Annals ofOncology 2:681-686,1991. © 1991 Kluwer Academic Publishers. Printed in the Netherlands.
Original article A randomized, double-blinded study comparing six doses of batanopride (BMY-25801) with methylprednisolone in patients receiving moderately emetogenic chemotherapy J. Rusthoven,1 J. Pater,2 L. Kaizer,4 K. Wilson,5 D. Osoba,8 J. Latreille,10 B. Findlay,9 W. S. Lofters,7 D. Warr,6 F. Laberge,11 T. Vandenberg,12 B. Zee,2 J. Goodlow,3 D. Johnston2 & L. Smaldone3 From Department of Medicine: ' McMaster University, Hamilton Regional Cancer Centre; 2National Cancer Institute of Canada Clinical Trials Group; 3Bristol-Myers Squibb; * University of Toronto, Credit Valley Hospital; 5 University of British Columbia, British Columbia Cancer Agency, Victoria Clinic; 6 University of Toronto, Princess Margaret Hospital; 'Queen's University, Kingston Regional Cancer Centre; 8 University of British Columbia, British Columbia Cancer Agency; 9Hotel Dieu Hospital; m Hotel Dieu Hospital, University of Montreal; "Laval University; nUniversity of Western Ontario, London Regional Cancer Centre, Canada
Summary. Several agents in a new class of antiemetic compounds, 5-hydroxytryptamine (5-HT3) antagonists, have shown promise as effective antiemetics with fewer side effects than metoclopramide. One of these agents, batanopride, produced no severe toxicity at doses that prevented emesis due to chemotherapy in early Phase I trials. We conducted a randomized, double-blinded, 7 arm clinical trial to: (1) identify the presence of a dose-response for complete protection from emesis, and (2) compare batanopride with a standard antiemetic, methylprednisolone if a dose-response was found not to exist. Prior to chemotherapy, six patient groups each received a single intravenous dose of batanopride ranging from 0.2 to 6.0 mg/kg whereas a seventh group received methylprednisolone 250 mg intravenously. Chemotherapy-naive cancer patients scheduled to receive moderately emetogenic chemotherapy were eligible. Primary treatment outcomes that were recorded and analyzed included the number of episodes of emesis, the time to the first episode of emesis as well as the frequency and severity of nausea. Two hundred and eight patients accrued between April 1989 and February 1990 were evaluable for response. A significant dose-response effect for complete protection from emesis was not seen over the first 24 hours after chemotherapy (p = 0.102). However, a linear dose-response effect for time to first emesis was evident in a multivariate analysis (p - 0.029). While the highest batanopride dose group was associated with a higher complete protection rate (CPR) than the control group, this group also exhibited a higher incidence of diarrhea (p = 0.013), hypotension, and electrocardiographic abnormalities. We conclude that batanopride is associated with significant side effects at doses that may be otherwise effective in this patient population. This trial design using multiple arms of different doses and a control arm is useful in validating efficacy data of new antiemetic agents derived from early Phase I trials. Key words: antiemetic, batanopride, chemotherapy-induced emesis, clinical trial, moderately-emetogenic chemotherapy, 5-hydroxytryptamine receptor antagonist Introduction Various drugs have been tested for their ability to reduce or prevent nausea and vomiting in patients receiving emetogenic chemotherapy [1-5]. While high-dose metoclopramide is very effective in patients receiving high-dose cisplatin-containing chemotherapy [4], its effectiveness in patients receiving other, more moderately emetogenic chemotherapy is less clear [5, 6]. The antiemetic effect of metoclopramide may be due to its ability to block receptors for 5-hydroxytryptamine (5HT3) as well as dopamine receptors [7]. This latter mechanism may also account for the extrapyramidal side effects associated with this drug. A new class of
drugs appears to competitively block 5-HT3 receptors but have little or no dopaminergic properties. One of these compounds, batanopride (BMY-25801), is highly effective in preventing emesis in ferrets when induced by cisplatin, cyclophosphamide, or doxorubicin [8]. In Phase I studies of cancer patients receiving cisplatin, batanopride produced no severe adverse effects at doses ranging from 1.2 to 8.0 mg/kg [8-10]. Early randomized clinical trials in chemotherapy-naive patients receiving cisplatin-based chemotherapy have shown a significantly better complete control of emesis (as compared to placebo) with no extrapyramidal effectsat 6.0 mg/kg (11,12). Dose-dependent electrocardiographic effects presented as QRS and QTC interval
682
prolongation with the latter increasing by 16% on average at the 6.0 mg/kg dose level [10-13]. While a recent randomized trial demonstrated a higher incidence of systolic hypotension at a 6 mg/kg dose of batanopride compared to a 1.2 mg/kg dose [14], other randomized trials comparing this same dose of batanopride with placebo found no difference [11, 12]. In another randomized trial of patients receiving non-cisplatincontaining chemotherapy, 60% of patients receiving 1.2 mg/kg of batanopride had complete protection from emesis compared to 25% of those receiving placebo (p-0.07) [15]. As a result of these data, several doses appeared to be effective and safe. We, therefore, designed a randomized, double-blinded clinical trial to determine if a dose-response relationships exists for batanopride in the rate of complete protection from emesis in patients receiving moderately emetogenic chemotherapy and, if that is not the case, that batanopride is associated with a complete protection rate (CPR) significantly superior to a standard medication. Methylprednisolone was chosen as a standard medication because of its previously demonstrated ability to completely prevent emesis in 45% of this patient pupulation [16].
interval >0.45 sec; cortdcosteroids within one week or any antiemetics, benzamides, neuroleptics, tranquilizers, anti-depressants, or antiarrhythmia agents within 24 hours of treatment; and patients unable to receive the planned chemotherapy within a 2 hour period. Written informed consent was obtained from all patients. Pretreatment assessment and drug administration
The pretreatment evaluation included history and physical examination; blood pressure, pulse and weight; complete blood counts, serum biochemistry, urinalysis and ECG. Following randomization, the assigned dose of batanopride or methylprednisolone was prepared by a centre pharmacist not involved in the study. The intravenous bag and tubing were wrapped in opaque material and the solution was administered in a double-blinded fashion at a constant rate over 15 minutes, beginning 30 minutes prior to the start of chemotherapy. Blood pressure and pulse were further assessed 15 minutes and 2 hours after the antiemetic was given. An ECG was repeated at 2 hours. Any investigations with abnormal results were repeated within 24 hours.
Materials and methods
Treatment outcomes
Eligibility
After drug administration, patients were observed for 2 hours in the clinic area. Patients were instructed to use a self-reporting diary to record events over the following 3 days. Nausea, anxiety, and drowsiness were recorded on visual analogue scales; food intake and episodes of emesis were recorded on categorical scales. In addition, patients were asked to record and time all episodes of emesis (Table 1). Particular emphasis was put on accurate recording during the first 24 hours. Patients recorded adverse events over the first 3 days using a diary. Five-point categorical scales were used to report episodes of emesis (0, 1-2, 3-5, 6-10, 11 or more) and food intake (much less than usual, less than usual, about the same as usual, more than usual) at 24 hour intervals. An episode of vomiting or retching was defined as vomiting or retching which is separated from a succeeding episode by at least one minute. The 100 mm VAS included words at each extreme of the scale connoting the extremes of the parameter (eg. 'no nausea' and 'extremely severe nausea' for severity of
The randomized, double-blinded design consisted of 7 patient groups; each of 6 groups received batanopride at 0.2, 0.4, 0.6, 1.2, 3.6, or 6.0 mg/kg as a single dose intravenously (iv) while another group received methylprednisolone 250 mg also intravenously as a single dose. Chemotherapy-naive patients were considered eligible if they were 18 years of age or older, presented with a performance status of 50 or greater on the Karnofsky scale, and were planned to receive moderately emetogenic chemotherapy. Such chemotherapy included one or more of the following drugs in doses greater than or equal to those specified: doxorubicin 40 mg/m2 as a single agent or 25 mg/m2 in combination; epirubicin 75 mg/m2 as single agent or 50 mg/m2 in combination; cisplatin between 20 and 49 mg/m2; carboplatin 300 mg/m2; nitrogen mustard 6 mg/m2. The following drugs were considered moderately emetogenic only when used at or above the given dose in combination with other cytotoxic agents: cyclophosphamide 600 mg/m2; mitoxantrone 10 mg/m2; mitomycin 10 mg/m2; dactinomycin 500 mg/m2; dacarbazine (DTIC) between 350 and 500 mg/m2. Exclusion criteria included clinically active ulcerative or obstructive disease of the gastrointestinal tract; clinical evidence of brain metastases; nausea, vomiting or diarrhea within 48 hours preceding chemotherapy; abnormal serum creatinine (>117 [xmol/l), total bilirubin (>26 (imol/1), or serum potassium (
Original article A randomized, double-blinded study comparing six doses of batanopride (BMY-25801) with methylprednisolone in patients receiving moderately emetogenic chemotherapy J. Rusthoven,1 J. Pater,2 L. Kaizer,4 K. Wilson,5 D. Osoba,8 J. Latreille,10 B. Findlay,9 W. S. Lofters,7 D. Warr,6 F. Laberge,11 T. Vandenberg,12 B. Zee,2 J. Goodlow,3 D. Johnston2 & L. Smaldone3 From Department of Medicine: ' McMaster University, Hamilton Regional Cancer Centre; 2National Cancer Institute of Canada Clinical Trials Group; 3Bristol-Myers Squibb; * University of Toronto, Credit Valley Hospital; 5 University of British Columbia, British Columbia Cancer Agency, Victoria Clinic; 6 University of Toronto, Princess Margaret Hospital; 'Queen's University, Kingston Regional Cancer Centre; 8 University of British Columbia, British Columbia Cancer Agency; 9Hotel Dieu Hospital; m Hotel Dieu Hospital, University of Montreal; "Laval University; nUniversity of Western Ontario, London Regional Cancer Centre, Canada
Summary. Several agents in a new class of antiemetic compounds, 5-hydroxytryptamine (5-HT3) antagonists, have shown promise as effective antiemetics with fewer side effects than metoclopramide. One of these agents, batanopride, produced no severe toxicity at doses that prevented emesis due to chemotherapy in early Phase I trials. We conducted a randomized, double-blinded, 7 arm clinical trial to: (1) identify the presence of a dose-response for complete protection from emesis, and (2) compare batanopride with a standard antiemetic, methylprednisolone if a dose-response was found not to exist. Prior to chemotherapy, six patient groups each received a single intravenous dose of batanopride ranging from 0.2 to 6.0 mg/kg whereas a seventh group received methylprednisolone 250 mg intravenously. Chemotherapy-naive cancer patients scheduled to receive moderately emetogenic chemotherapy were eligible. Primary treatment outcomes that were recorded and analyzed included the number of episodes of emesis, the time to the first episode of emesis as well as the frequency and severity of nausea. Two hundred and eight patients accrued between April 1989 and February 1990 were evaluable for response. A significant dose-response effect for complete protection from emesis was not seen over the first 24 hours after chemotherapy (p = 0.102). However, a linear dose-response effect for time to first emesis was evident in a multivariate analysis (p - 0.029). While the highest batanopride dose group was associated with a higher complete protection rate (CPR) than the control group, this group also exhibited a higher incidence of diarrhea (p = 0.013), hypotension, and electrocardiographic abnormalities. We conclude that batanopride is associated with significant side effects at doses that may be otherwise effective in this patient population. This trial design using multiple arms of different doses and a control arm is useful in validating efficacy data of new antiemetic agents derived from early Phase I trials. Key words: antiemetic, batanopride, chemotherapy-induced emesis, clinical trial, moderately-emetogenic chemotherapy, 5-hydroxytryptamine receptor antagonist Introduction Various drugs have been tested for their ability to reduce or prevent nausea and vomiting in patients receiving emetogenic chemotherapy [1-5]. While high-dose metoclopramide is very effective in patients receiving high-dose cisplatin-containing chemotherapy [4], its effectiveness in patients receiving other, more moderately emetogenic chemotherapy is less clear [5, 6]. The antiemetic effect of metoclopramide may be due to its ability to block receptors for 5-hydroxytryptamine (5HT3) as well as dopamine receptors [7]. This latter mechanism may also account for the extrapyramidal side effects associated with this drug. A new class of
drugs appears to competitively block 5-HT3 receptors but have little or no dopaminergic properties. One of these compounds, batanopride (BMY-25801), is highly effective in preventing emesis in ferrets when induced by cisplatin, cyclophosphamide, or doxorubicin [8]. In Phase I studies of cancer patients receiving cisplatin, batanopride produced no severe adverse effects at doses ranging from 1.2 to 8.0 mg/kg [8-10]. Early randomized clinical trials in chemotherapy-naive patients receiving cisplatin-based chemotherapy have shown a significantly better complete control of emesis (as compared to placebo) with no extrapyramidal effectsat 6.0 mg/kg (11,12). Dose-dependent electrocardiographic effects presented as QRS and QTC interval
682
prolongation with the latter increasing by 16% on average at the 6.0 mg/kg dose level [10-13]. While a recent randomized trial demonstrated a higher incidence of systolic hypotension at a 6 mg/kg dose of batanopride compared to a 1.2 mg/kg dose [14], other randomized trials comparing this same dose of batanopride with placebo found no difference [11, 12]. In another randomized trial of patients receiving non-cisplatincontaining chemotherapy, 60% of patients receiving 1.2 mg/kg of batanopride had complete protection from emesis compared to 25% of those receiving placebo (p-0.07) [15]. As a result of these data, several doses appeared to be effective and safe. We, therefore, designed a randomized, double-blinded clinical trial to determine if a dose-response relationships exists for batanopride in the rate of complete protection from emesis in patients receiving moderately emetogenic chemotherapy and, if that is not the case, that batanopride is associated with a complete protection rate (CPR) significantly superior to a standard medication. Methylprednisolone was chosen as a standard medication because of its previously demonstrated ability to completely prevent emesis in 45% of this patient pupulation [16].
interval >0.45 sec; cortdcosteroids within one week or any antiemetics, benzamides, neuroleptics, tranquilizers, anti-depressants, or antiarrhythmia agents within 24 hours of treatment; and patients unable to receive the planned chemotherapy within a 2 hour period. Written informed consent was obtained from all patients. Pretreatment assessment and drug administration
The pretreatment evaluation included history and physical examination; blood pressure, pulse and weight; complete blood counts, serum biochemistry, urinalysis and ECG. Following randomization, the assigned dose of batanopride or methylprednisolone was prepared by a centre pharmacist not involved in the study. The intravenous bag and tubing were wrapped in opaque material and the solution was administered in a double-blinded fashion at a constant rate over 15 minutes, beginning 30 minutes prior to the start of chemotherapy. Blood pressure and pulse were further assessed 15 minutes and 2 hours after the antiemetic was given. An ECG was repeated at 2 hours. Any investigations with abnormal results were repeated within 24 hours.
Materials and methods
Treatment outcomes
Eligibility
After drug administration, patients were observed for 2 hours in the clinic area. Patients were instructed to use a self-reporting diary to record events over the following 3 days. Nausea, anxiety, and drowsiness were recorded on visual analogue scales; food intake and episodes of emesis were recorded on categorical scales. In addition, patients were asked to record and time all episodes of emesis (Table 1). Particular emphasis was put on accurate recording during the first 24 hours. Patients recorded adverse events over the first 3 days using a diary. Five-point categorical scales were used to report episodes of emesis (0, 1-2, 3-5, 6-10, 11 or more) and food intake (much less than usual, less than usual, about the same as usual, more than usual) at 24 hour intervals. An episode of vomiting or retching was defined as vomiting or retching which is separated from a succeeding episode by at least one minute. The 100 mm VAS included words at each extreme of the scale connoting the extremes of the parameter (eg. 'no nausea' and 'extremely severe nausea' for severity of
The randomized, double-blinded design consisted of 7 patient groups; each of 6 groups received batanopride at 0.2, 0.4, 0.6, 1.2, 3.6, or 6.0 mg/kg as a single dose intravenously (iv) while another group received methylprednisolone 250 mg also intravenously as a single dose. Chemotherapy-naive patients were considered eligible if they were 18 years of age or older, presented with a performance status of 50 or greater on the Karnofsky scale, and were planned to receive moderately emetogenic chemotherapy. Such chemotherapy included one or more of the following drugs in doses greater than or equal to those specified: doxorubicin 40 mg/m2 as a single agent or 25 mg/m2 in combination; epirubicin 75 mg/m2 as single agent or 50 mg/m2 in combination; cisplatin between 20 and 49 mg/m2; carboplatin 300 mg/m2; nitrogen mustard 6 mg/m2. The following drugs were considered moderately emetogenic only when used at or above the given dose in combination with other cytotoxic agents: cyclophosphamide 600 mg/m2; mitoxantrone 10 mg/m2; mitomycin 10 mg/m2; dactinomycin 500 mg/m2; dacarbazine (DTIC) between 350 and 500 mg/m2. Exclusion criteria included clinically active ulcerative or obstructive disease of the gastrointestinal tract; clinical evidence of brain metastases; nausea, vomiting or diarrhea within 48 hours preceding chemotherapy; abnormal serum creatinine (>117 [xmol/l), total bilirubin (>26 (imol/1), or serum potassium (
