Search

In part A of this study, patients were randomised to cohorts receiving darbepoetin alfa at doses of 0.5 to 8.0 m.c.g. kg−1 wk−1 or to a control group receiving epoetin alfa at an initial dose of 150 U kg−1 three times weekly. In part B, the cohorts were darbepoetin alfa 3.0 to 9.0 m.c.g. kg−1 every 2 weeks or epoetin alfa, initial dose 40 000 U wk−1. Safety was assessed by adverse events, changes in blood pressure, and formation of antibodies to darbepoetin alfa. Efficacy was assessed by several haematologic endpoints, including change in haemoglobin from baseline. The adverse event profile of darbepoetin alfa was similar to that of epoetin alfa. No relationship between the rapidity of haemoglobin response and any adverse event was observed. No antibodies to darbepoetin alfa were detected. Higher doses of darbepoetin alfa increased the proportion of patients with a haemoglobin response and decreased the median time to response. The overall dose of darbepoetin alfa required to produce a mean increase in haemoglobin does not increase when the dosing interval is increased from 1 to 2 weeks. Therapy with darbepoetin alfa is safe and effective in producing a dose-related increase in haemoglobin levels in patients with cancer receiving chemotherapy. British Journal of Cancer (2002) 87, 268–276. doi:10.1038/sj.bjc.6600465 www.bjcancer.com © 2002 Cancer Research UK

Structure-activity relationships of a lead hydroxamic acid inhibitor of recombinant human stromelysin were systematically defined by taking advantage of a concise synthesis that allowed diverse functionality to be explored at each position in a template. An ex vivo rat model and an in vivo rabbit model of stromelysin-induced cartilage degradation were used to further optimize these analogs for oral activity and duration of action. The culmination of these modifications resulted in CGS 27023A, a potent, orally active stromelysin inhibitor that blocks the erosion of cartilage matrix.

The optimal hemoglobin concentration at which to initiate erythropoietic therapy for chemotherapy-induced anemia (CIA) is not well defined. This randomized, open-label, multicenter study evaluated the ability of darbepoetin alfa (300 μg every 3 weeks) to maintain hemoglobin levels ≥10g/dl in patients with CIA (hemoglobin ≥10.5 g/dl and ≤12.0 g/dl) randomized 1:1 to an immediate-intervention group (received darbepoetin alfa immediately) or observation group (received darbepoetin alfa if hemoglobin fell to

Capecitabine results in superior response rate, improved safety, and improved convenience compared with 5-fluorouracil (FU)/leucovorin (LV) in metastatic colorectal cancer (MCRC). Irinotecan in combination with 5-FU/LV has been shown to improve efficacy compared with 5-FU/LV alone in MCRC. Therefore, we evaluated the efficacy and safety of capecitabine plus irinotecan every 3 weeks (XELIRI regimen) as first-line treatment.Patients with MCRC who were65 years of age received irinotecan 250 mg/m i.v. on day 1 + capecitabine 1000 mg/m orally twice daily on days 1 to 14, every 3 weeks. Patientsor=65 years of age and those with impaired renal function or with a history of prior radiotherapy received lower doses of both agents (200 mg/m and 750 mg/m twice daily, respectively).A total of 52 patients (29 men, 23 women) were enrolled between October 2001 and August 2003. Median age was 57.5 years (range, 30-79 years); median Karnofsky performance status was 90 (range, 70-100). Treatment led to a response rate of 50% (ITT population) and a disease control rate of 71%. With a median cohort follow-up of 30.5 months, median time to progression and overall survival are 7.8 months (95% confidence interval, 5.6-10.0) and 16.8 months (95% confidence, 11.9 to not reached), respectively. Most common treatment-related grade 3/4 adverse events were neutropenia (25%), diarrhea (20%), vomiting (16%), dehydration (10%), nausea (6%), abdominal pain (6%), and hand-foot syndrome (6%).XELIRI is an active first-line treatment of MCRC. Implementation of upfront dose reductions for both agents in patients with risk factors for toxicity appears to have produced a safer regimen compared with previous studies of XELIRI without such dose reductions.

This is the first randomized, open-label, multicenter trial designed and powered to directly compare the hemoglobin (Hb) response to epoetin alfa (EPO), 40,000 U once weekly (QW), with that to darbepoetin alfa (DARB), 200 μ g every 2 weeks (Q2W), in anemic patients with cancer receiving chemotherapy (CT). Transfusion requirements, quality of life (QOL), and safety also were evaluated. Adults with solid tumors scheduled to receive CT for ≥12 weeks and with baseline Hb ≤11 g/dl were randomized to receive either EPO 40,000 U QW (n = 178) or DARB 200 μg Q2W (n = 180) s.c. for up to 16 weeks. Doses were increased for nonresponders (Hb increase 1.3 g/dl [EPO] or >1.0 g/dl [DARB] within any 2-week period) or for an Hb level >13 g/dl. The proportion of patients achieving a ≥1-g/dl Hb rise by week 5, the primary end point, was significantly higher with EPO (47.0%) than with DARB (32.5%), and EPO-treated patients achieved a ≥1-g/dl Hb increase significantly earlier than those receiving DARB (median, 35 days versus 46 days). The mean increase in Hb from baseline was significantly higher at weeks 5, 9, 13, and the end of the study with EPO than with DARB. The number of units transfused per patient was significantly lower for the EPO group than for the DARB group. The proportions of patients requiring transfusions, mean QOL improvements, and tolerability profiles were similar in the two groups.

BACKGROUND Anemia in patients receiving chemotherapy can be ameliorated with recombinant human erythropoietin (rHuEPO), which is administered one to three times per week. Darbepoetin α, 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 α at doses of 4.5 μg/kg per week until hemoglobin concentration ≥ 12 g/dL, then 1.5 μg/kg per week (Group 1); 4.5 μg/kg per week for 4 weeks, then 2.25 μg/kg per week for 8 weeks (Group 2); or 4.5 μg/kg per week for 4 weeks, then 3.0 μg/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 α 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 α 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 α was associated with an early and maintained reduction in patient-reported fatigue. The adverse event profile was comparable with all doses of darbepoetin α and rHuEPO. CONCLUSIONS Darbepoetin α, 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. Cancer 2003;97:1312–20. © 2003 American Cancer Society. DOI 10.1002/cncr.11186

As with other drugs, applications for marketing approval of new chemopreventive agents in the United States must include data from adequate and well-controlled clinical trials that demonstrate effectiveness and safety for the intended use. Knowledge of a drug's pharmacologic actions and metabolism may benefit protocol design, by identifying the patient populations and dosing schedules associated with a favorable risk/benefit profile. With availability of appropriate preclinical data, including standard assessments of an agent's toxicology, effects on reproductive performance, and genotoxicity, initial Phase I studies of 1-3 months may be performed in normal volunteers or an appropriate higher risk population. For chronic dosing studies of longer duration, preclinical toxicology studies of longer duration are relevant. Enrollment in chemoprevention studies should be directed toward individuals at sufficient risk of developing cancer so that potential benefit may counterbalance the unpredictable and possibly serious adverse effects that may be observed with prolonged administration of a study drug. Phase I and II studies with clinical dosing lasting up to 12 months often afford opportunities to assess drug effect on surrogate endpoint biomarkers that may correlate with endpoints of clinical effectiveness. Phase III and late phase II chemopreventive investigations should routinely utilize a prospective, randomized study design (double-masked and placebo-controlled, when possible). To support marketing approval, there must be evidence that a chemopreventive agent significantly delays or prevents the occurrence of malignancy, with acceptable safety. In some circumstances, modulation of a surrogate marker may provide a basis for marketing approval, before more definitive endpoint data become available. However, the acceptability of a surrogate depends on the nature and quality of the data supporting its predictive value. Given the considerations of large study size, long duration, and high cost that may hamper development of potential agents, studies designed to examine the predictive value of surrogate endpoint biomarkers are of great importance to the future development of chemoprevention research.

Increasingly, quality-of-life (QOL) end points are being incorporated into randomized, controlled clinical trials in oncology. The Oncologic Drugs Advisory Committee (U.S. Food and Drug Administration) has recommended that beneficial effects on QOL and/or survival be the basis for approval of new anticancer drugs. Therefore, from a regulatory standpoint, for drugs that do not have an impact on survival, demonstration of a favorable effect on QOL is more important than most other traditional measures used to assess efficacy, such as objective tumor response. Trials incorporating QOL questions will be evaluated on the basis of how well they address the stated objectives. The clinical protocol should delineate investigators' hypotheses and choice of validated instruments and should specify a detailed statistical analysis plan describing strategies for handling missing data. The U.S. Food and Drug Administration welcomes the opportunity to explore with investigators the use of QOL instruments in the design of cancer clinical trials.

Cyclophosphamide, 5-fluorouracil, methotrexate, and prednisone were administered for 165, 28-day cycles to 33 patients with metastatic breast cancer. Because of serious infections (fever larger than or equal to 101 degrees F. granulocytes less than 1,000/mm, 3 and hospitalization) and 1 drug death in the first 4 patients, oral calcium leucovorin, 20 to 30 mg/m2 orally, was given 2 days after methotrexate in subsequent treatment cycles. There were 26 cycles without calcium leucovorin and 6 serious infections; 139 cycles with calcium leucovorin and 5 serious infections (p = 0.002). Objective response was seen in 13 of 18 evaluable patients with no previous treatment and in only 2 of 11 patients with previous treatment (p = 0.0065). Equivalent doses were given to all subsets of patients. It is concluded that leucovorin added to the above combination of drugs can preserve antitumor activity while decreasing serious infections and that prior therapy significantly decreases the response rate to this combination.

Experience with chemotherapy in advanced gynecologic malignancies is limited. In 6 patients, 2 of 4 with carcinoma of the cervix, and 1 patient with carcinoma of the ovary achieved partial remission when treated with a regimen of high dose methotrexate (240 mg/m2) followed by leucovorin rescue. On patient with metastatic trophoblastic disease achieved complete response (greater than 24 months). The number of doses of leucovorin 'rescue' was based on creatinine clearance. The advantage of rapid response and moderate toxicity indicate the need for further study of this regimen in the treatment of gynecologic malignancies.

Primary lymphoma of the central nervous system (CNS) is extremely rare. A case of mixed histiocytic lymphocytic lymphoma of the CNS that initially occurred in the spinal cord is reported. Multicentric recurrence following radiotherapy was successfully treated with intrathecal methotrexate and the patient remains free of disease after 4 years. The role of intrathecal methotrexate as alternative therapy following irradiation failure is discussed.