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Phase I study of fotemustine in pediatric patients with refractory brain tumors
Darren R Hargrave1, Eric Bouffet, Janet Gammon
1New Agents and Innovative Therapy Program, The Hospital for Sick Children, University of Toronto, Ontario, Canada.
Background:
Fotemustine is a nitrosourea with theoretic and preclinical advantages over the original analogs, carmustine and lomustine, in the treatment of brain tumors. This is the first pediatric Phase I study of fotemustine.
Methods:
Patients younger than 21 with recurrent/resistant brain tumors were enrolled in a conventional Phase I study. Fotemustine was administered intravenously every 3 weeks at increasing dose levels starting at 100 mg/m(2). Toxicity and response data were monitored closely.
Results:
Fifteen evaluable patients entered the study and received a total of 45 courses of fotemustine (dose range, 100-175 mg/m(2)). Myelosuppression was observed, with the dose-limiting toxicity being Grade 4 neutropenia and thrombocytopenia. Toxicity was delayed and cumulative. The maximum tolerated dose was 150 mg/m(2) every 3 weeks. There were three documented radiologic responses (20% of patients) comprising one partial response and two minor responses in patients with a sarcoma, medulloblastoma, and ependymoma, respectively.
Conclusions:
Fotemustine administered at a dose of 150 mg/m(2) every 3 weeks is well tolerated in children and has antitumor activity in several brain tumors. This is the first dedicated Phase I study of a single agent nitrosourea in a pediatric population. More comparative studies should be undertaken to define the optimum nitrosourea analog for use in children with brain tumors.
Insights
Fotemustine, a novel nitrosourea, shows antitumor activity and is well-tolerated in children with brain tumors at a dose of 150 mg/m(2) every 3 weeks. This Phase I study establishes its potential for pediatric brain cancer treatment.
Area of Science:
- Pediatric Oncology
- Neuro-oncology
- Pharmacology
Background:
- Fotemustine is a nitrosourea with theoretical and preclinical advantages for brain tumor treatment.
- This study represents the first pediatric Phase I trial of fotemustine.
Purpose of the Study:
- To evaluate the safety and tolerability of fotemustine in pediatric patients with recurrent or resistant brain tumors.
- To determine the maximum tolerated dose (MTD) of fotemustine in this population.
Main Methods:
- A conventional Phase I study design was used.
- Fotemustine was administered intravenously every 3 weeks, escalating doses from 100 mg/m(2).
- Toxicity and response were closely monitored in patients younger than 21.
Main Results:
- Fifteen patients received 45 courses of fotemustine (100-175 mg/m(2)).
- Dose-limiting toxicity included Grade 4 neutropenia and thrombocytopenia; the MTD was 150 mg/m(2) every 3 weeks.
- Three patients (20%) showed radiologic responses (one partial, two minor) in sarcoma, medulloblastoma, and ependymoma.
Conclusions:
- Fotemustine at 150 mg/m(2) every 3 weeks is well-tolerated and demonstrates antitumor activity in pediatric brain tumors.
- This is the first dedicated Phase I study of a single-agent nitrosourea in pediatric patients.
- Further comparative studies are needed to optimize nitrosourea analog selection for pediatric brain tumors.
