A dose-escalation study with the novel formulation of the oral pan-class I PI3K inhibitor BEZ235, solid dispersion system (SDS) sachet, in patients with advanced solid tumors.

Peyton, James D.; Ahnert, Jordi Rodón; Burris, H.; Britten, Carolyn D.; Chen, L. C.; Tabernero, Josep; Duval, Vincent; Rouyrre, Nicolas; Silva, A. P.; Quadt, Cornelia; Baselga, José

doi:10.1200/jco.2011.29.15_suppl.3066

Cited by 40 publications

(31 citation statements)

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“…The RP2D of buparlisib in combination with trastuzumab was declared as buparlisib 100 mg/day and trastuzumab 2 mg/kg weekly. The combination of buparlisib and trastuzumab was generally well tolerated, and the safety profile was similar to that reported previously with single-agent buparlisib (23) and with other PI3K inhibitors (28)(29)(30)(31)(32). The pharmacokinetic profiles of buparlisib at both the 50-mg/day and 100-mg/day dose levels when administered in combination with trastuzumab were similar to those reported previously by Bendell and colleagues (23) for single-agent buparlisib.…”

Section: Discussionsupporting

confidence: 59%

Phase Ib Study of Buparlisib plus Trastuzumab in Patients with HER2-Positive Advanced or Metastatic Breast Cancer That Has Progressed on Trastuzumab-Based Therapy

Saura

Bendell

Jérusalem

et al. 2014

Clinical Cancer Research

118

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Purpose: Phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway activation in patients with HER2-positive (HER2 þ ) breast cancer has been implicated in de novo and acquired trastuzumab resistance.The purpose of this study was to determine the clinical activity of the PI3K inhibitor buparlisib (BKM120) in patients with HER2 þ advanced/metastatic breast cancer resistant to trastuzumab-based therapy.Experimental Design: In the dose-escalation portion of this phase I/II study, patients with trastuzumabresistant locally advanced or metastatic HER2 þ breast cancer were treated with daily oral doses of buparlisib and weekly intravenous trastuzumab (2 mg/kg). Dose escalation was guided by a Bayesian logistic regression model with overdose control. Results: Of 18 enrolled patients, 17 received buparlisib. One dose-limiting toxicity of grade 3 general weakness was reported at the 100-mg/day dose level (the single-agent maximum tolerated dose) and this dose level was declared the recommended phase II dose (RP2D) of buparlisib in combination with trastuzumab. Common (>25%) adverse events included rash (39%), hyperglycemia (33%), and diarrhea (28%). The pharmacokinetic profile of buparlisib was not affected by its combination with trastuzumab. At the RP2D, there were two (17%) partial responses, 7 (58%) patients had stable disease (!6 weeks), and the disease control rate was 75%. Pharmacodynamic studies showed inhibition of the PI3K/AKT/mTOR and RAS/MEK/ERK pathways.Conclusions: In this patient population, the combination of buparlisib and trastuzumab was well tolerated, and preliminary signs of clinical activity were observed. The phase II portion of this study will further explore the safety and efficacy of this combination at the RP2D. Clin Cancer Res; 20(7); 1935-45. Ó2014 AACR.

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Section: Discussionsupporting

confidence: 59%

Phase Ib Study of Buparlisib plus Trastuzumab in Patients with HER2-Positive Advanced or Metastatic Breast Cancer That Has Progressed on Trastuzumab-Based Therapy

Saura

Bendell

Jérusalem

et al. 2014

Clinical Cancer Research

118

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“…The plasma concentration in our WT mice was 200 ng/mL in line with the 1,000 ng/mL (peak) and 15 ng/mL (trough) plasma level at a dose of 50 mg/kg as reported by Maira and colleagues (42). Notably, this appears to be considerably lower than the 1,800 ng/mL found in patients as has been presented in a meeting report (43). No other (full) reports on the plasma pharmacokinetics of NVP-BEZ235 have been published, but apparently patients tolerate higher plasma levels than mice, and the efficacy of NVP-BEZ235 will likely be better at higher doses.…”

Section: Discussionmentioning

confidence: 45%

PI3K–mTOR Pathway Inhibition Exhibits Efficacy Against High-grade Glioma in Clinically Relevant Mouse Models

Lin

Gooijer

Hanekamp

et al. 2017

Clinical Cancer Research

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Purpose: The PI3K-AKT-mTOR signaling pathway is frequently activated in glioblastoma and offers several druggable targets. However, clinical efficacy of PI3K/mTOR inhibitors in glioblastoma has not yet been demonstrated. Insufficient drug delivery may limit the efficacy of PI3K/mTOR inhibitors against glioblastoma. The presence of the efflux transporters ABCB1/Abcb1 (P-glycoprotein, MDR1) and ABCG2/Abcg2 (BCRP) at the blood-brain barrier (BBB) restricts the brain penetration of many drugs.Experimental Design: We used in vitro drug transport assays and performed pharmacokinetic/pharmacodynamic studies in wild-type and ABC-transporter knockout mice. The efficacy of PI3K-mTOR inhibition was established using orthotopic allograft and genetically engineered spontaneous glioblastoma mouse models.Results: The mTOR inhibitors rapamycin and AZD8055 are substrates of ABCB1, whereas the dual PI3K/mTOR inhibitor NVP-BEZ235 and the PI3K inhibitor ZSTK474 are not. Moreover, ABCG2 transports NVP-BEZ235 and AZD8055, but not ZSTK474 or rapamycin. Concordantly, Abcb1a/bÀ/À mice revealed increased brain penetration of rapamycin (13-fold), AZD8055 (7.7-fold), and NVP-BEZ235 (4.5-fold), but not ZSTK474 relative to WT mice. Importantly, ABC transporters limited rapamycin brain penetration to subtherapeutic levels, while the reduction in NVP-BEZ235 brain penetration did not prevent target inhibition.

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“…Nausea, diarrhea, and vomiting are the only common toxicities, and the doselimiting toxicities are fatigue and thrombocytopenia. [99] …”

Section: Pi3k Inhibitorsmentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

et al. 2012

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The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin's lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen.Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual-and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignanc...

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A dose-escalation study with the novel formulation of the oral pan-class I PI3K inhibitor BEZ235, solid dispersion system (SDS) sachet, in patients with advanced solid tumors.

Cited by 40 publications

References 0 publications

Phase Ib Study of Buparlisib plus Trastuzumab in Patients with HER2-Positive Advanced or Metastatic Breast Cancer That Has Progressed on Trastuzumab-Based Therapy

Phase Ib Study of Buparlisib plus Trastuzumab in Patients with HER2-Positive Advanced or Metastatic Breast Cancer That Has Progressed on Trastuzumab-Based Therapy

PI3K–mTOR Pathway Inhibition Exhibits Efficacy Against High-grade Glioma in Clinically Relevant Mouse Models

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

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