Phase 1 multicenter study of vincristine sulfate liposomes injection and dexamethasone in adults with relapsed or refractory acute lymphoblastic leukemia.
BACKGROUND
Dose intensification of chemotherapy has improved outcome for younger adults with de novo acute lymphoblastic leukemia (ALL). Novel formulations of standard chemotherapy agents may further reduce the incidence of disease recurrence after frontline chemotherapy. Vincristine (VCR) sulfate liposomes injection (VSLI) is a sphingomyelin/cholesterol nanoparticle encapsulated VCR formulation that improves the pharmacokinetic profile of VCR without augmenting neurotoxicity.


METHODS
A phase 1 trial of weekly, intravenous VSLI at 1.5 mg/m(2), 1.825 mg/m(2), 2.0 mg/m(2), 2.25 mg/m(2), or 2.4 mg/m(2) was conducted to determine the maximum tolerated dose (MTD) using a standard, 3 + 3 dose-escalation design. Dexamethasone (40 mg) was given on Days 1 through 4 and on Days 11 through 14 of each 4-week cycle.


RESULTS
Thirty-six adults with relapsed/refractory ALL, all previously treated with conventional VCR, received at least 1 dose of VSLI. The MTD of VSLI was 2.25 mg/m(2) based on dose-limiting toxicities of grade 3 motor neuropathy, grade 4 seizure, and grade 4 hepatotoxicity in 1 patient each at the 2.4 mg/m(2) dose level. The most common toxicities attributed to VSLI included peripheral neuropathy (55%) and constipation (53%). A complete response (CR) was achieved in 7 of 36 patients (19%) based on an intent-to-treat analysis; the CR rate was 29% for the 14 patients who underwent therapy as their first salvage attempt. Four of 7 patients who achieved a CR underwent subsequent allogeneic stem cell transplantation in remission.


CONCLUSIONS
In this study, VSLI plus dexamethasone appeared to be an effective salvage therapy option for relapsed/refractory ALL. A phase 2, international, multicenter clinical trial assessing the efficacy of single-agent VSLI as second salvage therapy for patients with previously treated ALL is underway.
Thomas
Deborah A
DA
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. debthomas@mdanderson.org
Kantarjian
Hagop M
HM
Stock
Wendy
W
Heffner
Leonard T
LT
Faderl
Stefan
S
Garcia-Manero
Guillermo
G
Ferrajoli
Alessandra
A
Wierda
William
W
Pierce
Sherry
S
Lu
Biao
B
Deitcher
Steven R
SR
O'Brien
Susan
S
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003907:Dexamethasone / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008081:Liposomes; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy; D012008:Recurrence; D016879:Salvage Therapy; D014750:Vincristine / Q000008:administration & dosage*
D008081:Liposomes; D014750:Vincristine; D003907:Dexamethasone
Cancer Res. 1990 Feb 1;50(3):575-9
2297698
J Pediatr. 1994 Oct;125(4):642-9
7931891
Cancer Res. 1994 Jun 1;54(11):2830-3
8187061
Cancer Chemother Pharmacol. 1999;44(3):203-9
10453721
J Pharmacol Exp Ther. 2001 Sep;298(3):1206-12
11504822
Blood. 2008 Sep 1;112(5):1646-54
18502832
Br J Cancer. 1995 Mar;71(3):482-8
7880728
Ann Oncol. 2000 Jan;11(1):69-72
10690390
Cancer. 2006 Jan 1;106(1):120-7
16331634
Med Toxicol. 1986 Nov-Dec;1(6):421-7
3540519
Cancer. 1999 Oct 1;86(7):1216-30
10506707
Biochim Biophys Acta. 1993 Nov 7;1152(2):253-8
8218326
N Engl J Med. 1972 Jun 22;286(25):1369-70
5027400
Cancer. 2009 Dec 1;115(23):5490-8
19708032
J Clin Oncol. 1999 Feb;17(2):697-705
10080616
Cancer. 2008 Dec 1;113(11):3186-91
18846563
Int J Cancer. 2004 Jul 10;110(5):767-74
15146568
Cancer Res. 1976 Apr;36(4):1499-502
1260766
Br J Cancer. 1995 Oct;72(4):896-904
7547237
Cancer Res. 1977 Aug;37(8 Pt 1):2603-7
872088
Biochem Biophys Res Commun. 1972 May 26;47(4):685-91
5026289