Characteristics and outcome of pediatric patients enrolled in phase I oncology trials

Abstract

Purpose: To describe the characteristics of pediatric subjects who enroll in phase I trials, to determine the associations between pre-enrollment characteristics and the risk for toxicity, and to analyze response and survival outcomes.

Experimental design: Pre-enrollment characteristics and study outcomes were retrospectively analyzed for children with refractory solid tumors treated in one of 16 phase I trials with similar eligibility criteria at the National Cancer Institute between 1992 and 2005.

Results: The 262 subjects analyzed had received a median of two (range, 0-9) prior chemotherapy regimens, and were on one (range, 0-12) concomitant medication. The Eastern Cooperative Oncology Group performance status scores for subjects were 0 (29%), 1 (48%), and 2 (19%); 19% had received a prior stem cell transplantation and 73% had received prior radiation. Approximately 90% of subjects were evaluable for the primary trial endpoints (toxicity and pharmacokinetics). Seventeen percent of subjects experienced a dose-limiting toxicity (DLT), 5% discontinued the study drug because of toxicity, and a drug-related death occurred in one subject (0.4%). Variables associated with a higher risk for developing a DLT, by multiple logistic regression analysis, were drug dose and prior radiation, for myelosuppressive agents, and drug dose and performance status, for nonmyelosuppressive agents. The complete and partial response rate was 4%; however, 17% of subjects had stable disease (received three or more cycles). The median overall survival time from the time of enrollment was five months.

Conclusions: Primary trial objectives are achieved in approximately 90% of subjects with the standard phase I trial design and eligibility criteria despite the intensification of frontline and salvage therapies in pediatric subjects with cancer.

Figure 1.

Diagnoses of the 262 patients enrolled in pediatric phase I trials at the National Cancer Institute. The diagnoses were: brain tumor (n = 92); Ewing’s sarcoma (n = 35); other sarcoma (n = 33), which includes alveolar soft part sarcoma, desmoplastic round cell tumor, synovial sarcoma, and undifferentiated sarcoma; osteosarcoma (n = 26); rhabdomyosarcoma (n = 17); neuroblastoma (n = 27); Wilms’ tumor (n = 6); and other (n = 26), which includes carcinoma (n = 15), lymphoma (n = 1), germ-cell tumor (n = 2), and other embryonal tumors (n = 8), such as hepatoblastoma, pancreatoblastoma, and pleuropulmonary blastoma.

Figure 2.

Overall survival in 262 pediatric subjects with refractory solid tumors who were enrolled in a phase I trial at the National Cancer Institute (NCI). Survival is plotted from the time of enrollment in the first phase I trial at the NCI.