Bortezomib in Urothelial Cancer
Abstract No: 4677
Author(s): S. S. Sridhar, W. Stadler, L. Le, D. Hedley, G. Pond, J. Wright, E. Vokes, S. Thomas, M. Moore
Abstract:
Background: The ubiquitin-proteasome proteolytic pathway regulates the metabolism of several key proteins (p53, p21, p27, NF-kappaB) involved in cell cycle, apoptosis, metastasis and angiogenesis. PS341 (Bortezomib;Velcade) is a dipeptidyl boronic acid derivative that is a potent and highly specific inhibitor of the proteasome, which shows preclinical evidence of antitumor activity.
Methods: Patients had advanced or metastatic transitional cell cancer of the bladder, renal pelvis, or ureter treated with 1 or more prior lines of therapy for metastatic disease. The primary endpoint was response rate. Bortezomib was administered at a dose of 1.3mg/m2/day IV on days 1, 4, 8, and 11 of a 21 day cycle. Tumor response was assessed by RECIST criteria every 3 cycles. Tumor biopsies in suitable consenting patients were planned at baseline and within 24 hours of treatment on day 8 or 11 to assess pre and post-treatment levels of NF-kappaB and HIF1 alpha. In order to minimize the number of patients treated if the regimen was not active, a two stage phase II design will be used based upon P0 = 0.05, P1= 0.20, a = 0.10 and ß =0.10. In stage I 20 evaluable patients are planned with continuation if at least 2 patients have an objective tumour response.
Results: In total 18 pts (3F:15M), median age 70 (49-81) were entered on study and received a total of 34 cycles (range 1-3) of treatment. 1:11:2:1 had received 0:1:2:3 prior therapies for advanced disease. 11 pts are evaluable for response and all had progressive disease (PD); 7 are inevaluable (1 did not receive drug; 2 never completed 1 cycle due to toxicity; 4 too early). Most common adverse events, of any grade were fatigue (76% cycles), anemia (76%), lymphopenia (62%), and hyperglycemia (47%).
Conclusions: At present, single agent PS341 has not shown activity in advanced transitional cell cancer of the kidneys, ureters or bladder. Accrual continues to complete stage 1 of the study.
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Bortezomib in MM renal failure
Abstract No: 6714
Author(s): A. Mohrbacher, A. M. Levine
Abstract:
Background: Bortezomib is a highly active agent in multiple myeloma. Advanced stages of multiple myeloma are freqeuntly associated with progressive renal failure. We report here 6 cases of acute advanced deterioration of renal function on prior renal insuficiency in chronic MM patients, with complete or near complete reversal of severe renal dysfunction after treatment with Velcade and Dexamethasone.
Methods: Pts received Velcade 1.0 mg/m2/d IV d1,4,8,11 and Dexamethasone 20 mg IV d1,4,8,11
Results: Rapid reversal of acute deterioration of renal dysunction was demonstrated after treatment with Velcade and Dexamethasone in this retrospective review of patient cases. Improvement of renal function was generally evident quickly, often less than 2 weeks, earlier than expected from general myeloma tumor response. A review of a trial of treatment with Velcade where Dexamethasone was added in later cycles may address possible evidence of synergy of Velcade and dexamethasone in reversal of renal dysfunction. Animal models suggest NFkB, the target of Bortezomib, is upregulated in acute tubular injury from proteinuria and suggest further study of this drug's possible role in protecting renal function.
Conclusions: In summary, rapid and at times dramatic reversal of severe renal dysfunction is seen with Velcade and Dexamethasone, sparing the 6 patients above from imminent dialysis. Prevention of end stage renal failure is an important clinical goal given the prolonged survivals seen in myleoma patients in the current era, and the known impact of renal failure on their survival.
Patients Crea pre and post Bortezomib
Patient bun/Crea bun/Crea bun/Crea bun/Crea
1 mo Immed day or day or Prior Rx
prior Prior to mo post mo post
Bort Bort Bort
1 36 / 2.5 63 / 3.0 57 / 2.9 35 / 2.7 MP,Dex,Dox,ATO
1 mo 2 mo
2 26 / 1.8 74 / 2.5 32 / 2.3 MP,Dex
1 mo
3 12 / 0.7 14 / 2.6 26 / 1.4 19 / 1.5 VMCP,Dex
1+ mo 2 mo
4 37 / 2.2 43 / 2.6 25 / 1.4 17 / 1.2 MP,Dex,TD
1 mos 2 mo
5 26 / 3.0 113 / 10 85 / 6.8 47 / 3.7 TD
6d post 16d post
6 35 / 3.0 61 / 6.8 42 / 3.5 41 / 4.0 VAD
8 d post 1+ mo
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