Brehm TL, Kosty MP, et al: An all oral antiemetic regimen for patients undergoing high-dose chemotherapy with peripheral blood stem transplant. Bone Marrow Transplant 20:473-478,1997

8. Dockray GJ: Substance P and other tachykinins, in Walsh JH, Dockray GJ (eds): Gut Peptides: Biochemistry and Physiology. New York, NY, Raven, 1994, pp 401-415

9. Watson JW, Nagahisa A, Lucot JB, et al: The tachykinins and emesis: towards complete control, in Reynolds DJM, Andrews PLR, Davis CJ (eds): Serotonin and the Scientific Basis of Anti-emetic Therapy. Oxford, United Kingdom, Oxford Clinical Communications, 1995, pp 233-238

10. Tattersall FD, Rycroft W, Francis B, et al: Tachykinin NK₁ receptor antagonists act centrally to inhibit emesis induced by the chemotherapeutic agent cisplatin in ferrets. Neuropharmacology 35:1121-1129, 1996[Medline]

11. Rudd JA, Jordan CC, Naylor RJ: The action of the NK₁ tachykinin receptor antagonist CP-99,994 in antagonizing the acute and delayed emesis induced by cisplatin in the ferret. Br J Pharmacol 119:931-936, 1996[Medline]

12. Beattie DT, Beresford IJM, Connor HE, et al: The pharmacology of GR203040, a novel, potent and selective non-peptide tachykinin NK₁ receptor antagonist. Br J Pharmacol 116:3149-3157, 1995[Medline]

13. Bountra C, Bunce K, Dale T, et al: Anti-emetic profile of a non-peptide neurokinin NK₁ receptor antagonist CP-99,994 in ferrets. Eur J Pharmacol 249:R3-R4, 1993

14. Watson JW, Gonsalves SF, Fossa AA, et al: The antiemetic effects of CP-99,994 in the ferret and the dog: Role of the NK₁ receptor. Br J Pharmacol 115:84-94, 1995[Medline]

15. Tattersall FD, Rycroft W, Hill RG, et al: Enantioselective inhibition of apomorphine-induced emesis in the ferret by the neurokinin₁ receptor antagonist CP-99,994. Neuropharmacology 33:259-260, 1994[Medline]

16. Kris MG, Radford J, Pizzo BA, et al: Control of emesis following cisplatin by CP-122,721, a selective NK₁ receptor antagonist. J Natl Cancer Inst 89:817-818, 1997[Free Full Text]

17. Hesketh P: Management of cisplatin-induced delayed emesis. Oncology 53:73-77, 1996 (suppl)

18. Whitehead J: The Design and Analysis of Sequential Clinical Trials (ed 2). Chichester, United Kingdom, Ellis Horwood, 1992

19. Brunier H, Whitehead J: PEST: Planning and Evaluation of Sequential Trials, version 3.0: Operating Manual. Reading, United Kingdom: PEST Project, University of Reading, 1993

20. Whitehead J: On the bias of maximum likelihood estimation following a sequential test. Biometrika 73:573-581, 1996

21. Grunberg SM, Hesketh PJ: Control of chemotherapy-induced emesis. N Engl J Med 329:1790-1796, 1993[Free Full Text]

22. Clark RA, Gralla RJ: Delayed emesis: A dilemma in antiemetic control. Support Care Cancer 1:182-185, 1993[Medline]

23. Kris MG, Pisters KMW, Hinkley L: Delayed emesis following anticancer chemotherapy. Support Care Cancer 2:297-300, 1994[Medline]

24. Tavorath R, Hesketh PJ: Drug treatment of chemotherapy-induced delayed emesis. Drugs 52:639-648, 1996[Medline]

25. Tonato M, Roila F, Del Favero A: Methodology of antiemetic trials: A review. Ann Oncol 2:107-114,1991

Submitted April 1, 1998; accepted September 30, 1998.

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