Abstract B159: Phase I dose-escalation study of BKM120, an oral pan-class I PI3K inhibitor, in Japanese patients with advanced solid tumors.
Authors: Doi Toshihiko , Ando Yuichi , Bando Hideaki , Yoshino Takayuki , Inada Megumi , Mitsuma Ayako , Quadt Cornelia , Robson Matthew , Ohtsu Atsushi 
Published: June 2012

Abstract
Background: Signaling via the phosphatidylinositol 3-kinase (PI3K) pathway is critical to cancer cell growth, survival, and metabolism. BKM120 is a potent and highly specific oral pan-class I (α, β, γ, δ) PI3K inhibitor that has demonstrated clinical anti-tumor effects in a broad range of cancer types.
Patients and methods: This was a phase I, open-label, dose-escalation study of single-agent BKM120 in Japanese patients with advanced solid tumors. Patients received 28-day cycles of continuous BKM120 once daily until disease progression, unacceptable toxicity, investigator's decision or patient's refusal. Eligible patients had histologically-confirmed, advanced unresectable solid tumors and had progressed on standard therapy, were unable to tolerate standard therapy, or had disease for which no standard therapy exists. Dose escalation, determined by agreement of investigators and the sponsor, was guided by an adaptive Bayesian logistic regression model with overdose control.
Results: A total of 15 patients (median age 58 [range 22 to 71] yrs) received BKM120 once daily: 25 mg (n = 3), 50 mg (n = 3), and 100 mg (n = 9). The most common primary tumor sites were the salivary gland, rectum (n = 3 each), colon, and head & neck (n = 2 each). Patients were heavily pretreated (median 3 prior regimens [range 0–9]). One patient experienced a DLT (CTCAE grade 4 abnormal hepatic function at 100 mg BKM120 during cycle 1). Across all doses, the most common (≥ 4 patients) all-cause adverse events (AEs) were increased eosinophil count/eosinophilia, rash, increased blood insulin, constipation, decreased appetite, fatigue, increased alanine aminotransferase, anemia, increased insulin C-peptide, mood altered/psychiatric symptom, and pruritus. The most common (≥ 2 patients) non-dose limiting grade 3/4 AEs (all cause) were abnormal hepatic function (n = 5, including increased transaminase in 2 patients), and anemia (n = 2). Five patients experienced serious AEs (all cause): abnormal hepatic function (n = 3), pneumonitis, dyspnea, hyperglycemia, pneumonia, and delirium (n = 1 each). A patient with pneumonitis died 11 days after study drug discontinuation (100 mg cohort). There were 4 AE-associated discontinuations: 2 for increased transaminases (discontinuation on days 47 and 78 of treatment; 25 mg BKM120), 1 abnormal hepatic function (on day 30) and 1 increased lipase (on day 56; both 100 mg BKM120). Preliminary pharmacokinetic (PK) data showed rapid absorption, with Cmax occurring 1–3 hours post-dose. BKM120 accumulated ∼3-fold in achieving steady state. Doses ≥ 50 mg led to steady-state drug exposure (AUC0–24,ss) ≥ 10,000 ng*h/mL, a target preclinically estimated to be efficacious. Both Cmax and AUC increased dose proportionally between 25 and 100 mg. Five patients had stable disease (RECIST criteria) as the best response (8–24 weeks' duration). Based on the overall safety profile of BKM120, dose escalation over 100 mg was not pursued, and the recommended dose was declared as 100 mg once daily.
Conclusions: BKM120 administered orally once daily up to 100 mg was well tolerated. PK parameters were comparable with those of Western patients. Continuous BKM120 100 mg once daily was recommended in Japanese patients and will be taken forward in the clinical development program.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B159.