Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial

Abstract

PURPOSE Phosphatidylinositol 3-kinase (PI3K) signaling is highly active in glioblastomas. We assessed pharmacokinetics, pharmacodynamics, and efficacy of the pan-PI3K inhibitor buparlisib in patients with recurrent glioblastoma with PI3K pathway activation. METHODS This study was a multicenter, open-label, multi-arm, phase II trial in patients with PI3K pathway–activated glioblastoma at first or second recurrence. In cohort 1, patients scheduled for re-operation after progression received buparlisib for 7 to 13 days before surgery to evaluate brain penetration and modulation of the PI3K pathway in resected tumor tissue. In cohort 2, patients not eligible for re-operation received buparlisib until progression or unacceptable toxicity. Once daily oral buparlisib 100 mg was administered on a continuous 28-day schedule. Primary end points were PI3K pathway inhibition in tumor tissue and buparlisib pharmacokinetics in cohort 1 and 6-month progression-free survival (PFS6) in cohort 2. RESULTS Sixty-five patients were treated (cohort 1, n = 15; cohort 2, n = 50). In cohort 1, reduction of phosphorylated AKTS473 immunohistochemistry score was achieved in six (42.8%) of 14 patients, but effects on phosphoribosomal protein S6S235/236 and proliferation were not significant. Tumor-to-plasma drug level was 1.0. In cohort 2, four (8%) of 50 patients reached 6-month PFS6, and the median PFS was 1.7 months (95% CI, 1.4 to 1.8 months). The most common grade 3 or greater adverse events related to treatment were lipase elevation (n = 7 [10.8%]), fatigue (n = 4 [6.2%]), hyperglycemia (n = 3 [4.6%]), and elevated ALT (n = 3 [4.6%]). CONCLUSION Buparlisib had minimal single-agent efficacy in patients with PI3K-activated recurrent glioblastoma. Although buparlisib achieved significant brain penetration, the lack of clinical efficacy was explained by incomplete blockade of the PI3K pathway in tumor tissue. Integrative results suggest that additional study of PI3K inhibitors that achieve more-complete pathway inhibition may still be warranted.

Pre- and Postoperative Neratinib for HER2-Positive Breast Cancer Brain Metastases: Translational Breast Cancer Research Consortium 022

“…8 Heme was imaged as a marker of vasculature using matrix assisted laser desorption ionization (MALDI) mass spectrometry imaging (MSI) using a 9.4 Tesla Fourier transform ion cyclotron resonance (FT ICR) mass spectrometer. [9][10][11] More specifically, tissue sections were analyzed by LESA (Advion, Ithaca, NY) coupled to an amaZon Speed ion trap mass spectrometer (Bruker Daltonics, Billerica, MA). Sampling locations were selected with spacing of 1 mm in x and y dimensions to ensure there was no overlap between points.…”

Phase II trial of ponatinib in patients with bevacizumab‐refractory glioblastoma

“…Tumor genotyping was performed as part of routine clinical care in the CLIA‐certified facilities at Dana‐Farber Cancer Institute and/or Massachusetts General Hospital using methods as previously described …”

Buparlisib plus carboplatin or lomustine in patients with recurrent glioblastoma: a phase Ib/II, open-label, multicentre, randomised study

“…20 Buparlisib has also shown preclinical efficacy in various PI3K pathway-hyperactivated cancer models, including GBM. [21][22][23][24] Here, we report the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of buparlisib in combination with carboplatin or lomustine and the safety and preliminary antitumour activity of these combinations in patients with rGBM.…”