Avastin PII in mCC, monotherapy. Xeloda PII as monotherapy in similar population.
[520] Phase II dose escalation trial of Avastin™ (bevacizumab) in women with previously treated metastatic breast cancer.
Cobleigh MA, Miller KD, Langmuir VK, Reimann JD, Vassel AV, Novotny WF, Sledge GW Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL; Indiana University, Indianapolis, IN; Genentech, Inc, South San Francisco, CA
Breast cancer is known to produce vascular endothelial growth factor (VEGF), a key molecule in the regulation of angiogenesis. Increased VEGF protein and mRNA levels are associated with decreased overall and disease-free survival. It follows that inhibition of VEGF production may slow tumor growth and lead to longer survival. Therefore, a Phase II dose escalation trial of a recombinant humanized monoclonal antibody to VEGF (bevacizumab; rhuMAb VEGF) was undertaken. Methods: Seventy-five women with previously treated metastatic breast cancer were treated with Avastin at 3 mg/kg (n=18), 10 mg/kg (n=41) or 20 mg/kg (n=16) IV every 2 weeks until progression. The endpoints of the trial were safety, best objective response rate and pharmacokinetics. Results: The median age of patients in this trial was 48 years and patients had received a median of two prior chemotherapy regimens for metastatic disease. The median duration of treatment was 10 weeks. Dose-limiting toxicity was headache (Grade 3 in 1; Grade 4 in 1) associated with nausea and vomiting which occurred in 4 patients treated at 20 mg/kg. Four patients discontinued study participation because of adverse events: 1 with hypertensive encephalopathy and nephrotic syndrome at 3 mg/kg, 1 with proteinuria at 10 mg/kg, 1 with nephrotic syndrome at 20 mg/kg and 1 with severe headache, nausea and vomiting at 20 mg/kg. 7 of 75 (9.3%) patients had an objective response including 1 CR in a supraclavicular node at 10 mg/kg that recurred 3 months after completing 1 year of therapy. PR occurred in 6 patients (2 unconfirmed) with disease in lymph nodes, skin, pleura, bone and liver. Median duration of confirmed response was 5.6 months. Responders had smaller tumor burden, lower ECOG status and higher albumin at baseline than the overall population. 12 of 75 (17%) patients had an ongoing response or stable disease at the last tumor assessment at 5 months. Three patients were treated for one year or longer without disease progression. Median survival was 10.2 months. Conclusions: Avastin monotherapy results in objective response or disease stabilization in a significant number of patients. Adverse events of significance included hypertension and proteinuria. A Phase III trial combining Avastin with capecitabine is currently underway.
[435] Phase II study of capecitabine (Xeloda®) in pts with advanced breast cancer (ABC), previously treated with anthracyclines and taxanes.
Fumoleau P, Largillier R, Trillet-Lenoir V, Orfeuvre H, Extra J-M, Lesimple T, Culine S, Montestruc F, Mouri Z C.H. R.Gauducheau, St Herblain; C.H. A.Lacassagne, Nice; C.H. Lyon Sud, Pierre Bénite; C.H. Fleyriat, Bourg en Bresse; Institut Curie, Paris; Centre E. Marquis, Rennes; Centre Val d'Aurelle, Montpellier; Roche, Neuilly, France
Capecitabine, a tumor-selective, oral fluoropyrimidine, is highly active in ABC. It is enzymatically converted to 5-FU by thymidine phosphorylase which is found at higher concentrations in tumor than in normal tissue. The objective of this study was to evaluate the efficacy and safety of capecitabine at the dose of 1250 mg/m2, twice daily for 14 days followed by a one week rest period, in pts with ABC, previously treated with anthracyclines and taxanes. The principal study endpoint was time to progression (TTP).
126 pts were included between February 99 and October 00. In May 01, 95 pts were assessable for safety and 91 for efficacy. 87 of these 95 pts stopped treatment, mainly for progressive disease (60%) or adverse events (AEs) (23%).
Pts characteristics were : median age 54 years; ECOG/PS : 0 : 45%, 1 : 48%, 2 : 7%; predominant sites of metastases : bone : 25%, liver : 23% or lung : 20%. Median number of previous chemotherapy lines for advanced disease was 2 and median number of cycles delivered was 6.
Safety : the main grade 3/4 toxicities per pt were: hand-foot syndrome (no grade 4): 17/95 (18%); neutropenia: 13/95 (14%); and diarrhea: 8/95 (8%). The other principal grade 3 toxicities (no grade 4 observed) were: vomiting: 4/95 (4%), mucositis: 3/95 (3%) and fatigue: 2/95 (2%). Thirty one patients (33%) had a dose reduction mainly due to AEs.
Efficacy : the median TTP was 4.3 months (CI 95% : 3.4 - 6). At the 3rd cycle, among the 71 evaluable pts for response, there were 12/71 (17%; CI 95% : 8%-26%) partial responses and 27/71 (38%; CI95% : 27%-49%) stable disease.
Conclusion : the interim results of this phase II trial in ABC confirm capecitabine's antitumor activity in heavily pretreated pts. The median TTP (4.3 months) compares favorably to the 3.1 months reported in the pivotal study (Blum, JCO 99). |
