The POG wishes to continue timely performance of phase I studies of new cytotoxic, biologic, and maturational agents in children with advanced disease resistant to standard therapy. The MTD achieved and the associated toxicities will determine the dose, supportive care and precautions to be used in phase II trials in children. Pharmacokinetic and pharmacodynamic studies will be done on children at the starting dose, when there is evidence of a biologic effect and at the MTD. Biological assays will be obtained if a biological response modifier or maturational agent is under investigation. The starting dose level will be determined after consultation with the CTEP drug monitor. If the starting dose is 80% of the MTD in adults, the subsequent escalation of doses will be 20%. If phase I studies have not been done in adults then the starting dose will be 1/10 of the LD10 in mice (or 1/3 of the TDL in large animals) and a modified Fibonacci scheme will be used for dose escalation. Investigators will submit all data forms at weekly intervals to the Study Chairman and the Scientific Administrator. The Study Chairman and the CTEP drug monitor will be notified by telephone of any unusual, unexpected, unacceptable, previously unreported toxicity, or death on study. Every three months the Study Chairman will prepare a summary of the patients entered at each dose level, the toxicity observed, and the pharmacologic data for biologic studies obtained and send a copy to the Phase I Subcommittee Chairman and the Scientific Administrator. The Phase I Subcommittee Chairman will review these and submit them to the Phase I Chairman and the CTEP. Every six months, compliance to protocol requirements and timeliness of data submission will be reviewed by the Phase I Compliance Committee. Six months after the last patient entry, a manuscript will be prepared and submitted to the Writing Committee. All institutions entering patients on protocol will be audited at least once every three years.
