A phase II study of the combination of BKM120 (buparlisib) and bevacizumab in patients with relapsed/refractory glioblastoma multiforme (GBM).

Shih, Kent C.; Chowdhary, Sajeel; Becker, Kevin; Baehring, Joachim M.; Liggett, William H.; Burris, Howard A.; Hainsworth, John D.

doi:10.1200/jco.2015.33.15_suppl.2065

Cited by 9 publications

(7 citation statements)

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“…The observed AE profile was similar to that noted in previous studies of buparlisib, including fatigue and hyperglycemia (a known on‐target effect of PI3K pathway inhibition) 19,35 . Buparlisib penetrates the blood‐brain barrier, a characteristic that has been viewed as advantageous for the treatment of glioblastoma multiforme, 36,37 but as a consequence, this drug can cause neuropsychiatric toxicities: 2 mood‐related dose‐limiting toxicities and an overall 37% rate of treatment‐related mood disorders were observed in what to our knowledge is the first‐in‐human buparlisib study, all of which were reversible with discontinuation of the drug 19 . It is interesting to note that the rate of depression observed in this study was lower than that noted in previous trials 19,35 …”

Section: Discussionsupporting

confidence: 82%

A phase 2 trial of buparlisib in patients with platinum‐resistant metastatic urothelial carcinoma

McPherson

Reardon

Bhayankara

et al. 2020

Cancer

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BACKGROUND: The phosphatidyl 3-inositol kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway frequently is activated in patients with urothelial carcinoma (UC). In the current study, the authors performed a phase 2 study evaluating the efficacy of the panisoform class I PI3K inhibitor buparlisib in patients with platinum-refractory metastatic UC. METHODS: Two cohorts were recruited: an initial genetically unselected cohort and a subsequent expansion cohort of patients with PI3K/Akt/mTOR pathway-altered tumors. The primary endpoint was the 2-month progression-free survival rate. A rate of ≥80% was considered promising using a Simon 2-stage minimax design. Secondary endpoints included safety and correlation of markers of PI3K pathway activation with outcome. RESULTS: Six of 13 evaluable patients within the initial cohort demonstrated stable disease and 1 demonstrated a partial response, which was below the cutoff of 9 patients required to proceed to stage 2. Three of the patients with stable disease and the patient with a partial response harbored somatic TSC1 alterations. Four patients subsequently were recruited onto an expansion cohort: 3 patients with TSC1 alterations and 1 patient with a PIK3CA-activating mutation. No patient achieved disease control at 8 weeks and accrual was halted. Of the 19 patients evaluable for toxicity, 17 demonstrated treatment-related toxicities, 2 of whom had to discontinue therapy. CONCLUSIONS: Buparlisib was found to demonstrate modest activity in patients with metastatic UC whose tumors harbored TSC1 loss of function alterations; however, this was not a robust predictor of response to buparlisib. The pattern of genetic coalterations likely influences drug sensitivity. Given the modest clinical activity and substantial toxicity of buparlisib, future trials of PI3K inhibitors in patients with UC should focus on isoform-selective PI3K inhibitors in genomically selected patients. Cancer 2020;126:4532-4544.

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Section: Discussionsupporting

confidence: 82%

A phase 2 trial of buparlisib in patients with platinum‐resistant metastatic urothelial carcinoma

McPherson

Reardon

Bhayankara

et al. 2020

Cancer

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“…Median progression-free survival (PFS) and overall survival (OS) were 5.3 and 10.8 months, respectively. Overall response ratio (RR) was 32.3% (22 of 68), including 2 complete remission (CR) and 20 partial remission (PR) (NCT01349660) [ 41 , 42 ]. There are 4 ongoing or completed clinical trials of BKM120 combined with other drugs in patients with newly diagnosed or recurrent GBM.…”

Section: Introductionmentioning

confidence: 99%

Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development

et al. 2017

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Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary tumor in the central nervous system. One of the most widely used chemotherapeutic drugs for GBM is temozolomide, which is a DNA-alkylating agent and its efficacy is dependent on MGMT methylation status. Little progress in improving the prognosis of GBM patients has been made in the past ten years, urging the development of more effective molecular targeted therapies. Hyper-activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is frequently found in a variety of cancers including GBM, and it plays a central role in the regulation of tumor cell survival, growth, motility, angiogenesis and metabolism. Numerous PI3K inhibitors including pan-PI3K, isoform-selective and dual PI3K/mammalian target of rapamycin (mTOR) inhibitors have exhibited favorable preclinical results and entered clinical trials in a range of hematologic malignancies and solid tumors. Furthermore, combination of inhibitors targeting PI3K and other related pathways may exert synergism on suppressing tumor growth and improving patients’ prognosis. Currently, only a handful of PI3K inhibitors are in phase I/II clinical trials for GBM treatment. In this review, we focus on the importance of PI3K/Akt pathway in GBM, and summarize the current development of PI3K inhibitors alone or in combination with other inhibitors for GBM treatment from preclinical to clinical studies.

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“…The preliminary results from two early phase trials of buparlisib in patients with relapsed/refractory GBM have been recently reported. Shih and colleagues found that buparlisib at 60 mg/day in combination with standard dose of bevacizumab was well tolerated [105]. Wen et al showed that single-agent buparlisib at 100 mg/day is generally safe in patients with recurrent GBM.…”

Section: Introductionmentioning

confidence: 99%

Phosphatidylinositol 3-kinase (PI3K) inhibitors as cancer therapeutics

et al. 2013

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Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that regulate diverse cellular processes including proliferation, adhesion, survival, and motility. Dysregulated PI3K pathway signaling occurs in one-third of human tumors. Aberrantly activated PI3K signaling also confers sensitivity and resistance to conventional therapies. PI3K has been recognized as an attractive molecular target for novel anti-cancer molecules. In the last few years, several classes of potent and selective small molecule PI3K inhibitors have been developed, and at least fifteen compounds have progressed into clinical trials as new anticancer drugs. Among these, idelalisib has advanced to phase III trials in patients with advanced indolent non-Hodgkin’s lymphoma and mantle cell lymphoma. In this review, we summarized the major molecules of PI3K signaling pathway, and discussed the preclinical models and clinical trials of potent small-molecule PI3K inhibitors.

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A phase II study of the combination of BKM120 (buparlisib) and bevacizumab in patients with relapsed/refractory glioblastoma multiforme (GBM).

Cited by 9 publications

References 0 publications

A phase 2 trial of buparlisib in patients with platinum‐resistant metastatic urothelial carcinoma

A phase 2 trial of buparlisib in patients with platinum‐resistant metastatic urothelial carcinoma

Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development

Phosphatidylinositol 3-kinase (PI3K) inhibitors as cancer therapeutics

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