Buparlisib, a PI3K Inhibitor, Demonstrates Acceptable Tolerability and Preliminary Activity in a Phase I Trial of Patients with Advanced Leukemias.

Buparlisib, a PI3K Inhibitor, Demonstrates Acceptable Tolerability and Preliminary Activity in a Phase I Trial of Patients with Advanced Leukemias.

Am J Hematol. 2016 Sep 27;

Authors: Ragon BK, Kantarjian H, Jabbour E, Ravandi F, Cortes J, Borthakur G, DeBose L, Zeng Z, Schneider H, Pemmaraju N, Garcia-Manero G, Kornblau S, Wierda W, Burger J, DiNardo CD, Andreeff M, Konopleva M, Daver N

Abstract
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, 1 mixed phenotype leukemia) were enrolled. Twelve pts received BKM-120 80 mg/day and two 100 mg/day. The MTD was 80mg/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. This article is protected by copyright. All rights reserved.

PMID: 27673440 [PubMed - as supplied by publisher]

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