Buparlisib, a PI3K inhibitor, demonstrates acceptable tolerability and preliminary activity in a phase I trial of patients with advanced leukemias

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, 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.

The PI3K Pathway in Human Disease

“…Mucositis is also one of the main dose-limiting toxicities of the TORKi compounds (Table S1) AZD2014 (Basu et al, 2015) and CC-223 (Bendell et al, 2015a), and occurred frequently in a phase I trial of TAK-228 (Ghobrial et al, 2016). Mucositis was reported in phase I studies of pan-PI3K inhibitor buparlisib (BKM120) (Bendell et al, 2012; Ragon et al, 2017) and the dual PI3K/mTOR inhibitor BEZ235 (Bendell et al, 2015b; Carlo et al, 2016). The p110δ inhibitor idelalisib is associated with autoimmune colitis as discussed below, but also with lung and liver inflammation (Coutré et al, 2015) that might arise from increased innate immune stimulation.…”

Targeting PI3K in cancer: mechanisms and advances in clinical trials

“…Phase I studies of buparlisib in Japanese and Chinese patients with advanced solid tumors also established a recommended dose of 100 mg daily [107,108]. The MTD was 80 mg/d in a phase I study of buparlisib in patients with advanced acute leukemias [109]. A phase I trial in patients with advanced solid tumors suggested that the MTD of buparlisib in combination with standard doses of mFOLFOX6 (every 2 weeks of a 28-day cycle) was 40 mg daily; increased toxicity was observed compared to that expected from either buparlisib or mFOLFOX6 alone [110].…”

The Physiopathology of T- Cell Acute Lymphoblastic Leukemia: Focus on Molecular Aspects

“…BEZ235 had antiproliferative and proapoptotic effect in T-ALL cell lines (97), and a clinical trial has been started (NCT01756118). BKM120/Buparlisib showed modest efficacy and was tolerable in advanced acute leukemia (only 1 patient with T-ALL) in a recent clinical trial (98). As regards cytokine signaling, JAK-STAT pathway is activated in T-ALL and about 5% of cases are driven by tyrosine kinase oncogene fusions, particularly the NUP214-ABL1 rearrangement (86).…”