text: 1. Introduction
  Phase I clinical trials of new anticancer agents have been commonly conducted using the method of modified Fibonacci [1]. In brief, 3 patients are treated at a starting dose which is typically one tenth of the dose that is lethal to 10% of animals defined in preclinical studies. If none of the 3 patients experiences DLT, then the next 3 patients will be treated at the next higher dose. If DLT is observed, additional patients will be treated at the same or lower dose level to determine MTD according to a predetermined schema. The MTD is defined as the highest dose reached for which the incidence of DLT occurs in less than 33% of the subjects. Typically, intrapatient dose escalation is not allowed.
  There are several shortcomings associated with the modified-Fibonacci design. It has long been recognized that a substantial number of patients are likely to be treated at subtherapeutic doses [2, 3]. This is particularly true for drugs with potential anticancer activity. Since the primary purpose of phase I trials is to determine DLT and MTD, the efficacy of the drug may not be evident for certain tumor types as there are only a small number of patients enrolled into the trial. Furthermore, the modified-Fibonacci design does not take into account individual variations in therapeutic and toxicologic responses due to genomic polymorphisms [4, 5]. In addition, since there is a limit of 3 subjects allowed for each cohort, a waiting period of up to four weeks is commonly required before enrollment of the next cohort of subjects. This latter requirement creates anxiety of waiting for eligible patients.
  Several alternative phase I designs have been proposed which limit the number of patients accrued at each dose level and accelerate the dose escalation process [1, 6]. There has also been an increase in the number of clinical trials that include a component of intrapatient dose escalation although no formal validation with the modified-Fibonacci approach has been reported [7-9]. We have pioneered a population-based design to maximize therapeutic efficacy, to provide preliminary efficacy information and to allow derivation of a pMTD for subsequent phase II trials.
  Irinotecan and cisplatin have been shown to have promising efficacy in patients with small-cell lung cancer in phase III trial where irinotecan was given on a weekly schedule [10]. We wished to perform a population-based phase I trial of irinotecan, given every 3 weeks, and carboplatin, a platinated anticancer drug which is generally better tolerated than its cisplatin analog.
  
entities: ['tumor']
entities: Pathological_formation
entities: PMC-2673471-sec-01_T1
entities: ['small-cell lung cancer']
entities: Pathological_formation
entities: PMC-2673471-sec-01_T2