Randomized Phase II Study of the Neurokinin 1
`Receptor Antagonist CJ-11,974 in the Control
`of Cisplatin-Induced Emesis
`
`By P.J. Hesketh, R.J. Gralla, R.T. Webb, W. Ueno, S. DelPrete, M.E. Bachinsky,
`N.L. Dirlam, C.B. Stack, and S.L. Silberman
`
`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 mg/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
`
`THE INTRODUCTION OF SELECTIVE inhibitors of
`
`the 5-hydroxytryptamine type 3 (5-HT3) receptor
`represented a major advance in efforts to control chemother-
`apy-induced nausea and vomiting.1 A number of these
`agents are now available in oral and intravenous formula-
`tions 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, chemother-
`apy-induced emesis remains a substantial problem in a
`number of clinical situations, including cisplatin-induced
`
`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.
`Submitted April 1, 1998; accepted September 30, 1998.
`Supported by 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@aol.com.
`1999 by American Society of Clinical Oncology.
`0732-183X/99/1701-0338$3.00/0
`
`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 5 .090); days 2 through 5,
`67.8% (group 1) and 36.6% (group 2) (P 5 .0425,
`adjusted); days 1 through 5, 64.3% (group 1) and 30%
`(group 2) (P 5 .009). Patients in group 1 experienced
`significantly less nausea than patients in group 2 on day
`1 (P 5 .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 control-
`ling cisplatin-induced delayed emesis and may provide
`additive benefit in acute emesis and nausea control
`when combined with a 5-hydroxytryptamine-3 recep-
`tor antagonist and dexamethasone. Additional larger
`trials are indicated to confirm the clinical value of
`CJ-11,974.
`JClinOncol17:338-343. 1999byAmericanSociety
`ofClinicalOncology.
`
`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 antago-
`nist CP-99,994 has been demonstrated to prevent emesis
`induced by a wide range of emetic stimuli, such as apomor-
`phine, 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 antago-
`nists 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)
`
`338
`
`JournalofClinicalOncology,Vol 17, No 1 (January), 1999: pp 338-343
`
`Helsinn Healthcare Exhibit 2044
`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PGR2016-00007
`
`Page 1 of 6
`
`

`
`CJ-11,974 FOR CISPLATIN-INDUCED EMESIS
`
`chemotherapy-induced emesis. Two reports suggest poten-
`tial activity in delayed emesis as well. Rudd et al11 demon-
`strated that CP-99,994 could abolish both acute and delayed
`emesis after cisplatin administration in the ferret. In addi-
`tion, Kris et al16 recently reported the first clinical experi-
`ence 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 (Ki 5 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.
`
`339
`
`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 chemother-
`apy, known seizure disorder, clinically significant neuromuscular disor-
`der 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. Granis-
`etron 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.
`
`PATIENTS AND METHODS
`
`Study Design
`
`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.
`
`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.
`
`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 dexametha-
`sone 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, physi-
`cal 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 5 no nausea; 10 5 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.
`
`Page 2 of 6
`
`

`
`340
`
`Postdosing safety evaluations included the following: ECG 2 hours
`after the initial CJ-11,974 dosing, vital signs and a brief cardiopulmo-
`nary 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 medica-
`tion at any time if significant nausea or emesis developed.
`
`Effıcacy 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 compari-
`sons 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 x2 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
`
`HESKETH ET AL
`
`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.
`
`Patient Characteristics
`
`RESULTS
`
`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 with-
`drew 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 5 .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.
`
`Table 1. Patient Characteristics
`
`Antiemetic Treatment
`
`Gran/Dex
`1 CJ-11,974
`
`Gran/Dex
`1 Placebo
`
`Characteristic
`
`No. of patients
`Sex
`Male
`Female
`Age, years
`36-60
`61-70
`$ 71
`Mean
`Range
`Alcohol consumption, nondrinkers
`Primary cancer site
`Lung
`Ovary
`Esophagus/oropharynx
`Other/unspecified
`Cisplatin dose, mg/m2, mean
`Mean baseline creatinine clearance, ml/min
`
`No.
`
`30
`
`%
`
`100
`
`60
`40
`
`23
`37
`40
`
`67
`
`67
`10
`10
`13
`
`18
`12
`
`7
`11
`12
`
`20
`
`20
`3
`3
`4
`
`66
`36-81
`
`102
`76.5
`
`Abbreviations: Gran, granisetron; Dex, dexamethasone.
`
`No.
`
`31
`
`19
`12
`
`13
`13
`5
`
`%
`
`100
`
`61
`39
`
`42
`42
`16
`
`62
`40-76
`19
`61
`
`15
`2
`2
`12
`
`48
`6
`6
`39
`
`96
`89
`
`Page 3 of 6
`
`

`
`CJ-11,974 FOR CISPLATIN-INDUCED EMESIS
`
`Effıcacy
`
`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 experi-
`ence 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 5 .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 5 .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 5 .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 5 .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 5 .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 5 .306), and the proportions of
`patients with no emesis, no nausea, and no rescue medica-
`
`Table 2. Antiemetic Efficacy
`
`Antiemetic Treatment
`
`Gran/Dex
`1 CJ-11,974
`
`Gran/Dex
`1 Placebo
`
`Variable
`
`No. of assessable patients
`Complete control* (day 1)
`Complete control (days 2-5)
`Complete control (days 1-5)
`
`No.
`
`28
`24
`19
`18
`
`%
`
`100.0
`85.7†
`67.8‡
`64.3§
`
`No.
`
`30
`20
`11
`9
`
`%
`
`100.0
`66.7
`36.6
`30.0
`
`Abbreviations: Gran, granisetron; Dex, dexamethasone.
`*No emetic episodes.
`†P5 .090.
`‡P5 .042 (adjusted).
`§P5 .009.
`
`341
`
`Table 3. Antinausea Efficacy
`
`Antiemetic Treatment
`
`Gran/Dex
`1 CJ-11,974
`
`Gran/Dex
`1 Placebo
`
`Variable
`
`No. of assessable patients
`No nausea (day 1)
`No nausea (days 2-5)
`No nausea (days 1-5)
`
`No.
`
`28
`22
`12
`11
`
`%
`
`100.0
`78.6*
`42.9†
`39.3‡
`
`No.
`
`30
`15
`9
`8
`
`%
`
`100.0
`50.0
`30.0
`26.7
`
`Abbreviations: Gran, granisetron; Dex, dexamethasone.
`*P5 .024.
`†P5 .309.
`‡P5 .306.
`
`tion were 39% in group 1 and 17% in group 2 (P 5 .098).
`The distribution of time to first rescue for nausea or emesis
`differed between the two treatment groups, although not
`significantly (P 5 .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 con-
`
`Table 4. Treatment-Related Adverse Events
`
`Antiemetic Treatment
`
`Gran/Dex
`1 CJ-11,974
`
`Gran/Dex
`1 Placebo
`
`Variable
`
`No. of patients
`Headache
`Taste perversion
`Dizziness
`Pharyngitis
`Tinnitis
`
`No.
`
`30
`0
`2
`1
`1
`1
`
`%
`
`100.0
`0.0
`6.7
`3.0
`3.0
`3.0
`
`No.
`
`31
`2
`0
`0
`0
`0
`
`%
`
`100.0
`6.4
`0.0
`0.0
`0.0
`0.0
`
`Abbreviations: Gran, granisetron; Dex, dexamethasone.
`
`Page 4 of 6
`
`

`
`342
`
`founded 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
`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 vomit-
`ing.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 recep-
`tor 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 emetoge-
`nicity 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 de-
`layed 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 metoclopra-
`mide 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 neuroki-
`nin 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 pa-
`tients. 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
`
`HESKETH ET AL
`
`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 signifi-
`cant 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 clear-
`ances, 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, un-
`like 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) corrobora-
`tion 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.
`
`Page 5 of 6
`
`

`
`CJ-11,974 FOR CISPLATIN-INDUCED EMESIS
`
`343
`
`REFERENCES
`1. Hesketh PJ, Gandara DR: Serotonin antagonists: A new class of
`12. Beattie DT, Beresford IJM, Connor HE, et al: The pharmacology
`antiemetic agents. J Natl Cancer Inst 83:613-620, 1991
`of GR203040, a novel, potent and selective non-peptide tachykinin NK1
`2. Perez EA: Review of the preclinical pharmacology and compara-
`receptor antagonist. Br J Pharmacol 116:3149-3157, 1995
`tive efficacy of 5-hydroxytryptamine-3 receptor antagonists for chemo-
`13. Bountra C, Bunce K, Dale T, et al: Anti-emetic profile of a
`therapy-induced emesis. J Clin Oncol 13:1036-1043, 1995
`non-peptide neurokinin NK1 receptor antagonist CP-99,994 in ferrets.
`3. Morrow GR, Hickok JT, Rosenthal SN: Progress in reducing
`Eur J Pharmacol 249:R3-R4, 1993
`nausea and emesis: Comparisons of ondansetron (Zofran), granisetron
`14. Watson JW, Gonsalves SF, Fossa AA, et al: The antiemetic
`(Kytril) and tropisetron (Navoban). Cancer 76:343-357, 1996
`effects of CP-99,994 in the ferret and the dog: Role of the NK1 receptor.
`4. Hesketh PJ: Treatment of chemotherapy-induced emesis in the
`Br J Pharmacol 115:84-94, 1995
`1990s: Impact of the 5-HT3 receptor antagonists. Support Care Cancer
`15. Tattersall FD, Rycroft W, Hill RG, et al: Enantioselective
`2:286-292, 1994
`inhibition of apomorphine-induced emesis in the ferret by the neuroki-
`5. Hesketh PJ, Harvey WH, Beck TM, et al: A randomized,
`nin1 receptor antagonist CP-99,994. Neuropharmacology 33:259-260,
`double-blind comparison of intravenous ondansetron alone and in
`1994
`combination with intravenous dexamethasone in the prevention of
`16. Kris MG, Radford J, Pizzo BA, et al: Control of emesis
`high-dose cisplatin-induced emesis. J Clin Oncol 12:596-600, 1994
`following cisplatin by CP-122,721, a selective NK1 receptor antagonist.
`6. Roila F: Control of acute cisplatin-induced emesis over repeat
`J Natl Cancer Inst 89:817-818, 1997
`courses of chemotherapy. Oncology 53:65-72, 1996 (suppl 1)
`17. Hesketh P: Management of cisplatin-induced delayed emesis.
`7. Frakes LA, Brehm TL, Kosty MP, et al: An all oral antiemetic
`Oncology 53:73-77, 1996 (suppl)
`regimen for patients undergoing high-dose chemotherapy with periph-
`18. Whitehead J: The Design and Analysis of Sequential Clinical
`eral blood stem transplant. Bone Marrow Transplant 20:473-478,1997
`Trials (ed 2). Chichester, United Kingdom, Ellis Horwood, 1992
`8. Dockray GJ: Substance P and other tachykinins, in Walsh JH,
`19. Brunier H, Whitehead J: PEST: Planning and Evaluation of
`Dockray GJ (eds): Gut Peptides: Biochemistry and Physiology. New
`Sequential Trials, version 3.0: Operating Manual. Reading, United
`York, NY, Raven, 1994, pp 401-415
`Kingdom: PEST Project, University of Reading, 1993
`9. Watson JW, Nagahisa A, Lucot JB, et al: The tachykinins and
`20. Whitehead J: On the bias of maximum likelihood estimation
`emesis: towards complete control, in Reynolds DJM, Andrews PLR,
`following a sequential test. Biometrika 73:573-581, 1996
`Davis CJ (eds): Serotonin and the Scientific Basis of Anti-emetic
`21. Grunberg SM, Hesketh PJ: Control of chemotherapy-induced
`Therapy. Oxford, United Kingdom, Oxford Clinical Communications,
`emesis. N Engl J Med 329:1790-1796, 1993
`1995, pp 233-238
`22. Clark RA, Gralla RJ: Delayed emesis: A dilemma in antiemetic
`10. Tattersall FD, Rycroft W, Francis B, et al: Tachykinin NK1
`control. Support Care Cancer 1:182-185, 1993
`receptor antagonists act centrally to inhibit emesis induced by the
`23. Kris MG, Pisters KMW, Hinkley L: Delayed emesis following
`chemotherapeutic agent cisplatin in ferrets. Neuropharmacology 35:1121-
`anticancer chemotherapy. Support Care Cancer 2:297-300, 1994
`1129, 1996
`24. Tavorath R, Hesketh PJ: Drug treatment of chemotherapy-
`11. Rudd JA, Jordan CC, Naylor RJ: The action of the NK1
`induced delayed emesis. Drugs 52:639-648, 1996
`tachykinin receptor antagonist CP-99,994 in antagonizing the acute and
`25. Tonato M, Roila F, Del Favero A: Methodology of antiemetic
`delayed emesis induced by cisplatin in the ferret. Br J Pharmacol
`trials: A review. Ann Oncol 2:107-114,1991
`119:931-936, 1996
`
`Page 6 of 6