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Buparlisib is a brain penetrable pan-PI3K inhibitor.

ABSTRACT: Characterization of the genomic landscapes of intracranial tumours has revealed a clear role for the PI3K-AKT-mTOR pathway in tumorigenesis and tumour maintenance of these malignancies, making phosphatidylinositol 3-kinase (PI3K) inhibition a promising therapeutic strategy for these tumours. Buparlisib is a novel pan-PI3K inhibitor that is currently in clinical development for various cancers, including primary and secondary brain tumours. Importantly however, earlier studies have revealed that sufficient brain penetration is a prerequisite for antitumor efficacy against intracranial tumours. We therefore investigated the brain penetration of buparlisib using a comprehensive set of in vitro and in vivo mouse models. We demonstrate that buparlisib has an excellent brain penetration that is unaffected by efflux transporters at the blood-brain barrier, complete oral bioavailability and efficient intracranial target inhibition at clinically achievable plasma concentrations. Together, these characteristics make buparlisib the ideal candidate for intracranially-targeted therapeutic strategies that involve PI3K inhibition.

SUBMITTER: de Gooijer MC

PROVIDER: S-EPMC6050274 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Buparlisib is a brain penetrable pan-PI3K inhibitor.

de Gooijer Mark C MC Zhang Ping P Buil Levi C M LCM Çitirikkaya Ceren H CH Thota Nishita N Beijnen Jos H JH van Tellingen Olaf O

Scientific reports 20180717 1

Characterization of the genomic landscapes of intracranial tumours has revealed a clear role for the PI3K-AKT-mTOR pathway in tumorigenesis and tumour maintenance of these malignancies, making phosphatidylinositol 3-kinase (PI3K) inhibition a promising therapeutic strategy for these tumours. Buparlisib is a novel pan-PI3K inhibitor that is currently in clinical development for various cancers, including primary and secondary brain tumours. Importantly however, earlier studies have revealed that ...[more]

PMID: 30018387

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Project description:BACKGROUND:Treatment options for triple-negative breast cancer remain limited. Activation of the PI3K pathway via loss of PTEN and/or INPP4B is common. Buparlisib is an orally bioavailable, pan-class I PI3K inhibitor. We evaluated the safety and efficacy of buparlisib in patients with metastatic triple-negative breast cancer. METHODS:This was a single-arm phase 2 study enrolling patients with triple-negative metastatic breast cancer. Patients were treated with buparlisib at a starting dose of 100?mg daily. The primary endpoint was clinical benefit, defined as confirmed complete response (CR), partial response (PR), or stable disease (SD) for ??4?months, per RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. A subset of patients underwent pre- and on-treatment tumor tissue biopsies for correlative studies. RESULTS:Fifty patients were enrolled. Median number of cycles was 2 (range 1-10). The clinical benefit rate was 12% (6 patients, all SD ??4?months). Median PFS was 1.8?months (95% confidence interval [CI] 1.6-2.3). Median OS was 11.2?months (95% CI 6.2-25). The most frequent adverse events were fatigue (58% all grades, 8% grade 3), nausea (34% all grades, none grade 3), hyperglycemia (34% all grades, 4% grade 3), and anorexia (30% all grades, 2% grade 3). Eighteen percent of patients experienced depression (12% grade 1, 6% grade 2) and anxiety (10% grade 1, 8% grade 2). Alterations in PIK3CA/AKT1/PTEN were present in 6/27 patients with available targeted DNA sequencing (MSK-IMPACT), 3 of whom achieved SD as best overall response though none with clinical benefit ??4?months. Of five patients with paired baseline and on-treatment biopsies, reverse phase protein arrays (RPPA) analysis demonstrated reduction of S6 phosphorylation in 2 of 3 patients who achieved SD, and in none of the patients with progressive disease. CONCLUSIONS:Buparlisib was associated with prolonged SD in a very small subset of patients with triple-negative breast cancer; however, no confirmed objective responses were observed. Downmodulation of key nodes in the PI3K pathway was observed in patients who achieved SD. PI3K pathway inhibition alone may be insufficient as a therapeutic strategy for triple-negative breast cancer. TRIAL REGISTRATION:NCT01790932 . Registered on 13 February 2013; NCT01629615 . Registered on 27 June 2012.

Project description:Purpose We previously reported the phase I dose escalation study of buparlisib, a pan-class 1A PI3K inhibitor, combined with platinum/taxane-based chemotherapy in patients with advanced solid tumors. The combination was well tolerated and promising preliminary efficacy was observed in PTEN deficient tumors. This phase I dose expansion study now evaluates buparlisib plus high dose carboplatin and paclitaxel in unselected patients with advanced solid tumors and buparlisib plus standard dose carboplatin and paclitaxel in patients with PTEN deficient tumors (ClinicalTrials.gov, NCT01297452). Methods There were two expansion cohorts: Cohort A received continuous buparlisib (100 mg/daily) orally plus high dose carboplatin AUC 6 and paclitaxel 200 mg/m2; Cohort B treated patients with PTEN deficient tumors only and they received the recommended phase II dose (RP2D) of continuous buparlisib (100 mg/daily) orally plus standard dose carboplatin AUC 5 and paclitaxel 175 mg/m2. Both cohorts received chemotherapy intravenously on day 1 of the 21-day cycle with pegfilgrastim support. Primary endpoint in Cohort A was to evaluate the safety and tolerability of chemotherapy dose intensification with buparlisib and in Cohort B was to describe preliminary efficacy of the combination among patients with tumors harboring a PTEN mutation or homozygous deletion. Results 14 subjects were enrolled, 7 in Cohort A and 7 in Cohort B. Dose reductions were required in 5 (71%) and 3 (43%) patients, in cohort A and B respectively. Grade 3 adverse events in Cohort A included lymphopenia (n = 5 [71%]), hyperglycemia (n = 2, [29%]), diarrhea (n = 2, [29%]) and rash (n = 2, [29%]) and in cohort B included lymphopenia (n = 5 [71%]), hyperglycemia (n = 4 [57%]) and neutropenia (n = 2 [29%]. The mean number of cycles on protocol was 6. The overall objective response rate was 14% (2 /14). No objective responses were observed in the PTEN deficient cohort. Four out of 6 patients with stable disease (SD) had SD or better for ≥6 cycles, 2 of which had PTEN deficient tumors. Conclusion The addition of buparlisib to high dose carboplatin and paclitaxel was not tolerable. The combination did not reveal significant clinical activity amongst a small and heterogenous group of PTEN deficient tumors.

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Buparlisib is a brain penetrable pan-PI3K inhibitor.

Publications

Buparlisib is a brain penetrable pan-PI3K inhibitor.

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