Phase II study of obatoclax mesylate (GX15-070), a small-molecule BCL-2 family antagonist, for patients with myelofibrosis.
BACKGROUND
Myelofibrosis (MF) is a disease characterized by the overexpression of the antiapoptotic BCL-2 family of proteins (eg, BCL-XL and MCL-1).


METHODS
We conducted a multicenter, open-label, noncomparative phase II study of obatoclax mesylate, a small-molecule pan-BCL-2 antagonist, in patients with MF. Obatoclax was administered as a 24-hour infusion (on an outpatient basis) every 2 weeks at a fixed dose of 60 mg.


RESULTS
A total of 22 patients were enrolled, with a median age of 63 years (range, 43-89 years). Twelve were men, and all 22 patients were previously treated (median of 2 previous therapies). Ten patients (45%) had a Lille score of 1, and 9 patients (41%) had a Lille score of 2. Thirteen (59%) were red blood cell transfusion dependent. A median of 7 cycles of obatoclax were administered. No patient achieved complete or partial response according to International Working Group criteria. One patient (4%) demonstrated a clinical improvement (in terms of hemoglobin and platelet count) after 7 cycles of therapy. The improvement was sustained for 4 cycles of therapy, after which he underwent allogeneic stem cell transplantation. The most common adverse events included low-grade ataxia and fatigue in 50% of the patients. Dose reduction because of toxicity was required in 1 patient, whereas 2 patients were taken off the study because of grade 3 ataxia and grade 3 heart failure. Grade 3/4 anemia and thrombocytopenia were evident in 6 (27%) and 4 (18%) patients, respectively.


CONCLUSIONS
Obatoclax exhibits no significant clinical activity in patients with MF at the dose and schedule evaluated.
Parikh
Sameer A
SA
Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Kantarjian
Hagop
H
Schimmer
Aaron
A
Walsh
William
W
Asatiani
Ekatherine
E
El-Shami
Khaled
K
Winton
Elliott
E
Verstovsek
Srdan
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D007211:Indoles; D008297:Male; D008875:Middle Aged; D055728:Primary Myelofibrosis / Q000188:drug therapy* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage* / Q000009:adverse effects
D000970:Antineoplastic Agents; D007211:Indoles; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; C520962:obatoclax