U.S. Food and Drug Administration Approval: peginterferon-alfa-2b for the adjuvant treatment of patients with melanoma.

On March 29, 2011, the U.S. Food and Drug Administration approved peginterferon alfa-2b (PEG-IFN) (Sylatron™; Schering Corporation, Kenilworth, NJ) for the adjuvant treatment of melanoma patients with microscopic or gross nodal involvement following definitive surgical resection including complete lymphadenectomy. The approval was based on a single, open-label, multicenter trial enrolling 1,256 patients. After surgical resection, patients were randomized (1:1) to either PEG-IFN or observation for 5 years. PEG-IFN, 6 µg/kg per week, was administered s.c. for eight doses, followed by 3 µg/kg per week for up to 252 weeks. Stratification factors included microscopic or gross nodal involvement, number of positive nodes, Breslow thickness, ulceration, sex, and study center. Patients were assessed for recurrence by the investigators based on physical examination every 3 months for 2 years and every 6 months thereafter. The relapse-free survival (RFS) interval, the primary efficacy endpoint, was significantly longer in PEG-IFN-treated patients. The median RFS times were 34.8 months and 25.5 months, respectively. There was no statistically significant difference in the overall survival time. The most common (>60%) grade 1-4 adverse reactions were fatigue, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST), pyrexia, headache, anorexia, myalgia, nausea, chills, and injection site reactions. The most common serious adverse reactions were fatigue, increased ALT and AST, and pyrexia. Thirty-three percent of patients receiving PEG-IFN discontinued treatment as a result of adverse reactions. Five deaths were reported within 30 days of the last treatment dose, two resulting from cardiovascular disease considered as possibly related to treatment.

Eribulin mesylate for the treatment of patients with refractory metastatic breast cancer: use of a "physician's choice" control arm in a randomized approval trial.

This work describes the considerations that led to the approval by the U.S. Food and Drug Administration (FDA), on November 15, 2010, of eribulin mesylate (Halaven; Eisai, Inc.) for the treatment of patients with refractory metastatic breast cancer. The FDA review focused primarily on the results of a single randomized, open-label, multicenter trial of 762 patients with refractory locally advanced or metastatic breast cancer. The patients were randomized to receive eribulin or any single-agent treatment of the physician's choice, selected prior to randomization. The FDA's approval of eribulin mesylate was based on demonstration of a statistically significant prolongation of overall survival (OS) in patients who had been randomized to receive eribulin. The median OS was 13.1 months in the eribulin arm compared with 10.6 months in the control arm [HR 0.81 (95% CI, 0.66-0.99); P = 0.041]. Treatment with eribulin did not show a statistically significant treatment effect [HR 0.87 (95% CI, 0.71-1.05)] on progression-free survival as determined by independent review. This approval highlights the appropriate use of an innovative trial design and shows that improvement in OS is an achievable endpoint in the setting of advanced breast cancer. On the basis of the different conclusions arising from the OS and progression-free survival results, investigators should consider using OS as a primary endpoint in clinical trials for refractory breast cancer.

U.S. Food and Drug Administration approval: ofatumumab for the treatment of patients with chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab.

PURPOSE: To describe the data and analyses that led to the U.S. Food and Drug Administration (FDA) approval of ofatumumab (Arzerra, GlaxoSmithKline) for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab. EXPERIMENTAL DESIGN: The FDA reviewed the results of a planned interim analysis of a single-arm trial, enrolling 154 patients with CLL refractory to fludarabine, and a supportive dose-finding, activity-estimating trial in 33 patients with CLL. Patients in the primary efficacy study received ofatumumab weekly for eight doses, then every 4 weeks for an additional four doses; patients in the supportive trial received four weekly doses. In the primary efficacy study, endpoints were objective response rate and response duration. RESULTS: For regulatory purposes, the primary efficacy population consisted of 59 patients with CLL refractory to fludarabine and alemtuzumab. In this subgroup, the investigator-determined objective response rate was 42% [99% confidence interval (CI), 26-60], with a median duration of response of 6.5 months (95% CI, 5.8-8.3); all were partial responses. The most common adverse reactions in the primary efficacy study were neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections. Infusion reactions occurred in 44% of patients with the first infusion (300 mg) and 29% with the second infusion (2,000 mg). The most common serious adverse reactions were infections, neutropenia, and pyrexia. CONCLUSIONS: On October 26, 2009, the FDA granted accelerated approval to ofatumumab for the treatment of patients with CLL refractory to fludarabine and alemtuzumab, on the basis of demonstration of durable tumor shrinkage.

Continuing reassessment of the risks of erythropoiesis-stimulating agents in patients with cancer.

PURPOSE: Erythropoiesis-stimulating agents (ESA) are approved for the treatment of anemia in patients with nonmyeloid malignancies whose anemia is due to the effect of concomitantly administered chemotherapy. Since the 1993 approval of epoetin alfa in patients with cancer, the risk of thrombovascular events, decreased survival, and poorer tumor control have been increasingly recognized. The risks of ESAs in patients with cancer and the design of trials to assess these risks have been the topic of discussion at two Oncologic Drugs Advisory Committees in 2004 and 2007. EXPERIMENTAL DESIGN: Evaluation of randomized clinical trials comparing use of ESAs to transfusion support alone in patients with active cancer. RESULTS: Six studies (Breast Cancer Erythropoeitin Survival Trial, Evaluation of NeoRecormon on outcome in Head And Neck Cancer in Europe, Danish Head and Neck Cancer, Lymphoid Malignancy, CAN-20, and Anemia of Cancer) investigating ESAs in oncology patients showed decreased survival, decreased duration of locoregional tumor control, and/or increased risk of thrombovascular events. In these six studies, ESA dosing was targeted to achieve and maintain hemoglobin values in excess of current recommendations, and in three of the six studies, ESAs were administered to patients not receiving chemotherapy. CONCLUSIONS: ESAs increase the risk of thrombovascular events and result in decreased survival and poorer tumor control when administered to achieve hemoglobin levels of > or =12 g/dL in patients with nonmyeloid malignancies. No completed or ongoing randomized, controlled trial has addressed safety issues of ESAs in patients with chemotherapy-associated anemia using currently approved dosing regimens in an epidermal tumor type. Additional studies are needed to better characterize these risks.

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.