Next 5 or 6 posts from me will contain 11 ASCO Velcade abstracts.
If you're not interested just skip the next few posts from me.
Ian
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Phase I of bortezomib and Taxol
Abstract No: 3104
Author(s): C. L. Shapiro, B. Ramaswamy, D. Young, T. Lamb, D. Lucas, L. Shaaf, Z. Sahenk, M. Collamore, J. Byrd, J. Wright, M. Grever
Abstract:
Background: Bortezomib (B) (Velcade) inhibits the activation of NF-?B and may make tumor cells sensitive to chemotherapeutics, like paclitaxel, that activate NF-?B (Sunwoo et al Clin Ca Res 2001;7:1419-28). B and paclitaxel are additive in tumor growth delay models (Teicher et al Clin Can Res 1999;5:2638-45). We designed a phase I trial of escalating doses of weekly (wkly) B and paclitaxel. The primary objectives are to determine the dose of B that results in not more than 70-80% 20S-proteasome inhibition (20S-PI) when combined with paclitaxel, and to determine dose-limiting toxicity (DLT).
Methods: Eligibility included ECOG performance status < 2, and adequate end organ functions. Definitions of DLT: grade = 3 non-hematologic and grade 4 hematologic toxicity (excluding asymptomatic neutropenia).
Results: Twenty-five pts enrolled thus far. The first 4 pts were treated with wkly paclitaxel d1 and B d2 and 5 for 4 weeks (wks), cycles repeated every 6 wks. DLT and cumulative neurological toxicity led to the current schedule of wkly paclitaxel d1 and B d2 for 2 wks, cycles repeated every 3 wks. Dose escalations and results for 21 pts treated on the current schedule are described in the Table. Most adverse events (AE) were grade = 2; most grade 3 AE were reversible lab abnormalities; and there were no grade 4 AE. 20S-PI 1 hr following B alone was 44% [range 24-72%], and 48% [range 6-74%] after B and paclitaxel. 20S-PI was not dose-dependent over the small range of B dose levels. At dose level 2, 2 pancreatic cancer pts had sustained significant decreases in CA 19-9 with 1 having SD and 1 having a PR (not confirmed).
Conclusions: Thus far, the regimen has acceptable toxicity with evidence of antitumor activity. The trial will continue until the primary endpoints are reached. The results of p27 and Bax proteins in peripheral blood mononuclear cells, and serum inflammatory cytokines including TNF, IL-1, IL-6, C-reactive protein will be presented. Supported by NCI 2 UO1 CA- 076576-06.
Dose escalation of B/paclitaxel
Level B/Paclitaxel N Cycles Cycle 1
(mg/M2) DLT
1 0.6/80 6 14 1-grade 3 fatigue
1a 0.6/100 6 17 1-grade 3 fatigue
2 0.8/100 6 35 1-grade 3 fatigue
3 1.2/100 3 7 0
Associated Presentation(s):
A presentation was not made on this abstract |
