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A phase I antiemetic study of MDL 73,147EF, a novel 5-hydroxytryptamine antagonist in cancer patients receiving emetogenic chemotherapy
Annals of Oncology 5: 549-551, 1994. © 1994 Kluwer Academic Publishers. Printed in the Netherlands.
Original article A phase I antiemetic study of MDL 73,147EF, a novel 5-hydroxytryptamine antagonist in cancer patients receiving emetogenic chemotherapy
Clinical Pharmacology Unit and Medical Oncology Department, Centre Leon Berard, Lyon; ' Clinical Research Department, Merrell Dow Research Institute, Strasbourg, France
Summary Background: We conducted a phase I study with MDL 73.147EF, a new 5 hydroxytryptamine 3 (5-HT3) receptor antagonist, in 25 patients requiring emetogenic chemotherapy. Patients and methods: 5 groups of 5 patients received rising unit doses of MDL 73,147EF (10 to 50 mg) intravenously before chemotherapy, with two additional doses per day if needed. Nausea was assessed by a patient-completed visual analogue scale and episodes of vomiting were recorded by an independant observer.
Results: 42% of the patients were complete or major responders on day one. Five patients were given other rescue antiemetic therapy. Adverse effects included headache (16%) diarrhea (8%) and other minor events. The best results were obtained with the 30,40 and 50 mg doses. Conclusions: MDL 73.147EF is a well-tolerated and probably effective antiemetic agent which requires further evaluation in randomised controlled clinical studies.
Key words: MDL 73.147EF, 5-FTT3 receptor antagonist, antiemetic, cancer chemotherapy
Background
Patients and methods
Nausea and vomiting are major adverse effects of cytotoxic chemotherapy in cancer patients [1]. Significant progress has recently been made in the treatment of chemotherapy-induced emesis. The 5-HT3-antagonist (antiserotonergic) agents are the newest family of antiemetic drugs. MDL 73,147EF is a new 5-HT3 receptor antagonist incorporating a novel bridged pseudopelletierine ring system which prevents vomiting induced by cisplatin in the ferret, with a large therapeutic index and a more selective and sustained activity than its predecessor MDL 72,222 [2-5]. In a single-dose, dose-rising (1-30 mg) study of normal volunteers, the compound was well tolerated and doses of 10, 20 and 30 mg caused significant inhibition of the skin flare response to intradermal serotonin [6]. Therefore, these three doses, plus two larger ones of 40 and 50 mg, were chosen for the initial clinical development of this product in Europe
Patient eligibility
[7|We performed a phase I antiemetic trial of MDL 73,147EF in 25 cancer patients receiving moderately to highly emetogenic chemotherapy to assess the safety and tolerance of this agent, and to collect preliminary data concerning its antiemetic effect.
The inclusion criteria were: histologically confirmed cancer, intravenous cytotoxic chemotherapy, which should be high-dose cisplatin (>50 mg/m2 body surface) or carboplatin (>400 mg/m2), either alone or together with other intravenous cytotoxic chemotherapy, or any regimen known to induce severe nausea and vomiting also in naive or pretreated patients, regardless of whether they had responded to a previous antiemetic regimen; a performance status >50% (Karnofsky); age between 18 and 75 years; written informed consent; normal baseline laboratory values. The exclusion criteria were: child-bearing potential in women at risk of pregnancy; cerebral metastases with impaired supratentorial functions; administration of an established anti-emetic drug (metoclopramide, dexamethasone, dopamine D2 receptor antagonists and derivatives of cannabinoids) in the 12 hours before administration of cytotoxic chemotherapy; anticipatory nausea and vomiting; administration of another research drug in the previous 21 days.
Study design The study was approved by the Ethics Committee of the Claude Bernard University of Lyon. Five groups of 5 evaluable patients were to receive rising unit doses (10, 20, 30, 40 and 50 mg, respectively) of MDL 73,147EF, by intravenous injection. The first dose was given each day 15 minutes before the start of cytotoxic chemotherapy. If further anti-emetic treatment was required during the first 24 hours after the start of chemotherapy two additional doses of
Downloaded from https://academic.oup.com/annonc/article-abstract/5/6/549/252133 by Western Sydney University Library user on 14 January 2019
Y. Merrouche, G. Catimel, P. Rebattu, A. Dumortier, J. P. Guastalla, P. O'Grady1 & M. Clavel
550
Evaluation of toxicity and efficacy Heart rate and blood pressure were recorded just before administration of the initial dose of MDL 73.147EF and 15 and 30 minutes, 2 h, 4 h, 6 h, 8 h, 24 hours after the start of cytotoxic therapy. Thereafter, they were measured immediately before and 15 and 30 minutes after each subsequent administration of MDL 73.147EF. An adverse events checklist was completed 24 hours after the last intravenous injection. Nausea was assessed by a series of horinzontal visual analogue scales (VAS) each 10 cm in length and labelled 'no nausea' and 'nausea as bad as it could be' at the two extremes. Mild nausea was defined between 0 and <2.5 cm, moderate nausea between 2.5 and 7.5 cm and severe nausea between 7.5 cm and the end of the VAS. In addition, the patients were asked to define their nausea as absent, mild, moderate or severe. This evaluation as done just before administration of MDL 73.147EF and at 2, 4, 6, 8 and 24 hours after the start of each day's chemotherapy. The number of episodes of vomiting (0, 1, 2, 3, 4, 5, or >5) within each hour were counted by a nurse. These assessments were repeated 24, 48 and 72 hours after the end of the last day of chemotherapy.
Results Of the 25 patients, 15 were female, with a median age of 53 years. Twenty-three patients had previously received cytotoxic chemotherapy. Up to 5 types of cytotoxic agents per patient were administered over 1 day (n = 17), 2 days (n = 3) or 5 days (n - 5). The main types and daily dose ranges are described in Table 1. Twenty-three patients (92%) received cisplatin for a mean dose of 74 mg/m2 (+/— 23). Of the 23 patients who received cisplatin, 1, 16 and 6 received cisplatin <50, 50-99 and >100 mg/m2, respectively. Thus, the majority of the patients received highly emetogenic chemotherapeutic regimens. Ten patients received only 1 dose of MDL 73,147EF per day of cytotoxic chemotherapy, 11 patients received 1 additional dose on at least one day and 4 patients received 2 additional doses on at least 1 day. Five patients were given established antiemetic therapy for rescue. The mg/kg dose ranges at each discrete dose level were: 10 mg: 0.16-0.24 mg/kg; 20 mg: 0.24-0.38 mg/ kg; 30 mg: 0.43-0.69 mg/kg; 40 mg: 0.58-0.73 mg/kg; 50 mg: 0.56-0.83 mg/kg. MDL 73,147EF was extremely well tolerated by the patients: no major drug-related side effects were observed, no significant changes in pulse rate or blood pressure occurred following its administration, and laboratory parameters did not change substantially after treatment. Minor, possibly drug-related, side
effects included headache (n = 4), moderate diarrhea (n •= 2), fever probably related to bleomycin infusion (n - 2), malaise (n = 1), hot flush (n = 1), gastric pain (n = 1) and maculous indolent cutaneous eruption appearing two days after MDL 73,147EF infusion (n - 1). These side effects were mild and transient, and did not lead to alteration of the antiemetic treatment regimen in any of the patients. No extrapyramidal symptoms were observed and no additional side effects were seen in patients receiving repeated courses of MDL73,147EF. All patients were evaluable for response to treatment. The correlation between the 2 methods of nausea evaluation was complete. The antiemetic effects of MDL 73,147EF on day one are detailed in Table 2. Eleven of 25 patients (44%) obtained complete protection or a major response (<2 emetic episodes) on day 1. Results were similar for protection against nausea in twelve patients (47%) who experienced no or only moderate nausea. Table 1. Patient characteristics. Number (all evaluable) Median age (range, years) Male/female Median weight (kg) Karnofsky above 60% Prior chemotherapy Primary Ovarian Head and neck Melanoma Testicular Cervix Urinary tract Hodgkin's Breast Unknown Chemotherapy administered In combination: Cisplatin (50-120 mg/m2) Dacarbazine (350-450 mg/m2) Cyclophosphamide (500-750 mg/m2) Adriamycin (25-30 mg/m2) Etoposide (100 mg/m2) Fluorouracil (500-1000 mg/m2) Vindesine (3 mg/m2) Other Alone: Cisplatin (50-70 mg/m2)
25 53 (27-72) 10/15 62 (41-90) 23 23 6 6 5 2 2 1 1 1 1 23 6 7 3 2 6 5 11 2
Table 2. Antiemetic efficacy of MDL 73.147EF on day 1. Dose level (mg)
Emetic episodes
Nausea
0
1-2
3-5
>5
None
Moderate
Severe
10 20 30 40 50 Total
1 0 3 1 2 7
0 2 0 2 0 4
0 0 0 1 1 2
4 3 2 1 2 12
0 0 1 1 1 3
2 0 1 4 2 9
3 5 3 0 2 13
Downloaded from https://academic.oup.com/annonc/article-abstract/5/6/549/252133 by Western Sydney University Library user on 14 January 2019
MDL 73.147EF at the same dose level could be given provided that the previous dose or doses had been well-tolerated. The second dose was not to be given until the elapse of at least 6 hours since administration of the first dose. The third dose was not to be given until the elapse of at least 2 hours since the second dose. Established anti-emetic therapy could be given at any time after the start of the cytotoxic chemotherapy in instances of antiemetic failure. Biochemistry, complete blood count, and urinalysis were repeated every day following administration of MDL 73.147EF and 3 days after the last dose.
551
Conclusion We conducted an antiemetic phase I study (dose range 0.16 to 0.83 mg/kg) of MDL 73,147EF in 25 patients receiving cisplatin-based chemotherapy or some other cytotoxic regimen known to be potentially emetogenic during one to five days. Our study supports a previous clinical report that MDL 73,147EF is safe and well tolerated by patients [12]. Most of our patients had no detectable side effects related to MDL 73,147EF. Headache and diarrhea were noted in a few patients, as they were in the previous report [12]; however, these side effects were mild and transient. No patient experienced extrapyramidal side effects. This study confirms that the antiemetic activity of MDL 73,147EF is promising [12]. Monotherapy with intravenous MDL 73,147EF can prevent or control acute vomiting and nausea induced by highly emetogenetic chemotherapy in 44% of the patients. It must be underscored that the majority of our patients were at high risk of emesis: 92% had previously received chemotherapy, 92% received cisplatin as part of the chemotherapy regimen and 60% were female [1, 2]. Taking into account these characteristics, our results compare favorably with those reported by Kirchner et
al. in their early clinical trial of MDL 73,147EF [12]. In the majority of patients who receive cisplatin (50-120 mg/m2) without antiemetic cover, emesis is usually severe [1, 2]. Even in this subset of patients, the higher doses of MDL 73,147EF yielded good results. In view of its good tolerance and promising activity, MDL 73,147EF merits further evaluation in randomised controlled studies versus conventional antiemetic agents and also versus commercially available 5 FTT3 receptor antagonists. Acknowledgement We thank Mrs Regine Perez for help in preparing the manuscript. References 1. Grunberg SM, Hesketh PJ. Control of chemotherapy induced emesis. N Engl J Med 1993; 329:1790-6. 2. Miner WD, Sanger GJ. Inhibition of cisplatin induced vomiting by selective 5-hydroxytryptamine M-receptor antagonism. Br J Pharmacol 1986; 88:497-9. 3. Clavel M, Klein T, Metz R et al. A randomised comparative study of the antiemetic effect and safety of MDL 72.222 and 'standard anti-emetic therapy' in patients receiving cisplatin containing chemotherapy for malignant rumors. Cancer Comm 1989; 3: 321-2. 4. Gittos MW, Fatmi M. Potent 5-HT3 antagonist incorporating a novel bridge pseudopelletierine ring system. Les actualites de chimie therapeutique 1989; 16: 187-98. 5. MDL 73.147EF. Clinical Investigator's Brochure. Revised November 1990. 6. O'Grady P, Boyce MF, Hardenberg J. Effect of intravenous MDL 73,147EF on the flare response to intradermal 5-HT: A doubleblind, placebo-controlled, dose-rising, parallel-group study in normal volunteers. Project report NO 89-LP-ST-0190. 7. Kirchner V, Aapro M, Alberto P et al. Early clinical trial of MDL 73,147EF: A new 5-HT3 receptors antagonist for the prevention of chemotherapy-induced nausea and vomiting. Ann Oncol 1993; 4:481-4. Received 14 February 1994; accepted 29 March 1994. Correspondence to: Y. Merrouche, MD Medical Oncology Department Centre Leon Berard 28, rue Laennec 69373 Lyon Cedex 08, France
Downloaded from https://academic.oup.com/annonc/article-abstract/5/6/549/252133 by Western Sydney University Library user on 14 January 2019
Antiemetic effects during the 4 subsequent days were also satisfactory with complete or major protection ranging from 70%-80% of patients. Of the 23 patients receiving cisplatin-based chemotherapy regimens, complete protection or major response were seen in 1 of the 2 naive patients and in 10 of the 21 pretreated patients. The best results were obtained with the 30, 40 -and 50 -mg doses which achieved major efficacy (<2 emetic episodes) in 53% of the patients. The number of patients who received second and third doses were 2, 2, 0, 0 and 0 for the 10, 20, 30, 40 and 50 mg doses. Furthermore, the number of patients given established antiemetic therapy as escape medication for breakthrough symptoms were 2, 2, 0, 0 and 1 for the 10, 20, 30, 40 and 50 mg, respectively. Thus, there was a trend towards less need for repeated MDL 73,147EF administration and escape medication as the dose of MDL 73,147EF was increased.
Original article A phase I antiemetic study of MDL 73,147EF, a novel 5-hydroxytryptamine antagonist in cancer patients receiving emetogenic chemotherapy
Clinical Pharmacology Unit and Medical Oncology Department, Centre Leon Berard, Lyon; ' Clinical Research Department, Merrell Dow Research Institute, Strasbourg, France
Summary Background: We conducted a phase I study with MDL 73.147EF, a new 5 hydroxytryptamine 3 (5-HT3) receptor antagonist, in 25 patients requiring emetogenic chemotherapy. Patients and methods: 5 groups of 5 patients received rising unit doses of MDL 73,147EF (10 to 50 mg) intravenously before chemotherapy, with two additional doses per day if needed. Nausea was assessed by a patient-completed visual analogue scale and episodes of vomiting were recorded by an independant observer.
Results: 42% of the patients were complete or major responders on day one. Five patients were given other rescue antiemetic therapy. Adverse effects included headache (16%) diarrhea (8%) and other minor events. The best results were obtained with the 30,40 and 50 mg doses. Conclusions: MDL 73.147EF is a well-tolerated and probably effective antiemetic agent which requires further evaluation in randomised controlled clinical studies.
Key words: MDL 73.147EF, 5-FTT3 receptor antagonist, antiemetic, cancer chemotherapy
Background
Patients and methods
Nausea and vomiting are major adverse effects of cytotoxic chemotherapy in cancer patients [1]. Significant progress has recently been made in the treatment of chemotherapy-induced emesis. The 5-HT3-antagonist (antiserotonergic) agents are the newest family of antiemetic drugs. MDL 73,147EF is a new 5-HT3 receptor antagonist incorporating a novel bridged pseudopelletierine ring system which prevents vomiting induced by cisplatin in the ferret, with a large therapeutic index and a more selective and sustained activity than its predecessor MDL 72,222 [2-5]. In a single-dose, dose-rising (1-30 mg) study of normal volunteers, the compound was well tolerated and doses of 10, 20 and 30 mg caused significant inhibition of the skin flare response to intradermal serotonin [6]. Therefore, these three doses, plus two larger ones of 40 and 50 mg, were chosen for the initial clinical development of this product in Europe
Patient eligibility
[7|We performed a phase I antiemetic trial of MDL 73,147EF in 25 cancer patients receiving moderately to highly emetogenic chemotherapy to assess the safety and tolerance of this agent, and to collect preliminary data concerning its antiemetic effect.
The inclusion criteria were: histologically confirmed cancer, intravenous cytotoxic chemotherapy, which should be high-dose cisplatin (>50 mg/m2 body surface) or carboplatin (>400 mg/m2), either alone or together with other intravenous cytotoxic chemotherapy, or any regimen known to induce severe nausea and vomiting also in naive or pretreated patients, regardless of whether they had responded to a previous antiemetic regimen; a performance status >50% (Karnofsky); age between 18 and 75 years; written informed consent; normal baseline laboratory values. The exclusion criteria were: child-bearing potential in women at risk of pregnancy; cerebral metastases with impaired supratentorial functions; administration of an established anti-emetic drug (metoclopramide, dexamethasone, dopamine D2 receptor antagonists and derivatives of cannabinoids) in the 12 hours before administration of cytotoxic chemotherapy; anticipatory nausea and vomiting; administration of another research drug in the previous 21 days.
Study design The study was approved by the Ethics Committee of the Claude Bernard University of Lyon. Five groups of 5 evaluable patients were to receive rising unit doses (10, 20, 30, 40 and 50 mg, respectively) of MDL 73,147EF, by intravenous injection. The first dose was given each day 15 minutes before the start of cytotoxic chemotherapy. If further anti-emetic treatment was required during the first 24 hours after the start of chemotherapy two additional doses of
Downloaded from https://academic.oup.com/annonc/article-abstract/5/6/549/252133 by Western Sydney University Library user on 14 January 2019
Y. Merrouche, G. Catimel, P. Rebattu, A. Dumortier, J. P. Guastalla, P. O'Grady1 & M. Clavel
550
Evaluation of toxicity and efficacy Heart rate and blood pressure were recorded just before administration of the initial dose of MDL 73.147EF and 15 and 30 minutes, 2 h, 4 h, 6 h, 8 h, 24 hours after the start of cytotoxic therapy. Thereafter, they were measured immediately before and 15 and 30 minutes after each subsequent administration of MDL 73.147EF. An adverse events checklist was completed 24 hours after the last intravenous injection. Nausea was assessed by a series of horinzontal visual analogue scales (VAS) each 10 cm in length and labelled 'no nausea' and 'nausea as bad as it could be' at the two extremes. Mild nausea was defined between 0 and <2.5 cm, moderate nausea between 2.5 and 7.5 cm and severe nausea between 7.5 cm and the end of the VAS. In addition, the patients were asked to define their nausea as absent, mild, moderate or severe. This evaluation as done just before administration of MDL 73.147EF and at 2, 4, 6, 8 and 24 hours after the start of each day's chemotherapy. The number of episodes of vomiting (0, 1, 2, 3, 4, 5, or >5) within each hour were counted by a nurse. These assessments were repeated 24, 48 and 72 hours after the end of the last day of chemotherapy.
Results Of the 25 patients, 15 were female, with a median age of 53 years. Twenty-three patients had previously received cytotoxic chemotherapy. Up to 5 types of cytotoxic agents per patient were administered over 1 day (n = 17), 2 days (n = 3) or 5 days (n - 5). The main types and daily dose ranges are described in Table 1. Twenty-three patients (92%) received cisplatin for a mean dose of 74 mg/m2 (+/— 23). Of the 23 patients who received cisplatin, 1, 16 and 6 received cisplatin <50, 50-99 and >100 mg/m2, respectively. Thus, the majority of the patients received highly emetogenic chemotherapeutic regimens. Ten patients received only 1 dose of MDL 73,147EF per day of cytotoxic chemotherapy, 11 patients received 1 additional dose on at least one day and 4 patients received 2 additional doses on at least 1 day. Five patients were given established antiemetic therapy for rescue. The mg/kg dose ranges at each discrete dose level were: 10 mg: 0.16-0.24 mg/kg; 20 mg: 0.24-0.38 mg/ kg; 30 mg: 0.43-0.69 mg/kg; 40 mg: 0.58-0.73 mg/kg; 50 mg: 0.56-0.83 mg/kg. MDL 73,147EF was extremely well tolerated by the patients: no major drug-related side effects were observed, no significant changes in pulse rate or blood pressure occurred following its administration, and laboratory parameters did not change substantially after treatment. Minor, possibly drug-related, side
effects included headache (n = 4), moderate diarrhea (n •= 2), fever probably related to bleomycin infusion (n - 2), malaise (n = 1), hot flush (n = 1), gastric pain (n = 1) and maculous indolent cutaneous eruption appearing two days after MDL 73,147EF infusion (n - 1). These side effects were mild and transient, and did not lead to alteration of the antiemetic treatment regimen in any of the patients. No extrapyramidal symptoms were observed and no additional side effects were seen in patients receiving repeated courses of MDL73,147EF. All patients were evaluable for response to treatment. The correlation between the 2 methods of nausea evaluation was complete. The antiemetic effects of MDL 73,147EF on day one are detailed in Table 2. Eleven of 25 patients (44%) obtained complete protection or a major response (<2 emetic episodes) on day 1. Results were similar for protection against nausea in twelve patients (47%) who experienced no or only moderate nausea. Table 1. Patient characteristics. Number (all evaluable) Median age (range, years) Male/female Median weight (kg) Karnofsky above 60% Prior chemotherapy Primary Ovarian Head and neck Melanoma Testicular Cervix Urinary tract Hodgkin's Breast Unknown Chemotherapy administered In combination: Cisplatin (50-120 mg/m2) Dacarbazine (350-450 mg/m2) Cyclophosphamide (500-750 mg/m2) Adriamycin (25-30 mg/m2) Etoposide (100 mg/m2) Fluorouracil (500-1000 mg/m2) Vindesine (3 mg/m2) Other Alone: Cisplatin (50-70 mg/m2)
25 53 (27-72) 10/15 62 (41-90) 23 23 6 6 5 2 2 1 1 1 1 23 6 7 3 2 6 5 11 2
Table 2. Antiemetic efficacy of MDL 73.147EF on day 1. Dose level (mg)
Emetic episodes
Nausea
0
1-2
3-5
>5
None
Moderate
Severe
10 20 30 40 50 Total
1 0 3 1 2 7
0 2 0 2 0 4
0 0 0 1 1 2
4 3 2 1 2 12
0 0 1 1 1 3
2 0 1 4 2 9
3 5 3 0 2 13
Downloaded from https://academic.oup.com/annonc/article-abstract/5/6/549/252133 by Western Sydney University Library user on 14 January 2019
MDL 73.147EF at the same dose level could be given provided that the previous dose or doses had been well-tolerated. The second dose was not to be given until the elapse of at least 6 hours since administration of the first dose. The third dose was not to be given until the elapse of at least 2 hours since the second dose. Established anti-emetic therapy could be given at any time after the start of the cytotoxic chemotherapy in instances of antiemetic failure. Biochemistry, complete blood count, and urinalysis were repeated every day following administration of MDL 73.147EF and 3 days after the last dose.
551
Conclusion We conducted an antiemetic phase I study (dose range 0.16 to 0.83 mg/kg) of MDL 73,147EF in 25 patients receiving cisplatin-based chemotherapy or some other cytotoxic regimen known to be potentially emetogenic during one to five days. Our study supports a previous clinical report that MDL 73,147EF is safe and well tolerated by patients [12]. Most of our patients had no detectable side effects related to MDL 73,147EF. Headache and diarrhea were noted in a few patients, as they were in the previous report [12]; however, these side effects were mild and transient. No patient experienced extrapyramidal side effects. This study confirms that the antiemetic activity of MDL 73,147EF is promising [12]. Monotherapy with intravenous MDL 73,147EF can prevent or control acute vomiting and nausea induced by highly emetogenetic chemotherapy in 44% of the patients. It must be underscored that the majority of our patients were at high risk of emesis: 92% had previously received chemotherapy, 92% received cisplatin as part of the chemotherapy regimen and 60% were female [1, 2]. Taking into account these characteristics, our results compare favorably with those reported by Kirchner et
al. in their early clinical trial of MDL 73,147EF [12]. In the majority of patients who receive cisplatin (50-120 mg/m2) without antiemetic cover, emesis is usually severe [1, 2]. Even in this subset of patients, the higher doses of MDL 73,147EF yielded good results. In view of its good tolerance and promising activity, MDL 73,147EF merits further evaluation in randomised controlled studies versus conventional antiemetic agents and also versus commercially available 5 FTT3 receptor antagonists. Acknowledgement We thank Mrs Regine Perez for help in preparing the manuscript. References 1. Grunberg SM, Hesketh PJ. Control of chemotherapy induced emesis. N Engl J Med 1993; 329:1790-6. 2. Miner WD, Sanger GJ. Inhibition of cisplatin induced vomiting by selective 5-hydroxytryptamine M-receptor antagonism. Br J Pharmacol 1986; 88:497-9. 3. Clavel M, Klein T, Metz R et al. A randomised comparative study of the antiemetic effect and safety of MDL 72.222 and 'standard anti-emetic therapy' in patients receiving cisplatin containing chemotherapy for malignant rumors. Cancer Comm 1989; 3: 321-2. 4. Gittos MW, Fatmi M. Potent 5-HT3 antagonist incorporating a novel bridge pseudopelletierine ring system. Les actualites de chimie therapeutique 1989; 16: 187-98. 5. MDL 73.147EF. Clinical Investigator's Brochure. Revised November 1990. 6. O'Grady P, Boyce MF, Hardenberg J. Effect of intravenous MDL 73,147EF on the flare response to intradermal 5-HT: A doubleblind, placebo-controlled, dose-rising, parallel-group study in normal volunteers. Project report NO 89-LP-ST-0190. 7. Kirchner V, Aapro M, Alberto P et al. Early clinical trial of MDL 73,147EF: A new 5-HT3 receptors antagonist for the prevention of chemotherapy-induced nausea and vomiting. Ann Oncol 1993; 4:481-4. Received 14 February 1994; accepted 29 March 1994. Correspondence to: Y. Merrouche, MD Medical Oncology Department Centre Leon Berard 28, rue Laennec 69373 Lyon Cedex 08, France
Downloaded from https://academic.oup.com/annonc/article-abstract/5/6/549/252133 by Western Sydney University Library user on 14 January 2019
Antiemetic effects during the 4 subsequent days were also satisfactory with complete or major protection ranging from 70%-80% of patients. Of the 23 patients receiving cisplatin-based chemotherapy regimens, complete protection or major response were seen in 1 of the 2 naive patients and in 10 of the 21 pretreated patients. The best results were obtained with the 30, 40 -and 50 -mg doses which achieved major efficacy (<2 emetic episodes) in 53% of the patients. The number of patients who received second and third doses were 2, 2, 0, 0 and 0 for the 10, 20, 30, 40 and 50 mg doses. Furthermore, the number of patients given established antiemetic therapy as escape medication for breakthrough symptoms were 2, 2, 0, 0 and 1 for the 10, 20, 30, 40 and 50 mg, respectively. Thus, there was a trend towards less need for repeated MDL 73,147EF administration and escape medication as the dose of MDL 73,147EF was increased.