Buparlisib, a PI3K inhibitor, demonstrates acceptable tolerability and preliminary activity in a phase I trial of patients with advanced leukemias.
Phosphatidylinositol-3-kinase (PI3K) signaling plays a crucial role in oncogene-mediated tumor growth and proliferation. Buparlisib (BKM120) is an oral pan-class I PI3K inhibitor. This phase I study was conducted to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of BKM120 in patients (pts) with relapsed/refractory acute leukemias. Fourteen pts (12 acute myeloid leukemia, 1 acute lymphoblastic leukemia, and 1 mixed phenotype leukemia) were enrolled. Twelve pts received BKM-120 80 mg/day and two 100 mg/day. The MTD was 80 mg/day. Of the 14 patients treated, the best response was stable disease in one patient that lasted 82 days. The median survival for all patients was 75 days (range 10-568). Three patients with a 3q26 chromosome abnormality had a significantly improved median survival of 360 days (range 278-568) as compared to a median survival of 57 days (range, 10-125) among the 11 other patients. The most frequent drug-related toxicities included confusion, mucositis, dysphagia, and fatigue. Western blot profiling revealed a decrease in p-pS6K/total pS6K in 5/7 (71%) available patient samples with a mean quantitative inhibition of 65% (range, 32-100%) and a decrease in p-FOXO3/total FOXO3 in 4/6 (67%) samples with a mean quantitative inhibition of 93% (range, 89-100%). BKM120 administered at 80 mg/day showed modest efficacy and was tolerable in advanced acute leukemias. Am. J. Hematol. 92:7-11, 2017. © 2016 Wiley Periodicals, Inc.
Hematology/Oncology Fellowship, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Brittany Knick
BK
Ragon
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Hagop
H
Kantarjian
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Elias
E
Jabbour
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Farhad
F
Ravandi
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jorge
J
Cortes
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Gautam
G
Borthakur
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
LaKiesha
L
DeBose
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Zhihong
Z
Zeng
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Heather
H
Schneider
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Naveen
N
Pemmaraju
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Guillermo
G
Garcia-Manero
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Steven
S
Kornblau
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
William
W
Wierda
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jan
J
Burger
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Courtney D
CD
DiNardo
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Michael
M
Andreeff
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Marina
M
Konopleva
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Naval
N
Daver
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000631:Aminopyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D018572:Disease-Free Survival; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality
D000631:Aminopyridines; D000970:Antineoplastic Agents; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C571178:NVP-BKM120
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