RESEARCH & DEVELOPMENT

Topoisomerase inlnbitors show encouraging antitumour activity

The antineoplastic potential of the topoisomerase I inhibitors has been highlighted by the work of 2 US groups, one from San Antonio, Texas, and one from the Johns Hopkins Oncology Center, Baltimore.

Studies of topotecan ••• The San Antonio group reports that topotecan* was

fairiy we II tolerated in their phase I studies [see table].l While they believe that higher doses of topotecan may be feasible if a growth factor for platelets is identified, no partial or complete responses were observed with the doses used. However, partial responses have been observed in patients with non-small cell lung cancer in an ongoing study of the combination of topotecan and cisplatin, the researchers note.

More encouraging response rates with topotecan have been observed at the Johns Hopkins Oncology Center, particularly in patients with refractory non-small cell lung cancer and refractory or relapsed acute leukaemia.2 These researchers have also been investigating dose-escalation of topotecan with administration of granulocyte-macrophage colony­stimulating factor. In an ongoing study, they have observed only sporadic nonhaematological toxicity and thrombocytopenia with topotecan in doses as high as 4.2 mglm2/day for 5 days.

••• and other camptothecin analogues In the San Antonio studies of irinotecan

[CPT-Il]**, dose-intensity has been seriously limited by diarrhoea. 1 Nevertheless, partial responses have

Thble: Phase I studies

Drug Schedule No. of patlenta

s.n Antonio group , :

Topotecan Single 3()..mIn infusion 42 every 3 weeks

5-day continuous 14 infusion

3-day continuous 31 Infusion

frinotecan 9O-min weekfy infusion ? for 4 weeks In a 6-week cycle

Intopidne Single 3O-min infusion 30 every 3 weeks

John Hopkins Oncology CentIIr 2 :

Topotscan 3O-min infusion for 5 29 (refractory solid days in ~ cycles tumours)

Topolecan 5-day continuous 17 (refnlctory /relapsed infusion acute leukaemia)

lrinolecan 9O-min infusion every 32 (refnlctory solid 3 weeks tumours)

been noted in 2 patients with refractory colorectal cancer. Furthermore, administration of loperamide on a 2-hour schedule appears to prevent severe diarrhoea and allow some dose-intensification.

Three short-lived partial responses were achieved in the Johns Hopkins Oncology Center study of irinotecan, but there were a variety of dose-limiting toxlclti'es. '

According to the San Antonio researchers, the future of the newest agent intoplicine# may be in doubt unless a schedule can be devised that lessens or avoids the hepatotoxicity that has been observed. 1

Intoplicine is unique in that it inhibits both topoisomerase I and II. * SmithKline Beecham; phose /II

** Daiichi, yakult Honsha, RMne-Poulenc Rorer, Upjoluz; lounched in Japan

# RMne-Poulenc Rorer; suspended

t. Von Hoff DD, et al. Preclinical and phase I trials of topoisomerase I inhibitors. Cancer Chemotherapy and Pbannacology 34 (Suppl.): 41-45, Aug 1994

2. Slichenmyer WJ, et al. Camptothecin analogues: swdies from the Johns Hopkins Oncology Center. Cancer Chemotherapy and Pharmacology 34 (Suppl.):

53-57, Aug 1994 I003062IO

~ Editorial comment: Irinotecan was launched in Japan earlier this year [Inpharma 940: 22, 4 Jun 1994; 800266520]. However, the approval of this drug was controversial because of the deaths of 20 of the 477 patients who panicipated in clinical trials. Deaths wen' related to multiorgan failun' n'sulting from diarrhoea, and leucopenia [Inpharma 927: 21,5 Mar 1994; 800248863]. Strict guidelines for the use of irinotecan have been established and labelling carries appropriate warnings.

Mulmum tolended dOH Dose-lImltlng toxicity Response

22.5 mg/m2 Neutropenia 0

0.68 mg/m2/day (3.4 mg/m2) Neutropenia 0 Thrombocytopenia

1.6 mg/m2/day (4.8 mg/m2) Neutropenia 0 Thrombocytopenia

180 mg/m21week Dlantloea 2 parti.aI (colorectal cancer)

? Hepatotoxk:lty 0

1.5 mg/m2/day Neutropenia 1 complete (non-smaU oeIllung cancer) 3 partial (ovarian carcinoma non-smaU oeIllung cancer)

2.1 mg/ml/day Mucositis 1 complete, 1 partial

240 mg/m2 Nausea! vomtting, 3 partial (coiorectal, c:iarrhoea, cervical and renaJ cell neutropenia, carctnomas) thrombocytopenia

0156-2703/9410960-000111$01.rxf' Ad. InWrnationaI Limited 19M. All rlghta ~ INPHARMA- 22 Oct 19M

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