Annals ofOncology 3: 141-143, 1992. i 1992 Khm^r Academic Publishers. Printed in the Netherlands.

Original article A phase I trial of a new antiemetic drug — clebopride malate — in cisplatin-treated patients H. Bleiberg,1 M. Piccart,2 S. Lips,1 J. M. Panzer1 & J. B. N'Koua Mbon1 Service de Medecine Interne et Laboraioire d'Investigation Clinique H. J. Tagnon, Unite de Gastroenlerologie' et Unite de Chimiotherapie,2 Institut Jules Bordet, Centre des Tumcurs de I'Universite Libre de Bruxelles, Brussels, Belgium

Summary. Clebopride, a new benzamide derivative, has, in common with the other members of this group, antidopaminergic activity. In animals, its therapeutic ratio is superior to that of metoclopramide at doses free of side effects associated with hyperprolactinemia and extrapyramidal symptoms. The present study was designed to define the maximum tolerated dose (MTD) in patients with advanced histologically-proven cancer, treated with cisplatin at a dose of >50 mg/m2. Most of them were pretreated and refractory to standard antiemetics. Clebopride was started at a dosage of 0.10 mg/kg in a group of 6 patients and escalated by 0.2

mg at each dose level. A total of 30 patients were included. Side effects include somnolence, diarrhea and extrapyramidal-like symptoms. The latter occurred at almost all dose levels in 14% of the cycles and limited continuation of the study. Activity in this group of patients was encouraging but, considering the rate of extrapyramidal symptoms, further dose escalation is not indicated and activity at lower, nontoxic levels should be investigated.

Introduction

This study was carried out to define the maximum tolerated dose (MTD) of clebopride malate in cancer patients.

Clebopride (N-(l '-benzyl-4'-piperidyl)-2-methoxy-4amino-5-chloro-benzamide) is a new compound of the benzamide group which shares the antidopaminergic activities of the known benzamide derivative, metoclopramide. Clebopride acts on the hypothalamus (antagonism of apomorphine-induced hypothermia in the mouse), the chemoreceptor trigger zone of the area postrema (antagonism of apomorphine-induced vomiting in the dog), the mesolimbic system [1]. It also blocks the dopaminergic receptors in the gastrointestinal tract [2], suggesting that the drug might behave as a potent antiemetic and be used at dose levels free of side effects associated with hyperprolactinemia and extrapyramidal symptoms [3|. Plasma levels of clebopride can be adequately described using a three compartment model. The mean half-lives are greater in men than in women: 0.32 h and 0.17 h for the fast disposition phase, 3.05 h and 1.99 h for the slow disposition phase and 51 h and 28.3 h for the elimination phase, respectively. The drug has been developed in the form of its acid malate salt for oral and parenteral administration. Its low ED 50 and high LD50 values result in a therapeutic ratio superior to that of metoclopramide [1|. In chemotherapy-induced emesis, doses of 1 mg/day i.v. are pharmacologically active and well tolerated [4]. A dose-determining study started at 0.03 mg/kg has shown that 0.6 mg/kg induces no major side effects [5].

Key words: antiemetic, benzamide, cancer, cisplatin, phase I

Patients and methods The study was designed as an open, single-dose, dose-determining study. Patients with advanced, histologically-proven cancer, older than 18 years but younger than 70, requiring chemotherapy including cisplatin at a dose of >50 mg/m2, were eligible for the study. Chemotherapy-pretreated patients were eligible. Exclusion criteria included major gastrointestinal disease, head and neck cancers, any history of abnormal or serious allergy, anticipatory vomiting, patients receiving psychotropics, corticosteroids, antiemetics, prokinetics or any antisecretory drugs which could not be discontinued at least by 5 half-lives before start of the study. The patients had to remain in the hospital for at least 24 hours. Clebopride was diluted in 150 ml of NaCI 0,45% and given over 30 minutes, starting 60 minutes prior to cisplatin infusion. Clebopride was started at the dosage of 0.10 mg/kg in a group of 6 patients and esclated by 0.2 mg/kg at each dose level. The study was to be stopped if 2/6 patients had serious side effects or if none of the 6 patients experienced nausea or vomiting. No further treatment with clebopride was given during the next days. Rescue antiemetic consisted of dexamethasone 20 mg and lorazepam 1 or 2 mg (times 2) given i.v. If an adequate control of emesis was obtained, patients could be retreated at the same dose level or at a dose not exceeding 0.5 mg/kg. Side effects including somnolence, diarrhea and extrapyramidaJ symptoms were recorded. Somnolence was graded as none, mild (patients lethargic but aroused to verbal stimuli and completely oriented to time, place and persons), moderate (patients aroused only by physical stimuli and completely oriented when awakened) and marked (patients disoriented when awakened) [6]. Diarrhea was defined as unusual loose bowel movement during

142

symptoms was delayed, beginning only after the first six hours in 1 and 4 patients, respectively. On day 2, 1 patient vomited and 8 experienced nausea.

Table I. Number of cycles with side effects by dose level. Side effects

Somnolence Diarrhea Extrapyramidal symptoms

Dose level (mg/kgyno. cycles 0.1/6

0.3/7

2 0 0

3 1 1

1 2

0.5/12

0.7/10

0.9/7

9

3

7

1

Discussion

2 2

1

Clebopride malate is a substituted benzamide which was selected for further development on the basis of its potency, which is ten times higher than that of metoclopramide [3], and possibly for its lack of drug-induced Table 2. Activity of clebopride by dose level. extrapyramidal symptoms [2j. Surprisingly, extrapyDose level Nausea Vomiting Start of symptoms ramidal symptoms were observed in 14% of the cycles. They occurred in patients over 50 years old, suggesting 0 1 0 1-3 >3 6 hrs that at the doses of 0.1-0.9 mg/kg clebopride seems to induce more CNS toxicity than metoclopramide at the 0.1 0 4 2 0 2 4 6 dose of 2 mg/kg x 5. This study was designed to define 0.3 0 3 3 3 1 2 3 0.5 0 4 2 0 2 4 6 the MTD of clebopride. The starting dose was chosen 0.7 0 2 3 2 1 3 4 from unpublished data showing that no side effects 0.9 1 2 3 1 2 3 2 were observed using 0.6 mg/kg [5]. Our results are in Overall efficacy 1 15 13 6 8 16 21 contradiction to these data and show that extrapyramidal symptoms were not dose-related and occurred equally at all dose levels over 0.1 mg/kg. Compared to the observation period and graded as mild (1 bowel movement), 5-HT3 antagonists, this rate of extrapyramidal sympmoderate (2 bowel movements) or severe (>3 bowel movements). toms becomes unacceptable. Therefore, dose escalaIntensity of nausea and vomiting (0 — none, 1 - mild, 2 - mod- tion was discontinued at the dose level of 0.9 mg/kg. erate, 3 — severe), the number of vomiting episodes, the duration of Our trial was not designed to evaluate the drug's effithe symptoms and the side effects were recorded 3, 6, 24 and 48 h cacy. Indeed, our patients were previously treated and after starting cisplatin. most of them were not controlled by adequate antiemetics. Results in this patient population are very scarce, and are seldom if ever published. Furthermore, Results complete protection against nausea and vomiting is not A total of 30 patients were included by groups of 6 and a realistic goal in this selection of patients. Neverthewere given 0.1, 0.3, 0.5, 0.7 and 0.9 mg/kg of clebo- less, 6/30 patients had no vomiting episodes at all, and pride malate. They were pretreated with doxorubicin, a further 8/30 had a maximum of 3 vomiting episodes. cisplatin, cyclophosphamide, or a CCNU-containing Delay in the onset of vomiting was shown to be an regimen. All but three had vomiting episodes despite objective sign of activity [7]. In our series, 5 patients at antiemetic therapy (metoclopramide 2-3 mg/kg x 3 the dose levels of 0.7 mg/kg [1] and 0.9 mg/kg [4| expewith or without lorazepam 2 mg i.v.). Median age was rienced nausea and vomiting more than 6 h after start50 years (range 22-79). There were 26 females and 4 ing cisplatin infusion. males most of whom had breast [16] or lung cancers [7]. Although clebopride might be active in the prevenMild somnolence was the most pronounced symp- tion of chemotherapy-induced nausea and vomiting, tom in many patients, occurring at the dose level of 0.9 the rate of extra-pyramidal symptoms observed at mg/kg (Table 1). There was one case of moderate som- these dose levels proscribes further dose escalation. nolence observed at 0.7 and 0.9 mg/kg, and there were We do not recommend further investigation of no instances of marked somnolence. Starting from 0.3 clebopride malate due to its high rate of side effects mg/kg, diarrhea was encountered at each dose level (4 (and its only moderate antiemetic activity. mild, 1 moderate, 1 severe). Abnormal muscular contraction described as trismus, dyskinesia and trembling occurred in 6/30 patients with a median age of 57 Acknowledgement (range 47-80). This symptom was not dose-related and was observed at all dose levels above 0.1 mg/kg, pro- This work was supported in part by the Fonds National scribing further dose escalation. de la Recherche Scientifique Medicale (FRSM Overall 6/30 patients experienced no vomiting (3 3.4510.88, Brussels, Belgium). patients at 0.3 mg/kg, 2 at 0.7 mg/kg and 1 at 0.9 mg/ kg) and 8/30 had between 1 and 3 vomiting episodes (Table 2). At dose levels of 0.1 to 0.5 mg/kg symptoms References started within the first 6 hours following cisplatin administration. At 0.7 mg/kg and 0.9 mg/kg the onset of 1. Robert DJ. The pharmacological basis of the therapeutic activity

143

2. 3.

4.

5. 6.

of clebopride and related substituted benzamides. Curr Ther Res 1982;31:S1-S44. Roberts DJ. Modo des accion del clebopride como bloqueante selectivo de los receptores dopaminicos perifericos y centrales. Rev Eps Enferm Apar Dig 1979; 1:9-42. Wazer DE, Rotrosen J, Stanley M. The benzamides: Evidence for action at dopamine receptors - shortcomings of current models. In The Benzamides: Pharmacology, Neurobiology, and Clinical Aspects, 1982: 83-7. Diaz RV, Blanco EB, Navarro JE et al. Double-blind cross-over study of intravenous clebopride versus placebo in postanaesthetic vomiting. Rev Esp Enferm Apar Dig 1979; 56 (Suppl I): 63. Kali-Chemie (unpublished data). Kris MG, Gralla RJ, Clark AR, Tyson LB, Groshen S. Antiemetic control and prevention of side-effects of anticancer therapy with lorazepam or diphenhydramine when used in combina-

tion with metoclopramide plus dexamethasone. Cancer 1987; 60:2816-22. 7. Bleiberg H, Lips S, Dodion P, Piccart M, Panzer JM. Serotonin type 3 receptor antagonist BRL 43694 A in the treatment of nausea and vomiting induced by noncisplatin containing chemotherapy. Proc 5th Eur Conf C1in Oncol (ECCO-5), London, September 1989, abstr. P-0538. Received 15 February 1991; accepted 23 July 1991. Correspondence to: Dr. H. Bleiberg Unite de Gastroenterologie, Institut Jules Bordet rue Heger-Bordet 1 1000 Brussels Belgium

Fellowship Programme of the European Society for Medical Oncology

The Fellowship and Award Committee of the ESMO fosters a fellowship programme. The aim of this programme is to provide scholarships to young medical oncologists for 1 or 2 years of preclinical training in an outstanding European laboratory. These fellowships will be sponsored by a number of pharmaceutical firms. Boehringer Ingelheim, Hoffmann La Roche, Amgen, Glaxo and Sterling were the first companies to sponsor the programme, followed by Medgenix, Ciba-Geigy, Schering-Plough, Bristol-Myers Squibb, Farmitalia Carlo Erba and Eurocetus.

Eligibility criteria Candidates should meet the following requirements: -

Age limit: 35 Trained for at least 3 years Clinical experience in medical oncology The applicant, his/her present and his/her host institute, should be or should commit themselves to become an ESMO Member.

Candidates are invited to submit applications to Dr J.P. Armand, Chairman Fellowship Committee ESMO, Department of Medical Oncology, Institut Gustave Roussy, Unite de la Grange, F - 77176 Savigny-le-Temple, France, Tel. +33-1.60.63.90.33 - Fax +33-1.60.63.83.24. Application files should include: 1. 2. 3. 4.

Curriculum Vitae and career goals Host Institute of preference Letter of acceptance from the person at the host institute responsible for the project, including a detailed account of the future research programme, and approval by the Department Head A letter from the person responsible for the project at the origin institute including approval of Head of Department supporting the candidate's application and explaining his/her expectations careerwise

The deadline for submission of fellowship applications will be March 31, 1992. Selected recipients will be informed before end of May 1992 at the latest, for projects to commence in September or October 1992. The Fellowship Committee encourages applications in all areas pertaining to human cancer, with emphasis on clinically related laboratory projects. The amount of financial assistance provided will be roughly ECU 30,000.- per annum depending to a large extent on the cost of living in the host country. During the period spent in the host institution the fellowship recipients will be allocated a tutor whom he/she will be able to contact for any form of assistance or advice regarding their ongoing project and who will in general be responsible to ensure the follow-up of work in progress and liaise with the ESMO Fellowship Committee.