A Phase II Study of Coltuximab Ravtansine (SAR3419) Monotherapy in Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia

被引:54
作者
Kantarjian, Hagop M. [1 ]
Lioure, Bruno [2 ]
Kim, Stella K. [3 ]
Atallah, Ehab [4 ]
Leguay, Thibaut [5 ]
Kelly, Kevin [6 ]
Marolleau, Jean-Pierre [7 ]
Escoffre-Barbe, Martine [8 ]
Thomas, Xavier G. [9 ]
Cortes, Jorge [1 ]
Jabbour, Elias [1 ]
O'Brien, Susan [10 ]
Bories, Pierre [2 ]
Oprea, Corina [11 ]
Hatteville, Laurence [11 ]
Dombret, Herve [12 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA
[2] CHU Hautepierre, F-67098 Strasbourg, France
[3] Univ Texas Hlth, Sch Med, Robert Cizik Eye Clin, Houston, TX USA
[4] Med Coll Wisconsin, Milwaukee, WI 53226 USA
[5] Hosp Grp South, Pessac, France
[6] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA
[7] CHU Hosp South, Amiens, France
[8] Hosp Pontchaillou, Rennes, France
[9] Ctr Hosp Lyon Sud, F-69310 Pierre Benite, France
[10] Univ Calif Irvine, Irvine, CA USA
[11] Sanofi, Vitry Sur Seine, France
[12] Univ Paris Diderot, Univ Inst Hematol, Hosp St Louis, Paris, France
关键词
Adult; Antibody-drug conjugate; CD19; Maytansine derivatives; Safety; DOSE-ESCALATION; TRIAL; BLINATUMOMAB; CONJUGATE; THERAPY; ADULTS;
D O I
10.1016/j.clml.2015.12.004
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Therapy options are limited for adult patients with relapsed or refractory acute lymphoblastic leukemia (ALL). In the present phase II study, 36 patients with relapsed or refractory ALL were treated with the anti-CD19 antibody -drug conjugate, coltuximab ravtansine. Coltuximab ravtansine was well tolerated, but the clinical response rate was low (4 of 17 patients). Background: Long-term disease-free survival in adult patients with acute lymphoblastic leukemia (ALL) remains unsatisfactory, and the treatment options are limited for those patients with relapse or a failure to respond after initial therapy. We conducted a dose-escalation/expansion phase II, multicenter, single-arm study to determine the optimal dose of coltuximab ravtansine (SAR3419), an anti-CD19 antibody-drug conjugate, in this setting. Patients and Methods: The dose-escalation part of the study determined the selected dose of coltuximab ravtansine for the evaluation of efficacy and safety in the dose-expansion phase. Patients received coltuximab ravtansine induction therapy (<= 8 weekly doses)., The responding patients were eligible for maintenance therapy (biweekly administration for <= 24 weeks). Three dose levels of coltuximab ravtansine were examined: 55, 70, and 90 mg/m(2). The primary endpoint was the objective response rate (ORR). The secondary endpoints included the duration of response (DOR) and safety. Results: A total of 36 patients were treated: 19 during dose escalation and 17 during dose expansion. One dose-limiting toxicity was observed at 90 mg/m(2) (grade 3 peripheral motor neuropathy); therefore, 70 mg/m(2) was selected for the dose-expansion phase. Five patients discontinued therapy because of adverse events (AEs). The most common AEs were pyrexia, diarrhea, and nausea. Of the 17 evaluable patients treated at the selected dose, 4 had a disease response (estimated ORR using the Bayesian method: 25.5% (80% confidence interval, 14.2%-39.6%). The DOR was 1.9 months (range, 1-5.6 months). Because of these results, the study was prematurely discontinued. Conclusion: Coltuximab ravtansine was well tolerated but was associated with a low clinical response rate in patients with relapsed or refractory ALL. (C) 2016 Elsevier Inc. All rights reserved.
引用
收藏
页码:139 / 145
页数:7
相关论文
共 14 条
[1]   SAR3419: An Anti-CD19-Maytansinoid Immunoconjugate for the Treatment of B-Cell Malignancies [J].
Blanc, Veronique ;
Bousseau, Anne ;
Caron, Anne ;
Carrez, Chantal ;
Lutz, Robert J. ;
Lambert, John M. .
CLINICAL CANCER RESEARCH, 2011, 17 (20) :6448-6458
[2]   The Anti-CD19 Antibody-Drug Conjugate SAR3419 Prevents Hematolymphoid Relapse Postinduction Therapy in Preclinical Models of Pediatric Acute Lymphoblastic Leukemia [J].
Carol, Hernan ;
Szymanska, Barbara ;
Evans, Kathryn ;
Boehm, Ingrid ;
Houghton, Peter J. ;
Smith, Malcolm A. ;
Lock, Richard B. .
CLINICAL CANCER RESEARCH, 2013, 19 (07) :1795-1805
[3]  
Coiffier B, 2013, 55 AM SOC HEM ANN M
[4]   Long-term outcome of a pediatric-inspired regimen used for adults aged 18-50 years with newly diagnosed acute lymphoblastic leukemia [J].
DeAngelo, D. J. ;
Stevenson, K. E. ;
Dahlberg, S. E. ;
Silverman, L. B. ;
Couban, S. ;
Supko, J. G. ;
Amrein, P. C. ;
Ballen, K. K. ;
Seftel, M. D. ;
Turner, A. R. ;
Leber, B. ;
Howson-Jan, K. ;
Kelly, K. ;
Cohen, S. ;
Matthews, J. H. ;
Savoie, L. ;
Wadleigh, M. ;
Sirulnik, L. A. ;
Galinsky, I. ;
Neuberg, D. S. ;
Sallan, S. E. ;
Stone, R. M. .
LEUKEMIA, 2015, 29 (03) :526-534
[5]  
Faderl S., 2013, J CLIN ONCOL S, V31
[6]   Adult Acute Lymphoblastic Leukemia Concepts and Strategies [J].
Faderl, Stefan ;
O'Brien, Susan ;
Pui, Ching-Hon ;
Stock, Wendy ;
Wetzler, Meir ;
Hoelzer, Dieter ;
Kantarjian, Hagop M. .
CANCER, 2010, 116 (05) :1165-1176
[7]   In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993) [J].
Goldstone, Anthony H. ;
Richards, Susan M. ;
Lazarus, Hillard M. ;
Tallman, Martin S. ;
Buck, Georgina ;
Fielding, Adele K. ;
Burnett, Alan K. ;
Chopra, Raj ;
Wiernik, Peter H. ;
Foroni, Letizia ;
Paietta, Elisabeth ;
Litzow, Mark R. ;
Marks, David I. ;
Durrant, Jill ;
McMillan, Andrew ;
Franklin, Ian M. ;
Luger, Selina ;
Ciobanu, Niculae ;
Rowe, Jacob M. .
BLOOD, 2008, 111 (04) :1827-1833
[8]   Dose escalation trial designs based on a molecularly targeted endpoint [J].
Hunsberger, S ;
Rubinstein, LV ;
Dancey, J ;
Korn, EL .
STATISTICS IN MEDICINE, 2005, 24 (14) :2171-2181
[9]   Surface antigens analysis reveals significant expression of candidate targets for immunotherapy in adult acute lymphoid leukemia [J].
Piccaluga, Pier Paolo ;
Arpinati, Mario ;
Candoni, Anna ;
Laterza, Claudio ;
Paolini, Stefania ;
Gazzola, Anna ;
Sabattini, Elena ;
Visani, Giuseppe ;
Pileri, Stefano A. .
LEUKEMIA & LYMPHOMA, 2011, 52 (02) :325-327
[10]   Drug therapy - Treatment of acute lymphoblastic leukemia [J].
Pui, CH ;
Evans, WE .
NEW ENGLAND JOURNAL OF MEDICINE, 2006, 354 (02) :166-178