A Phase 1 dose-escalation trial of glufosfamide in combination with gemcitabine in solid tumors including pancreatic adenocarcinoma.

PURPOSE: To evaluate safety and pharmacokinetics and to establish the maximum tolerated dose of glufosfamide when administered in combination with gemcitabine in advanced solid tumors. METHODS: This Phase 1 dose-escalation study evaluated the combination of glufosfamide + gemcitabine in patients with advanced solid tumors. Cohorts of three to six patients were treated with glufosfamide doses from 1,500 to 4,500 mg/m(2) i.v. over 4 h on Day 1 and gemcitabine 1,000 mg/m(2) i.v. over 30 min on Days 1, 8 and 15 of every 28-day cycle. Detailed PK sampling was performed on days 1 and 8 of the first two cycles. RESULTS: Nineteen patients were enrolled. Two patients had dose-limiting toxicity: Grade 3 fatigue at 2,500 mg/m(2) and Grade 4 thrombocytopenia at 4,500 mg/m(2). Five patients completed six cycles and one patient remained on study for ten cycles. Two patients discontinued for adverse events. Grade 3/4 neutropenia and thrombocytopenia occurred in seven patients and five patients, respectively. The CrCL fell below 60 mL/min in two patients. There was one unconfirmed partial response and 10 of 19 (52.6%) patients had stable disease or better at 8 weeks and three patients had continuing stable disease at 24 weeks. Pharmacokinetic analyses suggest no interaction between glufosfamide and gemcitabine. CONCLUSION: Phase I data indicate that full dose glufosfamide (4,500 mg/m(2)) can be given safely in combination with gemcitabine. A Phase II study in patients with pancreatic adenocarcinoma is ongoing.

A randomized, active-control, pilot trial of front-loaded dosing regimens of darbepoetin-alfa for the treatment of patients with anemia during chemotherapy for malignant disease.

BACKGROUND: Anemia in patients receiving chemotherapy can be ameliorated with recombinant human erythropoietin (rHuEPO), which is administered one to three times per week. Darbepoetin alpha, a new erythropoietic agent, has longer serum residence time, allowing it to be administered less frequently. METHODS: Patients (n = 127) were randomized to receive study drug for 12 weeks: either rHuEPO 40,000 U with escalations to 60,000 U for nonresponders or darbepoetin alpha at doses of 4.5 microg/kg per week until hemoglobin concentration >or= 12 g/dL, then 1.5 microg/kg per week (Group 1); 4.5 microg/kg per week for 4 weeks, then 2.25 microg/kg per week for 8 weeks (Group 2); or 4.5 microg/kg per week for 4 weeks, then 3.0 microg/kg every 2 weeks (Group 3). Efficacy was measured using the mean change in hemoglobin level, the proportion of patients achieving a hemoglobin response, the time to response, and the mean change in Functional Assessment of Cancer Therapy-Fatigue Scale scores. Safety was assessed by reports of adverse events. RESULTS: Overall, after 4 weeks of treatment, the mean change (95% confidence interval [95%CI]) in hemoglobin concentration was 0.53 g/dL (95%CI, 0.05-1.02 g/dL), 0.70 g/dL (95%CI, 0.11-1.29 g/dL), and 0.90 g/dL (95%CI, 0.47-1.33 g/dL) in darbepoetin alpha Groups 1, 2, and 3, respectively, and 0.39 g/dL (95%CI, - 0.22-1.00 g/dL) in the rHuEPO group. By the end of the study, the mean change (95%CI) in hemoglobin concentration was 1.35 g/dL (95%CI, 0.67-2.02 g/dL), 1.35 g/dL (95%CI, 0.57-2.12 g/dL), and 1.28 g/dL (95%CI, 0.84-1.73 g/dL) in darbepoetin alpha Groups 1, 2, and 3, respectively, and 1.03 g/dL (95%CI, 0.53-1.53 g/dL) in the rHuEPO group. The early erythropoietic response in patients who were treated with darbepoetin alpha was associated with an early and maintained reduction in patient-reported fatigue. The adverse event profile was comparable with all doses of darbepoetin alpha and rHuEPO. CONCLUSIONS: Darbepoetin alpha, given as a front-loaded dose for 4 weeks and followed by lower and/or less frequent doses, appears to be efficacious and may decrease the time to response relative to treatment with rHuEPO.

Every-2-week darbepoetin alfa is comparable to rHuEPO in treating chemotherapy-induced anemia. Results of a combined analysis.

The safety and efficacy of darbepoetin alfa (Aranesp) at 3.0 microg/kg administered every 2 weeks and recombinant human erythropoietin (rHuEPO) given as 40,000 U weekly or 150 U/kg three times weekly were evaluated by pooling data from three darbepoetin alfa clinical studies. All studies enrolled anemic (hemoglobin < or = 11.0 g/dL) patients receiving multicycle chemotherapy. Open-label study drug was administered by subcutaneous injection. Hemoglobin concentrations, red blood cell transfusion requirements, and standard safety parameters were evaluated. Of 260 patients who received darbepoetin alfa at 3.0 microg/kg every 2 weeks and 115 patients who received rHuEPO three times weekly or once weekly, hematopoietic response (change in hemoglobin from baseline of > or = 2 g/dL or hemoglobin concentration of > or = 12 g/dL) was achieved in 71% (95% confidence interval [CI] = 65%-78%) of patients who received darbepoetin alfa every 2 weeks, comparable to the response in patients who received rHuEPO (71%; 95% CI = 61%-81%). The mean increase in hemoglobin concentration over 13 weeks was also similar: 1.48 g/dL (95% CI = 1.28-1.68 g/dL) for darbepoetin alfa and 1.31 g/dL (95% CI = 0.97-1.64 g/dL) for rHuEPO. The proportion of patients in the darbepoetin alfa group requiring transfusions was lower (7%; 95% CI = 4%-11%) than that in the rHuEPO group (14%; 95% CI = 8%-22%). Darbepoetin alfa every 2 weeks was well tolerated with a safety profile comparable to that of rHuEPO. In conclusion, darbepoetin alfa at a dose of 3.0 microg/kg given every 2 weeks safely increases hemoglobin concentration to the same extent as rHuEPO.

Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy.

BACKGROUND: Patients receiving chemotherapy often develop anemia. Darbepoetin alfa (Aranesp(TM)) is an erythropoiesis-stimulating glycoprotein that has been shown, in dose-finding studies, to be safe and clinically active when administered to patients with cancer every 1, 2, or 3 weeks. This phase III study compared the safety and efficacy of darbepoetin alfa with placebo in patients with lung cancer receiving chemotherapy. METHODS: In this multicenter, double-blind, placebo-controlled study, 320 anemic patients (hemoglobin or=25% improvement; mean difference = 13%; 95% CI = 2% to 23%, P =.019) than patients receiving placebo. Patients receiving darbepoetin alfa did not appear to have any untoward effect in disease outcome and did not develop antibodies to the drug. Adverse events were similar between the groups. CONCLUSIONS: Patients with chemotherapy-associated anemia can safely and effectively be treated with weekly darbepoetin alfa therapy. Darbepoetin alfa decreased blood transfusion requirements, increased hemoglobin concentration, and decreased fatigue. Although no conclusions can be drawn about survival from this study, the potential salutary effect on disease outcome warrants further investigation in a prospectively designed study.