A phase I study of the pan bcl-2 family inhibitor obatoclax mesylate in patients with advanced hematologic malignancies.
OBJECTIVE
The outcome of patients with refractory leukemia and myelodysplasia is poor, and new therapies are needed. The antiapoptotic proteins of the Bcl-2 family are overexpressed in these malignancies and are potential therapeutic targets. Therefore, we conducted a phase I clinical trial of the small-molecule pan-Bcl-2 inhibitor, obatoclax mesylate, in patients with refractory leukemia and myelodysplasia to assess its safety and define its optimal dose.


METHODS
Forty-four patients with refractory leukemia or myelodysplasia were treated with obatoclax mesylate by continuous intravenous infusion at increasing doses and frequencies.


RESULTS
A total of 306 infusions of obatoclax mesylate were administered with a median of 5 infusions per patient. The study drug was well tolerated up to the highest dose planned without dose-limiting toxicity. Grade 1/2 central nervous system symptoms were the most common adverse events attributable to the study drug. One patient with acute myeloid leukemia with mixed lineage leukemia t(9;11) rearrangement achieved a complete remission, which lasted 8 months. Three of 14 patients with myelodysplasia showed hematologic improvement with RBC or platelet transfusion independence.


CONCLUSIONS
Obatoclax mesylate is well tolerated and these results support its further investigation in patients with leukemia and myelodysplasia.
Schimmer
Aaron D
AD
Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada. aaron.schimmer@utoronto.ca
O'Brien
Susan
S
Kantarjian
Hagop
H
Brandwein
Joseph
J
Cheson
Bruce D
BD
Minden
Mark D
MD
Yee
Karen
K
Ravandi
Farhad
F
Giles
Francis
F
Schuh
Andre
A
Gupta
Vikas
V
Andreeff
Michael
M
Koller
Charles
C
Chang
Hong
H
Kamel-Reid
Suzanne
S
Berger
Mark
M
Viallet
Jean
J
Borthakur
Gautam
G
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006801:Humans; D007211:Indoles; D007938:Leukemia / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
D007211:Indoles; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; C520962:obatoclax