Phase 1 study of XL119, a rebeccamycin analog, in patients with refractory hematologic malignancies.
BACKGROUND
XL119 is a water-soluble derivative of rebeccamycin with dose-dependent myelosuppression as dose-limiting toxicity in phase 1 studies of solid tumors. A phase 1 study was conducted to determine the maximum tolerated dose and toxicities of XL119 in patients with advanced myelodysplastic syndrome and relapsed or refractory acute leukemias.


METHODS
Thirty-one patients were treated at 7 dose levels ranging from 140 to 260 mg/m(2)/daily times 5 in a 21-day cycle. Consenting patients had correlative biologic parameters studied.


RESULTS
Dose-limiting toxicity was grade 3/4 mucositis. The recommended phase 2 dose in hematologic malignancies is 240 mg/m(2)/daily times 5 in a 21-day cycle. Clinically significant reduction in bone marrow blasts were seen in 5 patients and additional patients had reductions in peripheral blood blasts. However, the responses were transient. Changes of plasma vascular endothelial growth factor levels from Day 1 to Day 7 correlated negatively with changes in peripheral blood blasts from Day 1 to Day 7.


CONCLUSIONS
Further assessment of XL119 in combination with other agents in patients with acute leukemias and high-risk myelodysplastic syndrome is warranted.
Borthakur
Gautam
G
Department of Leukemia, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030, USA. gborthak@mdanderson.org
Alvarado
Yesid
Y
Ravandi-Kashani
Farhad
F
Cortes
Jorge
J
Estrov
Zeev
Z
Faderl
Stefan
S
Ivy
Percy
P
Bueso-Ramos
Carlos
C
Nebiyou Bekele
B
B
Giles
Francis
F
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001424:Bacterial Infections / Q000150:complications; D001706:Biopsy; D001853:Bone Marrow / Q000187:drug effects; D002227:Carbazoles / Q000009:adverse effects / Q000737:chemistry* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005960:Glucosides / Q000009:adverse effects / Q000627:therapeutic use*; D019337:Hematologic Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D006801:Humans; D008297:Male; D008875:Middle Aged; D014777:Virus Diseases / Q000150:complications
D002227:Carbazoles; D005960:Glucosides; C053339:rebeccamycin; C093269:becatecarin