Phase I dose‐escalation study of buparlisib (BKM120), an oral pan‐class I PI3K inhibitor, in Japanese patients with advanced solid tumors

Abstract

Buparlisib (BKM120) is an oral pan-phosphatidylinositol 3-kinase inhibitor, targeting all four isoforms of class I PI3K (α, β, γ and δ). This open-label Phase I dose-escalation study was conducted to determine the maximum tolerated dose of continuous daily buparlisib in Japanese patients with advanced solid tumors. Secondary objectives included safety and tolerability, pharmacokinetics, antitumor activity and pharmacodynamic marker changes. Fifteen patients were treated at 25 mg/day (n = 3), 50 mg/day (n = 3) and 100 mg/day (n = 9) dose levels. One dose-limiting toxicity of Grade 4 abnormal liver function occurred at 100 mg/day. Considering the safety profile and the maximum tolerated dose in the first-in-man study of buparlisib in non-Japanese patients, further dose escalation was stopped and 100 mg/day was declared the recommended dose. The most common treatment-related adverse events were rash, abnormal hepatic function (including increased transaminase levels), increased blood insulin levels and increased eosinophil count. Hyperglycemia was experienced by two patients, one Grade 1 and one Grade 4, and mood alterations were experienced by three patients, two Grade 1 and one Grade 2. Pharmacokinetic results showed that buparlisib was rapidly absorbed in a dose-proportional manner. Best overall response was stable disease for six patients, including one unconfirmed partial response. In these Japanese patients with advanced solid tumors, buparlisib had a manageable safety profile, with similar pharmacokinetics to non-Japanese patients. The recommended dose of 100 mg/day will be used in future studies of buparlisib in Japanese patients.

Neoadjuvant buparlisib plus trastuzumab and paclitaxel for women with HER2+ primary breast cancer: A randomised, double-blind, placebo-controlled phase II trial (NeoPHOEBE)

“…In early phase clinical trials, buparlisib demonstrated promising efficacy and manageable safety profile providing the rationale for further clinical evaluation of buparlisib [21–24]. The Neo adjuvant P I3K inhibition in H ER2 O ver E xpressing B reast canc E r (NeoPHOEBE) trial was designed to evaluate the efficacy and safety of buparlisib plus trastuzumab and paclitaxel as neoadjuvant treatment for patients with untreated HER2+ primary breast cancer and the potential predictive value of PIK3CA mutations for higher tumour responses.…”

A phase 1b dose expansion study of the pan-class I PI3K inhibitor buparlisib (BKM120) plus carboplatin and paclitaxel in PTEN deficient tumors and with dose intensified carboplatin and paclitaxel

“…The phase II randomized study (Neophobia, NCT01816594) testing neoadjuvant Trastuzumab and paclitaxel +/− buparlisib in early-stage breast cancer patients, was stopped prematurely owing to a lack of pCR benefit and higher toxicity in the Buparlisib arm. [13,44] Notably no additional benefit was seen in the PIK3CA mutant subgroup receiving the pan- PI3K inhibitor. In stage IV squamous non-small cell lung cancer patients, both phase Ib/II trials testing the addition of Buparlisib in the first-line setting to 3-weekly carboplatin and paclitaxel (BASALT2; NCT01820325) and in the second-line setting to 3-weekly docetaxel (BASALT-3; NCT01911325), were terminated due to the challenging safety profile and marginal anti-tumor activity observed.…”

“…[9–13] Preclinical data have shown that as a class, PI3K inhibitors can enhance the antitumor activity of cytotoxic chemotherapy and combinatorial strategies with buparlisib are being explored with preliminary signs of clinical activity. [14–17] We previously reported a single-center dose escalation study ( n=30) of daily buparlisib combined with two parallel schedules of carboplatin (AUC 5) and paclitaxel (175 mg/m2 on day 1 with pegfilgrastim support or 80 mg/m2 on day 1, 8, and 15 without pegfilgrastim support) of an every 3 (q3) or q4 week cycle, respectively.…”

Class I phosphatidylinositol 3-kinase inhibitors for cancer therapy

“…Combinational use of BKM120 with cisplatin exhibits enhanced efficacy 57 . A phase I clinical study in Japan showed that BKM120 had a manageable safety profile, and could be rapidly absorbed in a dose-proportional manner 58 . Clinical efficacy and tolerability of BKM120 were also evaluated in postmenopausal women with estrogen receptor–positive metastatic breast cancer, in combination with fulvestrant using daily or intermittent schedules (days 1–5 each week).…”