Phase I/II Trial of Granisetron: A Novel 5-Hydroxytryptamine Antagonist for the Prevention of Chemotherapy-Induced Nausea and Vomiting By M. Addelmant, C. Erlichman, S. Fine, D. Warr, and C. Murray A new class of antiemetic agents, the 5-hydroxytryptamine (5-HT,) antagonists, have been shown to possess potent antiemetic properties in the ferret model. We conducted a phase 1/11 trial of the 5-HT, antagonist BRL43694 (granisetron) in 24 chemotherapy-na'ive patients who were receiving any combination of doxorubicin and/or cisplatin. The first 12 patients received 40 /pg/kg and the second 12 received 80 pg/kg of granisetron intravenously before beginning chemotherapy. Nausea was assessed by a patient-completed visual analogue scale and episodes of retching recorded by the patient and an independent observer. Fifty-two percent of the 22 evaluable patients had no retching or vomiting and 32% had no nausea during the first 24 hours after chemotherapy. Pharmacokinetic measurements were performed. The
CHEMOTHERAPY-induced
nausea and vomiting continues to be a significant problem in the care of patients receiving cancer chemotherapy. Existing antiemetic regimens such as high-dose metoclopramide, with or without dexamethasone,', 2 have demonstrated clinical efficacy. Nevertheless, severe nausea that at times limits the administration of potentially curative chemotherapy still occurs in many patients. Metoclopramide, which is a potent dopamine receptor antagonist, has been shown to be a weak antagonist of 5-hydroxytryptamine (5-HT) acting at the 5-HT 3 receptor. 3 Other dopamine antagonists such as domperidone, which lack 5-HT 3 antagonist activity, have little or no ability to prevent chemotherapyinduced nausea.4 This raises the possibility that the binding of metoclopramide to the 5HT 3 receptor may contribute to its antiemetic effect. Recently, BRL43694 (granisetron), a highly selective 5-HT 3 receptor antagonist that does not exhibit dopamine-receptor antagonism, has been synthesized. 5 It has been shown to possess potent antiemetic activity against cisplatin, cyclophosphamide, doxorubicin, and radiation-induced emesis in the ferret model.1'6' 7 In this model, high-dose metoclopramide is very effective but domperidone gives inferior results; these findings parallel studies in humans.1'8
disposition of granisetron was best described using a two-compartment model. The area under the plasma concentration curve (AUC) was 277 ± 226 ng • h/mL and 359 ± 282 ng.h/mL at 40 and 80 pg/kg, respectively. The total body clearance was 0.319 ± 0.315 L/kg/hr and 0.483 ± 0.504 L/kg/hr at the 40 and 80 pg/kg doses. Wide interpatient variation in model independent parameters was observed. There was no suggestion of dose-dependent efficacy at the two dose levels studied. We conclude that granisetron shows promise as a well-tolerated and effective antiemetic. Randomized trials comparing this drug with standard regimens are currently underway. J Clin Oncol 8:337-34 1. @ 1990 by American Society of Clinical Oncology.
Therapeutic benefit was achieved at doses that ranged from 5 to 500 ,g/kg. Animal toxicology indicated that there was a large therapeutic index with dose-limiting toxicity consisting of seizures and ECG changes at doses of 10 mg/ kg.9
This preclinical data led us to perform a phase I/II trial of granisetron in 24 cancer patients receiving moderately to highly emetogenic chemotherapy for the first time to assess the safety, tolerance, and pharmacokinetics of this drug. Data concerning efficacy were collected as well. METHODS Patients were eligible for this study if they had received no prior chemotherapy, had histologically confirmed cancer,
From the Departmentsof Medicine and Nursing, Princess MargaretHospital, Toronto; and the Departmentsof Medicine and Pharmacology, University of Toronto, Toronto, Canada. tDeceased. Submitted October 31, 1988; accepted September 13, 1989. Supported by a grantfrom Beecham Clinical Pharmacology, CanadaInc. Address reprint requests to C. Erlichman, MD, Princess Margaret Hospital, 500 Sherbourne Street, Toronto, Canada M4X 1K9. © 1990 by AmericanSociety of Clinical Oncology. 0732-183X/90/0802-0001$3.00/0
Journal of Clinical Oncology, Vol 8, No 2 (February), 1990: pp 337-341
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ADDELMAN ET AL
were to receive combination chemotherapy containing either doxorubicin, cisplatin, or both, had an Eastern Cooperative Oncology Group (ECOG) status of 0, 1, 2, or 3, were over 18 years old, and provided written consent. Exclusion criteria included serum creatinine greater than 1.5 normal or creatinine clearance less than 30 mL/min, elevation of hepatic enzymes greater than 2 x normal, WBC count less than 3 x 9 10'/L, platelets less than 100 x 10 /L, nausea and vomiting before chemotherapy, concurrent steroid therapy, cerebral tumors, concurrent treatment with major psychotropic agents, and a history of seizures or significant cardiovascular disease. The study design was a sequential dose escalation in which 12 patients were entered at each dose level of 40 and 80 Ag/kg of granisetron. The drug was administered intravenously, once only. Patients were screened before drug administration with a 24-hour Holter monitor, ECG, and appropriate blood tests to determine eligibility. Granisetron was given intravenously by infusion pump over 30 minutes in 50 mL of 0.9% saline immediately before chemotherapy. The chemotherapy administration was begun within 15 minutes of the completion of the granisetron infusion in all patients. Cardiac monitoring was performed for the first 6 hours of the study with a bedside ECG monitor. Holter monitoring was performed during the 24 hours following the start of the granisetron infusion. Blood pressure and pulse were measured before the start of the infusion and at hourly intervals for the first 4 hours and then at 8, 12, and 24 hours. Blood samples were taken for hemoglobin, WBC count, platelets, bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma GT, alkaline phosphatase, serum electrolytes, glucose, creatinine and routine urinalysis before the infusion and at 4 and 24 hours afterwards. Five mL of blood was drawn for drug analysis through a heparin lock inserted into the arm opposite drug administration before infusion, at the end of the infusion, and at /2, 1, 2, 3, 4, 5, 6, 8, 12 and 24 hours after the infusion. The blood was kept on ice until centrifuged and plasma removed and stored at - 70 0 C until analyzed. Vomiting was determined by using a categorical five-point scale dividing the number of episodes of emesis or retching into 0, 1 to 2, 3 to 5, 6 to 10, and 11 or more episodes. The appropriate category was selected by the patient for seven assessment intervals: hourly, for the first 4 hours, and then at 6, 12, and 24 hours after the infusion. Nausea, assessed by patient-completed visual analogue scale, was performed before treatment, then also hourly for 4 hours and at 6, 12, and 24 hours after the infusion. This scale consisted of a 10 cm line for severity of nausea. The left end of the scale denoted no symptoms and the right end denoted very severe nausea. Further antiemetics of any type other than metoclopramide or domperidone were allowed if vomiting occurred. An adverse events checklist was completed 24 hours after the granisetron infusion. Biochemistry, complete blood count, and a urinalysis were repeated between 4 and 7 days following treatment. Plasma samples were analyzed for granisetron by highperformance liquid chromatography (HPLC) with fluorescence detection. Details of the analytic technique are described elsewhere.'° The lower limit of reliable determination was 0.05 ng/mL. The data were fit to multiexponential equations and model-independent parameters were calcu-
lated. Area under the plasma concentration curve (AUC) was determined using the trapezoidal method between time 0 and the last data point. The AUC from the last data point and infinity was calculated by dividing the final observation by the terminal rate constant. The total AUC was defined as the sum of these two calculations. Clearance was calculated as dose/AUC and apparent volume of distribution was calculated as clearance/terminal rate constant.
RESULTS
The chemotherapy administered to the 24 study patients is listed in Table 1. The dose of doxorubicin for 10 of the 11 patients receiving this drug was 50 mg/m2. Eleven of 14 patients
received doses of cisplatin that were 21 50 mg/m2 (range, 25 to 120 mg/m 2). No arrhythmias were noted on the bedside monitor during the 6 hours after the infusion of granisetron. The Holter monitor recorded asymptomatic arrhythmias in three patients during the 24-hour study period. The first patient developed five beats of supraventricular tachycardia 11 hours after the granisetron infusion. Seven runs of supraventricular tachycardia were noted in the second patient, the longest lasting for 51 beats. In the third patient, four beats of ventricular tachycardia at 6 hours after granisetron, during an episode of acute urinary retention, were detected. There was one patient death during the 24-hour study period due to progressive respiratory failure from extensive lung and pleural metastases. The patient died 19 hours after granisetron was given. There were no documented cardiac abnormalities on the Holter monitor before the respiratory arrest leading to the patient's death. No acute effect on pulse or blood pressure attributable to granisetron was seen in patients enrolled on the study. Table 1. Chemotherapy Delivered Number of Patients 8 2 5 3 2 2 1 1
Drugs (mg/m') Doxorubicin (50), cyclophosphamide (500), 5FU (500) Doxorubicin (50), cyclophosphamide (1,000), vincristine (1.5) Cisplatin (50), cyclophosphamide (500-750) Cisplatin (120), mitomycin (8), vinblastine (5) Cisplatin (50, 70) Cisplatin (25), VP16 (100) Cisplatin (60) Cisplatin (45), doxorubicin (45)
Abbreviation: VP16, etoposide.
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339
PHASE 1/11 TRIAL OF GRANISETRON
Peripheral blood counts were unchanged in all evaluable patients during the initial 24-hour study period. Leukopenia secondary to chemotherapy was observed 1 week after drug administration. One patient had an acute elevation of the AST and ALT at 24 hours after treatment associated with a febrile episode, which resolved subsequently. A similar febrile episode 1 week later, unassociated with any drugs, resulted in a similar reversible elevation of liver enzymes. Three patients developed elevated AST and ALT beginning 1 week after treatment. One patient had a doubling of the AST and ALT, and a second patient had approximately a tripling of the same enzymes. Both of these patients had liver metastases from breast cancer. The third patient had an isolated 4.8-fold elevation of the AST at 1 week. This patient had no known liver metastases and had received fluorouracil (5-FU), doxorubicin, and cyclophosphamide for metastatic breast cancer. The most common adverse event during the study period was headache, which occurred in 10 patients. Most patients described their headaches as mild, but two patients indicated these headaches were moderately severe. Symptoms described at 24 hours after treatment are listed in Table 2. None of these complaints were severe. No extrapyramidal symptoms were described by any patients. Twenty-two patients were evaluable for efficacy. One of the two unevaluable patients was the patient who died. She completed the visual analogue scale for 12 hours after chemotherapy and reported no nausea. The second unevaluable patient had nausea and vomiting before treatment that was not known by the study personnel Table 2. Adverse Events at 24 Hours Symptom
Number of Patients
Headache Diarrhea Insomnia Flushing Labile mood Dry mouth Anxiety weakness Fatigue Dizziness Constipation
10 4 4 3 2 2 2 2 2 1 1
Iiv
3
1
2
01
0-1
4-6 6-12 12-24 1-2 2-3 3-4 Hours after BRL 43694
Fig 1. Mean linear analogue scores of nausea severity for time periods following the infusion of BRL43694. The error bars represent ± SE of the mean.
before the patient's inclusion in the study. The results of the visual analogue scale assessment for severity of nausea for the remaining patients are displayed graphically in Fig 1. Of the 22 evaluable patients, 12 (55%) had no retching or vomiting during the 24-hour study period. Seven of 22 patients (32%) had no nausea at all, and only one of 22 had more than two episodes of vomiting. Seven patients were given additional antiemetics. Four received prochlorperazine, one received dimenhydrinate, one received lorazepam, and one received lorazepam and dexamethasone. In the three patients receiving cisplatin at a dose of 120 mg/m2, one patient described mild nausea without retching or vomiting, the second described slight nausea with one episode of retching 12 hours after chemotherapy, and the third patient had an isolated episode of retching associated with acute urinary retention. After relief of the obstruction, no further nausea occurred in this patient. All three of these patients, however, had nausea and vomiting 2 or 3 days after chemotherapy. Table 3 summarizes the pharmacokinetic parameters characterizing the disposition of granisetron in this patient population. The individual patient data and the mean data were best fit to a biexponential equation consistent with a twocompartment model. The model independent parameters of AUC, total body clearance, and volume of distribution demonstrated a wide interpatient variation. Whereas the variation in the total body clearance was 20-fold, the volume of
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340
ADDELMAN ET AL Table 3. Summary of Mean Parameters (± SD) Obtained From the Analysis of Individual Patient Plasma BRL43694 Concentrations DOSE (mcg/kg)
Number of Patients
40
12
80
12
C..x (ng/mL)
t1/2, (h)
AUC (ng - h/mL)
CI (L/h/kg)
V, (L/kg)
27.2 (10.7) 67.7 (40.1)
11.6 (6.93) 9.76 (7.68)
277 (226) 359 (282)
0.319 (0.315) 0.483 (0.504)
3.26 (1.45) 3.34 (0.89)
Abbreviations: C...,, peak plasma level; t,/2z, terminal plasma half-life; CI, total body clearance; V,, volume distribution.
distribution varied three- to fivefold only. The maximum plasma concentrations achieved at the two dose levels studied showed a similar wide variation between patients. However, the mean value at the 40 Ag/kg dose was approximately one-half that at 80 Mg/kg. The mean AUC at 80 Mg/kg was 1.30 times greater than that at 40 Ag/kg. The difference was not significant (P < .05, t test). Clearances and volume of distribution did not change significantly at the two doses studied. DISCUSSION Granisetron is a novel compound with specific 5-HT 3 antagonist characteristics. The identification of this receptor has suggested a key role for 5-HT in the mechanism of chemotherapyinduced nausea and vomiting. In our study, granisetron was generally well tolerated. Headache occurred in 10 patients. This has been noted in investigations of other 5-HT 3 blockers.1 Mild elevation of transaminases occurred 1 week after treatment in three patients, two of whom had liver metastases. The significance of this observation is unknown. It has been noted in other trials of 5-HT 3 blockers given to chemotherapy patients, but was not noted to occur in healthy volunteers. 12 One acute elevation of transaminases appeared to be clearly related to factors other than the administration of granisetron. Asymptomatic self-limited arrhythmias occurred in three patients. Arrhythmias have been reported in patients receiving both doxorubicin' 3 and cisplatin.14 No arrhythmias have been reported in healthy volunteers receiving granisetron.' 2 Our data suggest that granisetron may possess significant antiemetic activity in patients receiving Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) or cisplatin-based chemotherapy for the first time. Three patients were treated with high doses of cisplatin. Two of them each had one episode of retching and the third
had mild nausea and no vomiting during the study period. Studies have suggested that patients receiving high doses of cisplatin may have a median number of 10 episodes of retching within the first 24 hours. 5 The data in Fig 1 may be compared with visual analogue scale data of an identical form obtained in a previous National Cancer Institute of Canada (NCIC) study of methylprednisolone and low-dose metoclopramide, employing similarly emetogenic chemotherapy.' 6 In that study, the mean scores for degree of nausea were greater than 1.8 for all time periods after treatment with methylprednisolone, and greater than 2.8 for all time periods after treatment with low-dose metoclopramide. The maximum mean score for patients treated with methylprednisolone was 3.3, after low-dose metoclopramide, 5.0. Our data (Fig 1) showed no time period where the mean score was greater than 1.4. Only four of the 14 patients receiving cisplatin experienced any nausea within the first 6 hours after chemotherapy. This compares favorably with the time of onset of nausea after cisplatin in previous reports of patients not receiving antiemetics. 15 Ten of the 22 evaluable patients experienced some vomiting during the study period. However, this was limited to no more than two episodes in all but one patient, who had four episodes. Although 15 of 22 patients developed some nausea, this was generally mild. Complete protection from emesis at 24 hours was observed in five of nine patients receiving doxorubicin, seven of 12 receiving cisplatin, and zero of one receiving both doxorubicin and cisplatin. No differences in either efficacy or safety were detected between groups receiving low- or highdose granisetron. There was no correlation between any of the pharmacological parameters and antiemetic efficacy. Due to the small sample size, however, the power to detect such relationships was low.
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341
PHASE I/I1 TRIAL OF GRANISETRON
The disposition of granisetron in this patient population raises several issues. The wide variation in AUC and hence, clearance, suggests that drug dosing on a weight or surface area basis may not achieve predictable plasma concentrations. This variability may be due to hepatic drug metabolism, as only small amounts of the parent compound have been identified in the urine.' 7 Further studies regarding drug metabolism are required to define the importance of this factor. Interestingly, the terminal half-life (t,/2z) of this drug in patients appears to be longer than that of normal volunteers. We found that the t 1 /2z was 11.6 and 9.76 hours for the 40 and 80 Ag/kg dose, respectively. The tl/2z was 4.04 and 5.35 hours at 40 and 80 Ag/kg, respectively, in normal volunteers (Beecham, June 1988 personal communication). This may reflect a difference in drug metabolism that the illness imparts on the pa-
tient, drug interactions with antineoplastic agents coadministered, or changes in plasma protein binding in patients with cancer. Additional pharmacological studies will be required to clarify this issue. The results of this phase I/II study are promising indicators that granisetron is an important advance in the management of nausea and vomiting in patients receiving chemotherapy. The limited degree of nausea and low frequency of vomiting preclude our determining whether a dose-response relationship exists with this small sample size. The role of this drug in routine clinical care must await the results of carefully designed prospective randomized double-blind trials comparing granisetron with standard agents. Two such trials are being performed at present by the Clinical Trials Group of the NCIC.
REFERENCES 1. Kris MG, Gralla RJ, Ryson LB, et al: Improved control of cisplatin-induced emesis with high-dose metoclopramide, dexamethasone, and diphenhydramine: Results of consecutive trials in 255 patients. Cancer 55:527-534, 1985 2. Gralla RJ, Itri LM, Pisko SE, et al: Antiemetic efficacy of high dose metoclopramide: Randomized trials with placebo and prochlorperazine in patients with chemotherapyinduced nausea and vomiting. New Engl J Med 305:905-909, 1981 3. Miner WD, Sanger GJ: Inhibition of cis-platin induced vomiting by selective 5-hydroxytryptamine M-receptor antagonism. Br J Pharmacol 88:497-499, 1986 4. Miner WD, Sanger GJ, Turner DH: Comparison of the effect of BRL24924, metoclopramide and domperidone on cis-platin induced emesis in the ferret. Br J Pharmacol Proc 88:374, 1986 (suppl) 5. Boyle EA, Miner WD, Sanger GJ: Antiemetic activity of BRL43694, a novel 5-HT 3 receptor antagonist. Br J Cancer 56:227, 1987 (abstr) 6. Boyle EA, Miner WD, Sanger GJ: Different anticancer therapies evoke emesis by mechanisms that can be blocked by the 5-HT 3 antagonist BRL43694. Br J Pharmacol Proc 91:418, 1987 (suppl) 7. Miner WD, Sanger GJ, Turner DH: Evidence that 5-hydroxytryptamine 3-receptors mediate cytotoxic drug and radiation-evoked emesis. Br J Cancer 56:159-162, 1987 8. Roila F, Tonato M, Basurto C, et al: Double-blind control trial of the antiemetic efficacy and toxicity of metholprednisolone (MP), metoclopramide (MTC) and domperidone (DMP) in breast cancer patients treated with IVCMF. Europ J Cancer Clin Oncol 23:615-617, 1987
9. BRL43694: A novel anti-emetic: Preclinical data summary. Beecham Pharmaceuticals Research Div, Coldharbour Road, Harlow, Essex, 1987 10. Clarkson A, Coates PE, Zussman BD: A Specific HPLC method for the determination of BRL43694 in plasma and urine. Br J Clin Pharmacol 25:136p, 1988 (abstr, suppl) 11. Hesketh PJ, Murphy WK, Khojasteh A et al: GRC507/75 (gr-38032F): A novel compound effective in the treatment of cisplatin-induced nausea and vomiting. Proc Am Soc Clin Oncol 7:280, 1988 (abstr) 12. Beecham Research Laboratories: Manual for clinical investigators. June 1987 13. Steinberg JS, Cohen AJ, Wasserman AG, et al: Acute arrhythmogenicity of doxorubicin administration. Cancer 60:1213-1218, 1987 14. Hashimi LA, Khalyl MF, Salen PA: Supraventricular tachycardia. A probable complication of platinum treatment. Oncol41:174-175, 1984 15. Kovach JS, Moertel CG, Schutt AJ et al: Phase II study of cis-diamininedichloroplastinum (NSC-119875) in advanced carcinoma of the large bowel. Cancer Chem Rep 57:357-359, 1973 16. Osoba D, Erlichman C, Willan AR, et al: Superiority of methylprednisolone sodium succinate over low dose metoclopramide hydrochloride in the prevention of nausea and vomiting produced by cancer chemotherapy. Clin and Invest Med 9:225-231, 1986 17. Zussman BD, Clarkson A, Coates PE, et al: The pharmacokinetic profile of BRL43694, a novel 5-HT 3 receptor antagonist in healthy male volunteers. Br J Clin Pharmacol, 25:107p (abstr, suppl)
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CHEMOTHERAPY-induced
nausea and vomiting continues to be a significant problem in the care of patients receiving cancer chemotherapy. Existing antiemetic regimens such as high-dose metoclopramide, with or without dexamethasone,', 2 have demonstrated clinical efficacy. Nevertheless, severe nausea that at times limits the administration of potentially curative chemotherapy still occurs in many patients. Metoclopramide, which is a potent dopamine receptor antagonist, has been shown to be a weak antagonist of 5-hydroxytryptamine (5-HT) acting at the 5-HT 3 receptor. 3 Other dopamine antagonists such as domperidone, which lack 5-HT 3 antagonist activity, have little or no ability to prevent chemotherapyinduced nausea.4 This raises the possibility that the binding of metoclopramide to the 5HT 3 receptor may contribute to its antiemetic effect. Recently, BRL43694 (granisetron), a highly selective 5-HT 3 receptor antagonist that does not exhibit dopamine-receptor antagonism, has been synthesized. 5 It has been shown to possess potent antiemetic activity against cisplatin, cyclophosphamide, doxorubicin, and radiation-induced emesis in the ferret model.1'6' 7 In this model, high-dose metoclopramide is very effective but domperidone gives inferior results; these findings parallel studies in humans.1'8
disposition of granisetron was best described using a two-compartment model. The area under the plasma concentration curve (AUC) was 277 ± 226 ng • h/mL and 359 ± 282 ng.h/mL at 40 and 80 pg/kg, respectively. The total body clearance was 0.319 ± 0.315 L/kg/hr and 0.483 ± 0.504 L/kg/hr at the 40 and 80 pg/kg doses. Wide interpatient variation in model independent parameters was observed. There was no suggestion of dose-dependent efficacy at the two dose levels studied. We conclude that granisetron shows promise as a well-tolerated and effective antiemetic. Randomized trials comparing this drug with standard regimens are currently underway. J Clin Oncol 8:337-34 1. @ 1990 by American Society of Clinical Oncology.
Therapeutic benefit was achieved at doses that ranged from 5 to 500 ,g/kg. Animal toxicology indicated that there was a large therapeutic index with dose-limiting toxicity consisting of seizures and ECG changes at doses of 10 mg/ kg.9
This preclinical data led us to perform a phase I/II trial of granisetron in 24 cancer patients receiving moderately to highly emetogenic chemotherapy for the first time to assess the safety, tolerance, and pharmacokinetics of this drug. Data concerning efficacy were collected as well. METHODS Patients were eligible for this study if they had received no prior chemotherapy, had histologically confirmed cancer,
From the Departmentsof Medicine and Nursing, Princess MargaretHospital, Toronto; and the Departmentsof Medicine and Pharmacology, University of Toronto, Toronto, Canada. tDeceased. Submitted October 31, 1988; accepted September 13, 1989. Supported by a grantfrom Beecham Clinical Pharmacology, CanadaInc. Address reprint requests to C. Erlichman, MD, Princess Margaret Hospital, 500 Sherbourne Street, Toronto, Canada M4X 1K9. © 1990 by AmericanSociety of Clinical Oncology. 0732-183X/90/0802-0001$3.00/0
Journal of Clinical Oncology, Vol 8, No 2 (February), 1990: pp 337-341
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337
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ADDELMAN ET AL
were to receive combination chemotherapy containing either doxorubicin, cisplatin, or both, had an Eastern Cooperative Oncology Group (ECOG) status of 0, 1, 2, or 3, were over 18 years old, and provided written consent. Exclusion criteria included serum creatinine greater than 1.5 normal or creatinine clearance less than 30 mL/min, elevation of hepatic enzymes greater than 2 x normal, WBC count less than 3 x 9 10'/L, platelets less than 100 x 10 /L, nausea and vomiting before chemotherapy, concurrent steroid therapy, cerebral tumors, concurrent treatment with major psychotropic agents, and a history of seizures or significant cardiovascular disease. The study design was a sequential dose escalation in which 12 patients were entered at each dose level of 40 and 80 Ag/kg of granisetron. The drug was administered intravenously, once only. Patients were screened before drug administration with a 24-hour Holter monitor, ECG, and appropriate blood tests to determine eligibility. Granisetron was given intravenously by infusion pump over 30 minutes in 50 mL of 0.9% saline immediately before chemotherapy. The chemotherapy administration was begun within 15 minutes of the completion of the granisetron infusion in all patients. Cardiac monitoring was performed for the first 6 hours of the study with a bedside ECG monitor. Holter monitoring was performed during the 24 hours following the start of the granisetron infusion. Blood pressure and pulse were measured before the start of the infusion and at hourly intervals for the first 4 hours and then at 8, 12, and 24 hours. Blood samples were taken for hemoglobin, WBC count, platelets, bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma GT, alkaline phosphatase, serum electrolytes, glucose, creatinine and routine urinalysis before the infusion and at 4 and 24 hours afterwards. Five mL of blood was drawn for drug analysis through a heparin lock inserted into the arm opposite drug administration before infusion, at the end of the infusion, and at /2, 1, 2, 3, 4, 5, 6, 8, 12 and 24 hours after the infusion. The blood was kept on ice until centrifuged and plasma removed and stored at - 70 0 C until analyzed. Vomiting was determined by using a categorical five-point scale dividing the number of episodes of emesis or retching into 0, 1 to 2, 3 to 5, 6 to 10, and 11 or more episodes. The appropriate category was selected by the patient for seven assessment intervals: hourly, for the first 4 hours, and then at 6, 12, and 24 hours after the infusion. Nausea, assessed by patient-completed visual analogue scale, was performed before treatment, then also hourly for 4 hours and at 6, 12, and 24 hours after the infusion. This scale consisted of a 10 cm line for severity of nausea. The left end of the scale denoted no symptoms and the right end denoted very severe nausea. Further antiemetics of any type other than metoclopramide or domperidone were allowed if vomiting occurred. An adverse events checklist was completed 24 hours after the granisetron infusion. Biochemistry, complete blood count, and a urinalysis were repeated between 4 and 7 days following treatment. Plasma samples were analyzed for granisetron by highperformance liquid chromatography (HPLC) with fluorescence detection. Details of the analytic technique are described elsewhere.'° The lower limit of reliable determination was 0.05 ng/mL. The data were fit to multiexponential equations and model-independent parameters were calcu-
lated. Area under the plasma concentration curve (AUC) was determined using the trapezoidal method between time 0 and the last data point. The AUC from the last data point and infinity was calculated by dividing the final observation by the terminal rate constant. The total AUC was defined as the sum of these two calculations. Clearance was calculated as dose/AUC and apparent volume of distribution was calculated as clearance/terminal rate constant.
RESULTS
The chemotherapy administered to the 24 study patients is listed in Table 1. The dose of doxorubicin for 10 of the 11 patients receiving this drug was 50 mg/m2. Eleven of 14 patients
received doses of cisplatin that were 21 50 mg/m2 (range, 25 to 120 mg/m 2). No arrhythmias were noted on the bedside monitor during the 6 hours after the infusion of granisetron. The Holter monitor recorded asymptomatic arrhythmias in three patients during the 24-hour study period. The first patient developed five beats of supraventricular tachycardia 11 hours after the granisetron infusion. Seven runs of supraventricular tachycardia were noted in the second patient, the longest lasting for 51 beats. In the third patient, four beats of ventricular tachycardia at 6 hours after granisetron, during an episode of acute urinary retention, were detected. There was one patient death during the 24-hour study period due to progressive respiratory failure from extensive lung and pleural metastases. The patient died 19 hours after granisetron was given. There were no documented cardiac abnormalities on the Holter monitor before the respiratory arrest leading to the patient's death. No acute effect on pulse or blood pressure attributable to granisetron was seen in patients enrolled on the study. Table 1. Chemotherapy Delivered Number of Patients 8 2 5 3 2 2 1 1
Drugs (mg/m') Doxorubicin (50), cyclophosphamide (500), 5FU (500) Doxorubicin (50), cyclophosphamide (1,000), vincristine (1.5) Cisplatin (50), cyclophosphamide (500-750) Cisplatin (120), mitomycin (8), vinblastine (5) Cisplatin (50, 70) Cisplatin (25), VP16 (100) Cisplatin (60) Cisplatin (45), doxorubicin (45)
Abbreviation: VP16, etoposide.
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339
PHASE 1/11 TRIAL OF GRANISETRON
Peripheral blood counts were unchanged in all evaluable patients during the initial 24-hour study period. Leukopenia secondary to chemotherapy was observed 1 week after drug administration. One patient had an acute elevation of the AST and ALT at 24 hours after treatment associated with a febrile episode, which resolved subsequently. A similar febrile episode 1 week later, unassociated with any drugs, resulted in a similar reversible elevation of liver enzymes. Three patients developed elevated AST and ALT beginning 1 week after treatment. One patient had a doubling of the AST and ALT, and a second patient had approximately a tripling of the same enzymes. Both of these patients had liver metastases from breast cancer. The third patient had an isolated 4.8-fold elevation of the AST at 1 week. This patient had no known liver metastases and had received fluorouracil (5-FU), doxorubicin, and cyclophosphamide for metastatic breast cancer. The most common adverse event during the study period was headache, which occurred in 10 patients. Most patients described their headaches as mild, but two patients indicated these headaches were moderately severe. Symptoms described at 24 hours after treatment are listed in Table 2. None of these complaints were severe. No extrapyramidal symptoms were described by any patients. Twenty-two patients were evaluable for efficacy. One of the two unevaluable patients was the patient who died. She completed the visual analogue scale for 12 hours after chemotherapy and reported no nausea. The second unevaluable patient had nausea and vomiting before treatment that was not known by the study personnel Table 2. Adverse Events at 24 Hours Symptom
Number of Patients
Headache Diarrhea Insomnia Flushing Labile mood Dry mouth Anxiety weakness Fatigue Dizziness Constipation
10 4 4 3 2 2 2 2 2 1 1
Iiv
3
1
2
01
0-1
4-6 6-12 12-24 1-2 2-3 3-4 Hours after BRL 43694
Fig 1. Mean linear analogue scores of nausea severity for time periods following the infusion of BRL43694. The error bars represent ± SE of the mean.
before the patient's inclusion in the study. The results of the visual analogue scale assessment for severity of nausea for the remaining patients are displayed graphically in Fig 1. Of the 22 evaluable patients, 12 (55%) had no retching or vomiting during the 24-hour study period. Seven of 22 patients (32%) had no nausea at all, and only one of 22 had more than two episodes of vomiting. Seven patients were given additional antiemetics. Four received prochlorperazine, one received dimenhydrinate, one received lorazepam, and one received lorazepam and dexamethasone. In the three patients receiving cisplatin at a dose of 120 mg/m2, one patient described mild nausea without retching or vomiting, the second described slight nausea with one episode of retching 12 hours after chemotherapy, and the third patient had an isolated episode of retching associated with acute urinary retention. After relief of the obstruction, no further nausea occurred in this patient. All three of these patients, however, had nausea and vomiting 2 or 3 days after chemotherapy. Table 3 summarizes the pharmacokinetic parameters characterizing the disposition of granisetron in this patient population. The individual patient data and the mean data were best fit to a biexponential equation consistent with a twocompartment model. The model independent parameters of AUC, total body clearance, and volume of distribution demonstrated a wide interpatient variation. Whereas the variation in the total body clearance was 20-fold, the volume of
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340
ADDELMAN ET AL Table 3. Summary of Mean Parameters (± SD) Obtained From the Analysis of Individual Patient Plasma BRL43694 Concentrations DOSE (mcg/kg)
Number of Patients
40
12
80
12
C..x (ng/mL)
t1/2, (h)
AUC (ng - h/mL)
CI (L/h/kg)
V, (L/kg)
27.2 (10.7) 67.7 (40.1)
11.6 (6.93) 9.76 (7.68)
277 (226) 359 (282)
0.319 (0.315) 0.483 (0.504)
3.26 (1.45) 3.34 (0.89)
Abbreviations: C...,, peak plasma level; t,/2z, terminal plasma half-life; CI, total body clearance; V,, volume distribution.
distribution varied three- to fivefold only. The maximum plasma concentrations achieved at the two dose levels studied showed a similar wide variation between patients. However, the mean value at the 40 Ag/kg dose was approximately one-half that at 80 Mg/kg. The mean AUC at 80 Mg/kg was 1.30 times greater than that at 40 Ag/kg. The difference was not significant (P < .05, t test). Clearances and volume of distribution did not change significantly at the two doses studied. DISCUSSION Granisetron is a novel compound with specific 5-HT 3 antagonist characteristics. The identification of this receptor has suggested a key role for 5-HT in the mechanism of chemotherapyinduced nausea and vomiting. In our study, granisetron was generally well tolerated. Headache occurred in 10 patients. This has been noted in investigations of other 5-HT 3 blockers.1 Mild elevation of transaminases occurred 1 week after treatment in three patients, two of whom had liver metastases. The significance of this observation is unknown. It has been noted in other trials of 5-HT 3 blockers given to chemotherapy patients, but was not noted to occur in healthy volunteers. 12 One acute elevation of transaminases appeared to be clearly related to factors other than the administration of granisetron. Asymptomatic self-limited arrhythmias occurred in three patients. Arrhythmias have been reported in patients receiving both doxorubicin' 3 and cisplatin.14 No arrhythmias have been reported in healthy volunteers receiving granisetron.' 2 Our data suggest that granisetron may possess significant antiemetic activity in patients receiving Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) or cisplatin-based chemotherapy for the first time. Three patients were treated with high doses of cisplatin. Two of them each had one episode of retching and the third
had mild nausea and no vomiting during the study period. Studies have suggested that patients receiving high doses of cisplatin may have a median number of 10 episodes of retching within the first 24 hours. 5 The data in Fig 1 may be compared with visual analogue scale data of an identical form obtained in a previous National Cancer Institute of Canada (NCIC) study of methylprednisolone and low-dose metoclopramide, employing similarly emetogenic chemotherapy.' 6 In that study, the mean scores for degree of nausea were greater than 1.8 for all time periods after treatment with methylprednisolone, and greater than 2.8 for all time periods after treatment with low-dose metoclopramide. The maximum mean score for patients treated with methylprednisolone was 3.3, after low-dose metoclopramide, 5.0. Our data (Fig 1) showed no time period where the mean score was greater than 1.4. Only four of the 14 patients receiving cisplatin experienced any nausea within the first 6 hours after chemotherapy. This compares favorably with the time of onset of nausea after cisplatin in previous reports of patients not receiving antiemetics. 15 Ten of the 22 evaluable patients experienced some vomiting during the study period. However, this was limited to no more than two episodes in all but one patient, who had four episodes. Although 15 of 22 patients developed some nausea, this was generally mild. Complete protection from emesis at 24 hours was observed in five of nine patients receiving doxorubicin, seven of 12 receiving cisplatin, and zero of one receiving both doxorubicin and cisplatin. No differences in either efficacy or safety were detected between groups receiving low- or highdose granisetron. There was no correlation between any of the pharmacological parameters and antiemetic efficacy. Due to the small sample size, however, the power to detect such relationships was low.
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341
PHASE I/I1 TRIAL OF GRANISETRON
The disposition of granisetron in this patient population raises several issues. The wide variation in AUC and hence, clearance, suggests that drug dosing on a weight or surface area basis may not achieve predictable plasma concentrations. This variability may be due to hepatic drug metabolism, as only small amounts of the parent compound have been identified in the urine.' 7 Further studies regarding drug metabolism are required to define the importance of this factor. Interestingly, the terminal half-life (t,/2z) of this drug in patients appears to be longer than that of normal volunteers. We found that the t 1 /2z was 11.6 and 9.76 hours for the 40 and 80 Ag/kg dose, respectively. The tl/2z was 4.04 and 5.35 hours at 40 and 80 Ag/kg, respectively, in normal volunteers (Beecham, June 1988 personal communication). This may reflect a difference in drug metabolism that the illness imparts on the pa-
tient, drug interactions with antineoplastic agents coadministered, or changes in plasma protein binding in patients with cancer. Additional pharmacological studies will be required to clarify this issue. The results of this phase I/II study are promising indicators that granisetron is an important advance in the management of nausea and vomiting in patients receiving chemotherapy. The limited degree of nausea and low frequency of vomiting preclude our determining whether a dose-response relationship exists with this small sample size. The role of this drug in routine clinical care must await the results of carefully designed prospective randomized double-blind trials comparing granisetron with standard agents. Two such trials are being performed at present by the Clinical Trials Group of the NCIC.
REFERENCES 1. Kris MG, Gralla RJ, Ryson LB, et al: Improved control of cisplatin-induced emesis with high-dose metoclopramide, dexamethasone, and diphenhydramine: Results of consecutive trials in 255 patients. Cancer 55:527-534, 1985 2. Gralla RJ, Itri LM, Pisko SE, et al: Antiemetic efficacy of high dose metoclopramide: Randomized trials with placebo and prochlorperazine in patients with chemotherapyinduced nausea and vomiting. New Engl J Med 305:905-909, 1981 3. Miner WD, Sanger GJ: Inhibition of cis-platin induced vomiting by selective 5-hydroxytryptamine M-receptor antagonism. Br J Pharmacol 88:497-499, 1986 4. Miner WD, Sanger GJ, Turner DH: Comparison of the effect of BRL24924, metoclopramide and domperidone on cis-platin induced emesis in the ferret. Br J Pharmacol Proc 88:374, 1986 (suppl) 5. Boyle EA, Miner WD, Sanger GJ: Antiemetic activity of BRL43694, a novel 5-HT 3 receptor antagonist. Br J Cancer 56:227, 1987 (abstr) 6. Boyle EA, Miner WD, Sanger GJ: Different anticancer therapies evoke emesis by mechanisms that can be blocked by the 5-HT 3 antagonist BRL43694. Br J Pharmacol Proc 91:418, 1987 (suppl) 7. Miner WD, Sanger GJ, Turner DH: Evidence that 5-hydroxytryptamine 3-receptors mediate cytotoxic drug and radiation-evoked emesis. Br J Cancer 56:159-162, 1987 8. Roila F, Tonato M, Basurto C, et al: Double-blind control trial of the antiemetic efficacy and toxicity of metholprednisolone (MP), metoclopramide (MTC) and domperidone (DMP) in breast cancer patients treated with IVCMF. Europ J Cancer Clin Oncol 23:615-617, 1987
9. BRL43694: A novel anti-emetic: Preclinical data summary. Beecham Pharmaceuticals Research Div, Coldharbour Road, Harlow, Essex, 1987 10. Clarkson A, Coates PE, Zussman BD: A Specific HPLC method for the determination of BRL43694 in plasma and urine. Br J Clin Pharmacol 25:136p, 1988 (abstr, suppl) 11. Hesketh PJ, Murphy WK, Khojasteh A et al: GRC507/75 (gr-38032F): A novel compound effective in the treatment of cisplatin-induced nausea and vomiting. Proc Am Soc Clin Oncol 7:280, 1988 (abstr) 12. Beecham Research Laboratories: Manual for clinical investigators. June 1987 13. Steinberg JS, Cohen AJ, Wasserman AG, et al: Acute arrhythmogenicity of doxorubicin administration. Cancer 60:1213-1218, 1987 14. Hashimi LA, Khalyl MF, Salen PA: Supraventricular tachycardia. A probable complication of platinum treatment. Oncol41:174-175, 1984 15. Kovach JS, Moertel CG, Schutt AJ et al: Phase II study of cis-diamininedichloroplastinum (NSC-119875) in advanced carcinoma of the large bowel. Cancer Chem Rep 57:357-359, 1973 16. Osoba D, Erlichman C, Willan AR, et al: Superiority of methylprednisolone sodium succinate over low dose metoclopramide hydrochloride in the prevention of nausea and vomiting produced by cancer chemotherapy. Clin and Invest Med 9:225-231, 1986 17. Zussman BD, Clarkson A, Coates PE, et al: The pharmacokinetic profile of BRL43694, a novel 5-HT 3 receptor antagonist in healthy male volunteers. Br J Clin Pharmacol, 25:107p (abstr, suppl)
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