Phase 1/2 study of DFP-10917 administered by continuous intravenous infusion in patients with recurrent or refractory acute myeloid leukemia.

BACKGROUND: DFP-10917, a deoxycytidine nucleoside analogue, has a unique mechanism of action resulting in leukemic cell death when administered for prolonged periods at low doses. The current phase 1/2 study investigated the safety, maximum tolerated dose, and evidence of antileukemic activity for DFP-10917 administered by 7-day or 14-day continuous intravenous infusion in patients with recurrent or refractory acute myeloid leukemia (AML). METHODS: In the phase 1 dose escalation portion of the study, patients were administered DFP-10917 by 7-day continuous intravenous infusion plus 21-day rest (stage 1) or 14-day continuous intravenous infusion plus 14-day rest (stage 2). The primary objectives of phase 1 were to determine the maximum tolerated dose, the phase 2 dose, and the dose-limiting toxicities (DLTs) of DFP-10917. The primary objectives of phase 2 were to evaluate the overall response rate of DFP-10917 using complete response (CR), CR without platelet recovery (CRp), CR with incomplete blood count recovery (CRi) or partial response. RESULTS: In stage 1 of phase 1 (4-35 mg/m2 /day as a 7-day continuous intravenous infusion), a DLT of grade 3 diarrhea occurred at a dose of 35 mg/m2 /day. In stage 2 of phase 1, a dose of 10 mg/m2 /day as a 14-day continuous intravenous infusion resulted in DLTs of prolonged hypocellularity, abdominal pain, diarrhea, and vomiting. The dose of 6 mg/m2 /day as a 14-day continuous intravenous infusion was found to be well tolerated and was selected for phase 2. Response rates in patients in phase 2 (N = 29) were 20.7% CR, 3.4% CRp, and 24.1% CRi. The overall response rate was 48.3% (95% confidence interval, 29.4%-67.5%). CONCLUSIONS: DFP-10917 as a 14-day continuous intravenous infusion at a dose of 6 mg/m2 /day can be administered safely and appears to be effective in patients with recurrent or refractory AML. A phase 3 investigation comparing DFP-10917 monotherapy versus standard of care in an early recurrent or refractory AML setting is warranted.

Tissue collection for correlative studies in childhood cancer clinical trials: ethical considerations and special imperatives.

Federal regulations prescribe distinct protections for children participating in research studies. Procedures for collecting tissue specimens from children solely for research purposes must pose no more than a minor increase over minimum risk, thereby limiting the approvable correlative biologic studies to evaluate molecularly targeted agents in children with cancer. Ethical issues arise when approvable correlative studies are a mandatory component of an early-phase pediatric clinical trial of new anticancer agents. The National Cancer Institute Cancer Therapy Evaluation Program sponsored a workshop in 2002 to discuss tissue collection for correlative biologic studies in early-phase childhood cancer clinical studies of molecularly targeted agents. Workshop participants recommended the following: (1) tissue specimens for correlative studies should provide vital clinical and scientific results to qualify for early-phase pediatric study consideration; (2) parents should receive a realistic appraisal of the risks, requirements, and potential for benefit of phase I protocol participation; (3) investigators should clearly distinguish clinically necessary procedures from research procedures of no benefit to the child to improve correlative study informed consent; and (4) participation in correlative research studies included in clinical trials generally should be voluntary. The need to acquire important biologic data regarding new molecular agents will challenge the ingenuity of pediatric cancer researchers, necessitating the application of highly sensitive laboratory assay methods, new imaging procedures, and preclinical models of childhood cancer. Such innovative methods can allow necessary scientific information to be obtained while simultaneously respecting the protections appropriately afforded to children participating in research studies and minimizing the burden of research participation for children with cancer and their families.

Commentary on "European collaboration in trials of new agents for children with cancer" by Ablett et al.

Recent progress in establishing a European network to conduct paediatric oncology phase I/II clinical trials calls attention to the challenges facing researchers developing new agents for children with cancer. These challenges include: ensuring that effective infrastructures are in place to safely and efficiently conduct early phase clinical trials in children while meeting all ethical and regulatory requirements associated with such trials; obtaining timely access to new agents from pharmaceutical sponsors for both preclinical testing and for phase I and phase II testing; and effectively prioritizing new agents for evaluation in children so that those agents most likely to benefit children with specific cancers are brought forward for clinical testing. The use of public funds to develop and maintain clinical trials infrastructures devoted to paediatric oncology drug development can help in addressing these challenges and can facilitate the timely paediatric evaluation of new agents, thereby contributing to the goal of identifying more effective treatments for children with cancer.

Comparison of intermittent versus continuous infusion of propofol for elective oncology procedures in children.

OBJECTIVE: To compare the effects of administering propofol as a continuous infusion vs. bolus dosing in children undergoing ambulatory oncologic procedures in the pediatric intensive care unit (PICU). DESIGN: Prospective, randomized study. SETTING: Tertiary PICU in a university hospital. PATIENTS: Ambulatory oncology patients scheduled for diagnostic or therapeutic procedures with propofol anesthesia in the PICU were eligible for enrollment. INTERVENTIONS: Patients were randomly assigned to receive either continuous infusion or bolus administration of propofol in a protocol-driven manner. All patients received an initial bolus of 1.5 mg/kg, with additional 0.5 mg/kg doses until complete induction. Continuous infusions were started at 0.1 mg/kg/min and, if needed, increased 20% after a bolus of 0.5 mg/kg. Bolus group patients were given doses of 0.5 mg/kg if needed. Ramsay scores of < 5 were used as criteria for additional dosing. MEASUREMENTS AND MAIN RESULTS: Eighteen patients undergoing 40 separate procedures were enrolled during the study period. Twenty procedures each were performed with continuous or bolus administration of propofol. No differences were present between groups in demographic characteristics, induction dose and time, procedure and recovery times, or adverse events. All patients had adequate anesthesia and favorable satisfaction scores. More boluses were needed in the bolus group (8.5 +/- 4.6 vs. 5.4 +/- 2.9; p < .05). Average systolic blood pressure decreased more in the continuous infusion group (26.4% +/- 12 vs. 19.3% +/- 10; p < .05). Total propofol dose was higher in the continuous infusion group (8.0 mg/kg +/- 3.8 vs. 5.7 mg/kg +/- 2.4; p < .05). CONCLUSION: Both continuous and bolus administration of propofol provided conditions for conducting oncologic procedures that were satisfying to patients, their families, and physicians. Continuous infusions were associated with a larger total dose and greater decreases in systolic blood pressure. Physician preference is likely to dictate which method is used.