Phase II, Randomized, Controlled, Double-Blinded Trial of Weekly Elesclomol Plus Paclitaxel Versus Paclitaxel Alone for Stage IV Metastatic Melanoma

被引:139
作者
O'Day, Steven [1 ]
Gonzalez, Rene
Lawson, David
Weber, Robert
Hutchins, Laura
Anderson, Clay
Haddad, Jonathan
Kong, Steven
Williams, Anthony
Jacobson, Eric
机构
[1] Angeles Clin & Res Inst, Santa Monica, CA 90404 USA
关键词
DISSEMINATED MALIGNANT-MELANOMA; 2ND-LINE THERAPY; INTERFERON-ALPHA; SOLID TUMORS; COMBINATION; BIOCHEMOTHERAPY; INTERLEUKIN-2; DACARBAZINE; TAXOL; CHEMOTHERAPY;
D O I
10.1200/JCO.2008.17.1579
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose Elesclomol is a novel, small-molecule, oxidative stress inducer believed to exert selective cytotoxicity by increasing intracellular concentrations of reactive oxygen species, which results in cell death via mitochondrial apoptosis. We evaluated whether the addition of elesclomol to weekly paclitaxel could improve efficacy in patients with stage IV metastatic melanoma. Patients and Methods We randomly assigned patients with metastatic melanoma, measurable disease, and one or fewer prior chemotherapy regimens to elesclomol 213 mg/m(2) plus paclitaxel 80 mg/m(2) (E + P) or to paclitaxel 80 mg/m(2) alone at a 2: 1 ratio; regimens were given as a 1-hour intravenous infusion weekly, during 3 of every 4 weeks until disease progression per Response Evaluation Criteria in Solid Tumors or death occurred. Patients who experienced progression were unblended, and patients on paclitaxel alone were permitted to cross over to E + P. The primary efficacy end point was progression-free survival (PFS); secondary end points were response rate (RR), toxicity, and overall survival (OS; analyzed post hoc). Results At 21 US sites, 53 patients were randomly assigned to E + P, and 28 patients were randomly assigned to paclitaxel. The addition of elesclomol to paclitaxel yielded a doubling of median PFS (112 v 56 days) and a 41.7% risk reduction for disease progression/death (hazard ratio, 0.583; P = .035). Respective RRs for the E + P and paclitaxel groups were 15% and 3%; median OS was 11.9 v 7.8 months. Of patients on paclitaxel alone, 19 (68%) of 28 crossed over to E + P after they experienced progression. Weekly E + P was well tolerated. Conclusion E + P resulted in a statistically significant doubling of median PFS, with an acceptable toxicity profile and encouraging OS. A multinational, phase III trial (SYMMETRY) of E + P compared with paclitaxel alone in metastatic melanoma has closed.
引用
收藏
页码:5452 / 5458
页数:7
相关论文
共 41 条
[1]  
Antoine EC, 1997, CANCER J SCI AM, V3, pS16
[2]   Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma:: A phase III study [J].
Avril, MF ;
Aamdal, S ;
Grob, JJ ;
Hauschild, A ;
Mohr, P ;
Bonerandi, JJ ;
Weichenthal, M ;
Neuber, K ;
Bieber, T ;
Gilde, K ;
Porta, VG ;
Fra, J ;
Bonneterre, J ;
Saïag, P ;
Kamanabrou, D ;
Pehamberger, H ;
Sufliarsky, J ;
Larriba, JLG ;
Scherrer, A ;
Menu, Y .
JOURNAL OF CLINICAL ONCOLOGY, 2004, 22 (06) :1118-1125
[3]   Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: The oblimersen melanoma study group [J].
Bedikian, Agop Y. ;
Millward, Michael ;
Pehamberger, Hubert ;
Conry, Robert ;
Gore, Martin ;
Trefzer, Uwe ;
Pavlick, Anna C. ;
DeConti, Ronald ;
Hersh, Evan M. ;
Hersey, Peter ;
Kirkwood, John M. ;
Haluska, Frank G. .
JOURNAL OF CLINICAL ONCOLOGY, 2006, 24 (29) :4738-4745
[4]   Phase II evaluation of paclitaxel by short intravenous infusion in metastatic melanoma [J].
Bedikian, AY ;
Plager, C ;
Papadopoulos, N ;
Eton, O ;
Ellerhorst, J ;
Smith, T .
MELANOMA RESEARCH, 2004, 14 (01) :63-66
[5]   Phase I clinical trial of STA-4783 in combination with paclitaxel in patients with refractory solid tumors [J].
Berkenblit, Anna ;
Eder, Joseph P., Jr. ;
Ryan, David P. ;
Seiden, Michael V. ;
Tatsuta, Noriaki ;
Sherman, Matthew L. ;
Dahl, Thomas A. ;
Dezube, Bruce J. ;
Supko, Jeffrey G. .
CLINICAL CANCER RESEARCH, 2007, 13 (02) :584-590
[6]  
COX DR, 1972, J R STAT SOC B, V187, P220
[7]   Reaching first base in the treatment of metastatic melanoma [J].
Eggermont, Alexander M. M. .
JOURNAL OF CLINICAL ONCOLOGY, 2006, 24 (29) :4673-4674
[8]   Re-evaluating the role of dacarbazine in metastatic melanoma: what have we learned in 30 years? [J].
Eggermont, AMM ;
Kirkwood, JM .
EUROPEAN JOURNAL OF CANCER, 2004, 40 (12) :1825-1836
[9]  
EINZIG AI, 1991, INVEST NEW DRUG, V9, P59
[10]   Sequential biochemotherapy versus chemotherapy for metastatic melanoma: Results from a phase III randomized trial [J].
Eton, O ;
Legha, SS ;
Bedikian, AY ;
Lee, JJ ;
Buzaid, AC ;
Hodges, C ;
Ring, SE ;
Papadopoulos, NE ;
Plager, C ;
East, MJ ;
Zhan, F ;
Benjamin, RS .
JOURNAL OF CLINICAL ONCOLOGY, 2002, 20 (08) :2045-2052