Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors

Rodón, Jordi; Braña, Irene; Siu, Lillian L.; Jonge, Maja J. De; Homji, Natasha F; Mills, David; Tomaso, Emmanuelle di; Sarr, Céline; Trandafir, L.; Massacesi, Cristian; Eskens, Ferry A.L.M.; Bendell, Johanna C.

doi:10.1007/s10637-014-0082-9

Cited by 170 publications

(157 citation statements)

References 43 publications

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“…Similar to previous reports of dose-dependent inhibition of pS6 in the skin with singleagent buparlisib (45), the most prominent inhibition of pS6 was seen at the highest dose of buparlisib. Furthermore, of the skin biopsies analyzed, the greatest reduction in pS6 was associated with the best clinical response, and thus further investigation into the use of pS6 levels in skin as a surrogate biomarker for response is warranted.…”

Section: Discussionsupporting

confidence: 90%

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

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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: 90%

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

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118

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“…Evidence suggests that PI3K-selective targeting can potentially suppress this pathway. In this regard, several types of PI3K inhibitors are currently being investigated (7), including, NVP-BKM120, which is reported to be effective against several types of malignancies in cell- (4,(8)(9)(10)) and laboratory animal-based studies (11).…”

Section: Introductionmentioning

confidence: 99%

Effects of NVP‑BEZ235, a dual phosphatidylinositolï¿½3-kinase/mammalian target of rapamycin inhibitor, on HTLV-1-infected T-cell lines

2018

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Abstract. Adult T-cell leukemia (ATL) is an aggressive type of malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). In ATL, the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is constitutively active, promoting cell proliferation, survival and chemoresistance. Thus, the PI3K signaling pathway is an attractive therapeutic target for ATL. In the present study, the effects of RAD001 (an mTOR inhibitor), NVP-BKM120 (a pan-PI3K inhibitor) and NVP-BEZ235 (a novel dual PI3K/mTOR inhibitor) on cultured HTLV-1-infected T-cell lines were compared. The results demonstrated that NVP-BEZ235 was more efficacious compared with RAD001 and NVP-BKM120 at inhibiting cell growth. NVP-BEZ235 exhibited cytostatic rather than cytotoxic effects on various HTLV-1-infected T-cell lines, where it induced cell cycle arrest at G 1 phase. NVP-BEZ235 downregulated cyclin D1, cyclin D2, cyclin E, cyclin dependent kinase (CDK)2 and CDK4 expression, and the phosphorylation of retinoblastoma protein. In C.B-17/Icr-severe combined immune deficiency mice implanted with HTLV-1-infected HUT-102 cells, oral NVP-BEZ235 caused marked retardation of tumor growth compared with the control. The present in vitro and in vivo studies highlight the efficacious dual inhibition of PI3K, and mTOR following NVP-BEZ235 treatment. Thus, the results of the current study provide preclinical rationale for phase I clinical studies to examine the effects of NVP-BEZ235 in patients with ATL.

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“…Furthermore, BKM120 induced partial metabolic responses by fluorodeoxyglucose positron emission tomography ( 18 F-FDG PET) in 21 of 54 evaluable patients after 28 days of treatment, demonstrating the capability of 18 F-FDG PET as a PD biomarker; however, no association with progression-free survival, best response as per Response Evaluation Criteria in Solid Tumors (RECIST), or best percent change in CT scan was identified. 42 Dose-dependent inhibition of phosphorylation of S6 in the skin with singleagent BKM120 has been reported. 41,42,50 Indeed, the greatest reduction in phosphorylated S6 was associated with the best clinical response, highlighting phosphorylated S6 levels in the skin as a potentially useful surrogate biomarker of response to PI3K inhibition.…”

Section: Xl765 (Sanofi) Voxtalisibmentioning

confidence: 99%

“…42 Dose-dependent inhibition of phosphorylation of S6 in the skin with singleagent BKM120 has been reported. 41,42,50 Indeed, the greatest reduction in phosphorylated S6 was associated with the best clinical response, highlighting phosphorylated S6 levels in the skin as a potentially useful surrogate biomarker of response to PI3K inhibition. 50 In the phase I study of pictilisib, in addition to the decreases in AKT phosphorylation in platelet-rich plasma (PRP) and tumor, and the reduction in S6 phosphorylation observed in tumor (described earlier) following pictilisib treatment, other PD biomarkers also demonstrated evidence of target modulation.…”

Section: Xl765 (Sanofi) Voxtalisibmentioning

confidence: 99%

“…Of the pan-class I PI3K inhibitors in clinical development, BKM120 (buparlisib) is the furthest developed and is being extensively evaluated in hormonepositive breast cancer, often in combination with endocrine therapy. 41,42 Buparlisib has potent, pan-class I PI3K inhibitory PROPERTIES against p110-α, -β, -δ, and -γ enzymes at IC 50 of 52, 166, 116, and 262 nM, respectively. 43 Other panclass I PI3K inhibitors in clinical development include XL147 (IC 50 of 39, 36, 23, and 383 nM against p110-α, -β, -δ, and -γ, respectively), GDC-0941 (pictilisib; IC 50 of 3 nM against p110-α and -δ enzymes), BAY80-6946 (copanlisib; IC 50 of 0.469 nM against p110-α and 3.72 nM against p110-β), PX-866 (sonolisib; IC 50 of 0.1-88 nM), and CH5132799 (IC 50 of 14 nM against p110-α).…”

Section: Inhibitors Of the Pi3k/akt/mtor Signaling Pathwaymentioning

confidence: 99%

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Pharmacodynamic Biomarker Development for PI3K Pathway Therapeutics

Josephs

Sarker

2015

Translational Oncogenomics

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AbstrAct:The phosphatidylinositol 3-kinase (PI3K) signaling pathway is integral to many essential cell processes, including cell growth, differentiation, proliferation, motility, and metabolism. Somatic mutations and genetic amplifications that result in activation of the pathway are frequently detected in cancer. This has led to the development of rationally designed therapeutics targeting key members of the pathway. Critical to the successful development of these drugs are pharmacodynamic biomarkers that aim to define the degree of target and pathway inhibition. In this review, we discuss the pharmacodynamic biomarkers that have been utilized in early-phase clinical trials of PI3K pathway inhibitors. We focus on the challenges related to development and interpretation of these assays, their optimal integration with pharmacokinetic and predictive biomarkers, and future strategies to ensure successful development of PI3K pathway inhibitors within a personalized medicine paradigm for cancer.

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Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors

Cited by 170 publications

References 43 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

Effects of NVP‑BEZ235, a dual phosphatidylinositolï¿½3-kinase/mammalian target of rapamycin inhibitor, on HTLV-1-infected T-cell lines

Pharmacodynamic Biomarker Development for PI3K Pathway Therapeutics

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