Treatment > Cisplatin · Temozolomide Clinical Trials

Meeting Abstract

Dose-finding study and O6-alkyltransferase depletion of cisplatin combined with temozolomide in pediatric solid malignancies

Birgit Geoerger, Gilles Vassal, Francois Doz, Marie A Raquin, Didier Frappaz, Pascal Chastagner, Herve Rubie, Jean-Claude Gentet, John O'Quigley, Kamal Djazouli, Geoffrey P Margison, Francois Pein

Institut Gustave Roussy, Villejuif, France; Institut Curie, Paris, France; Centre Léon Bérard, Lyon, France; Hopital d'Enfants, Nancy, France; Hopital Purpan, Toulouse, France; Hopital de la Timone, Marseille, France; Schering-Plough, Paris, France; CRC Carcinogenesis Group, Paterson Institute for Cancer Research, Manchester, UK.

Cisplatin has been suggested to have additive activity with the oral imidazotetrazinone Temozolomide (TMZ) due to inactivation of the DNA repair enzyme O6–alkyl-guanine-DNA alkyltransferase (O6ATase). 

Objective: To determine recommended doses, toxicities, and antitumor activity in pediatric patients, and to evaluate O6ATase depletion in peripheral blood lymphocytes (PBL) during the combination treatment. 
Cisplatin (mg/m2) was administered on day 0, followed by oral TMZ (mg/m2/d) daily for 5 consecutive days every 4 weeks at dose levels 80/150, 80/200, 100/200. 
Dose escalation was performed using Continual Reassessment Method. 
Blood samples were collected before Cisplatin, before the first TMZ dose and on day 5 to assay O6ATase activity in PBL. Between May and November 2001, 22 registered patients (16 male) have been treated. 
Median age at treatment was 15 years (4.4-19.9). 
Main diagnoses were malignant brain tumors, neuroblastoma, soft tissue sarcoma. 
21/22 patients were evaluable for toxicity and received a total of 44 cycles (median: 2 per patient, range 1–7). 
Eleven patients were pretreated with high-dose chemotherapy, craniospinal irradiation or had bone marrow involvement. Dose limiting toxicity (4 hematologic, 1 infection) was observed in 1/6 and 1/4 non-heavily pretreated and in 2/9 and 1/2 heavily pretreated patients at 80/150 mg/m2 and 80/200 mg/m2, respectively. 
Toxicities were thrombocytopenia, neutropenia, mild nausea, vomiting, apathia. 
Grade 2 renal insufficiency and grade 1 hearing loss was observed after 5 and 6 cycles in 1 patient, respectively. 
Partial tumor response was achieved within 4 cycles in a malignant glioma, previously progressing under TMZ alone and radiation therapy. 
Median O6ATase activity in PBL decreased significantly after 5 days of TMZ treatment. 

In conclusion, Cisplatin followed by TMZ is well tolerated in childhood and adolescence without additional toxicity to single-agent treatments. 
The recommended dose was defined at 80/150 mg/m2 in heavily pretreated patients; MTD is not yet reached in other patients.

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