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Investigational New Drugs
Published in: Investigational New Drugs 4/2014

01-08-2014 | PHASE I STUDIES

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

Authors: Jordi Rodon, Irene Braña, Lillian L Siu, Maja J De Jonge, Natasha Homji, David Mills, Emmanuelle Di Tomaso, Celine Sarr, Lucia Trandafir, Cristian Massacesi, Ferry Eskens, Johanna C Bendell

Published in: Investigational New Drugs | Issue 4/2014

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Summary

Purpose The pan-Class I PI3K inhibitor buparlisib (BKM120) has shown activity in a range of preclinical cancer models. This first-in-man study was initiated to identify the maximum tolerated dose (MTD) of buparlisib (100 mg/day) and to assess safety and preliminary efficacy. Methods Patients with advanced solid tumors (N = 83) enrolled in a Phase I dose-escalation and -expansion study of single-agent buparlisib. Patients in the dose-expansion arm (n = 43) had tumor samples with PIK3CA and/or PTEN alterations. Results The most common cancers were colorectal (n = 31) and breast cancer (n = 21). Median number of prior antineoplastic regimens was four (range: 1–12). Grade 3/4 adverse events (AEs) included asthenia (12.0 %) and performance status decrease (9.6 %). Treatment-related AEs (all grades) included decreased appetite, diarrhea, nausea (each in 33 % of patients), hyperglycemia (31 %) and rash (29 %). One confirmed partial response (PR; triple-negative breast cancer) and three unconfirmed PRs (parotid gland carcinoma, epithelioid hemangiothelioma, ER + breast cancer) were reported. Tumor molecular status did not predict clinical benefit in the full study cohort, or among the colorectal or breast cancer subpopulations. Pharmacodynamic biomarkers (18F-FDG-PET, C-peptide, pS6) demonstrated dose-dependent changes; however, tumor heterogeneity precluded a clear correlation with clinical benefit. Conclusion Buparlisib was well tolerated up to the 100 mg/day dose and showed preliminary activity in patients with advanced cancers. Future studies in more homogeneous patient populations will evaluate buparlisib in combination with other agents and further investigate the use of predictive biomarkers.
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Literature
1.
2.
Huang WC, Hung MC (2009) Induction of Akt activity by chemotherapy confers acquired resistance. J Formos Med Assoc 108(3):180–194
3.
Nahta R, O’Regan RM (2010) Evolving strategies for overcoming resistance to HER2-directed therapy: targeting the PI3K/Akt/mTOR pathway. Clin Breast Cancer 10(Suppl 3):S72–S78CrossRefPubMed
4.
5.
Kolasa IK, Rembiszewska A, Felisiak A, Ziolkowska-Seta I, Murawska M, Moes J et al (2009) PIK3CA amplification associates with resistance to chemotherapy in ovarian cancer patients. Cancer Biol Ther 8(1):21–26CrossRefPubMed
6.
7.
The Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455(7216):1061–1068
8.
Cancer Genome Atlas Research Network, Hammerman PS, Hayes DN, Wilkerson MD, Schultz N, Bose R et al (2012) Comprehensive genomic characterization of squamous cell lung cancers. Nature 489(7417):519–525CrossRef
9.
Cancer Genome Atlas Network (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70CrossRef
10.
Maira SM, Pecchi S, Huang A, Burger M, Knapp M, Sterker D et al (2012) Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol Cancer Ther 11(2):317–328CrossRefPubMed
11.
Koul D, Shen R, LaFortune TA, Tiao N, Kim YW, Liu JL et al (2010) NVP-BKM120: a selective pan-PI3 kinase inhibitor induces G2/M arrest in glioma cell lines via FOXO3a and GADD45a loop. American Association for Cancer Research Congress. [abstract 350]
12.
Schnell CR, Arnal S, Becquet M, Allegrini P, Voliva C, Cozens R et al (2010) NVP-BKM120, a pan class I PI3K inhibitor impairs microvascular permeability and tumor growth as detected by DCE-MRI and IFP measurements via radio-telemetry: comparison with NVP-BEZ235. American Association for Cancer Research Congress. [abstract 4472]
13.
Maira M, Menezes D, Pecchi S, Shoemaker K, Burger M, Schnell C et al (2010) NVP-BKM120, a novel inhibitor of phosphoinosotide 3-kinase in phase I/II clinical trials, shows significant antitumor activity in xenograft and primary tumor models. AACR Meeting Abstracts. 4497 (abstract)
14.
Voliva CF, Pecchi S, Burger M, Nagel T, Schnell C, Fritsch C et al (2010) Biological characterization of NVP-BKM120, a novel inhibitor of phosphoinosotide 3-kinase in phase I/II clinical trials. AACR Meeting Abstracts 4498 (abstract)
15.
Bendell JC, Rodon J, Burris HA, de Jonge M, Verweij J, Birle D et al (2012) Phase I, dose-escalation study of BKM120, an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol 30(3):282–290CrossRefPubMed
16.
Spitzer RL, Kroenke K, Williams JB, Lowe B (2006) A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med 166(10):1092–1097CrossRefPubMed
17.
18.
Babb J, Rogatko A, Zacks S (1998) Cancer Phase I clinical trials: efficient dose escalation with overdose control. Stat Med 17(10):1103–1120CrossRefPubMed
19.
Young H, Baum R, Cremerius U, Herholz K, Hoekstra O, Lammertsma AA et al (1999) Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. european organization for research and treatment of cancer (EORTC) PET study group. Eur J Cancer 35(13):1773–1782CrossRefPubMed
20.
Foukas LC, Claret M, Pearce W, Okkenhaug K, Meek S, Peskett E et al (2006) Critical role for the p110alpha phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature 441(7091):366–370CrossRefPubMed
21.
Taniguchi CM, Emanuelli B, Kahn CR (2006) Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 7(2):85–96CrossRefPubMed
22.
Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O et al (2006) A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell 125(4):733–747PubMedCentralCrossRefPubMed
23.
Von Hoff DD, LoRusso P, Tibes R, Shapiro G, Weiss GJ, Ware JA et al (2010) A first-in-human phase I study to evaluate the pan-PI3K inhibitor GDC-0941 administered QD or BID in patients with advanced solid tumors. ASCO Meeting Abstracts 28(15_suppl):2541
24.
Peyton JD, Rodon Ahnert J, Burris H, Britten C, Chen LC, Tabernero J et al (2011) 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. ASCO Meeting Abstracts 29(15_suppl):3066
25.
Wagner AJ, Bendell JC, Dolly S, Morgan JA, Ware JA, Fredrickson J et al (2011) A first-in-human phase I study to evaluate GDC-0980, an oral PI3K/mTOR inhibitor, administered QD in patients with advanced solid tumors. J Clin Oncol 29(suppl):abstract 3020 (poster presentation)
26.
Munster PN, van der Noll R, Voest EE, Dees EC, Tan AR, Specht JM et al (2011) Phase I first-in-human study of the PI3 kinase inhibitor GSK2126458 (GSK458) in patients with advanced solid tumors (study P3K112826). ASCO Meeting Abstracts 29(15_suppl):3018
27.
Nanni P, Nicoletti G, Palladini A, Croci S, Murgo A, Ianzano ML et al (2012) Multiorgan metastasis of human HER-2(+) breast cancer in Rag2(−/−);Il2rg(−/−) mice and treatment with PI3K inhibitor. PLoS One 7(6):e39626PubMedCentralCrossRefPubMed
28.
Tohda C, Nakanishi R, Kadowaki M (2009) Hyperactivity, memory deficit and anxiety-related behaviors in mice lacking the p85alpha subunit of phosphoinositide-3 kinase. Brain Dev 31(1):69–74CrossRefPubMed
29.
Ackermann TF, Hortnagl H, Wolfer DP, Colacicco G, Sohr R, Lang F et al (2008) Phosphatidylinositide dependent kinase deficiency increases anxiety and decreases GABA and serotonin abundance in the amygdala. Cell Physiol Biochem 22(5–6):735–744CrossRefPubMed
30.
Kalkman HO (2006) The role of the phosphatidylinositide 3-kinase-protein kinase B pathway in schizophrenia. Pharmacol Ther 110(1):117–134CrossRefPubMed
31.
A phase I dose escalation study of BKM120 with radiation therapy and temozolomide in patients with newly diagnosed glioblastoma - ClinicalTrials.gov (NCT01473901) [homepage on the Internet]. [cited 4/3/2013]
32.
Safety and efficacy of BKM120 in combination with trastuzumab in patients with relapsing HER2 overexpressing breast cancer who have previously failed trastuzumab - ClinicalTrials.gov (NCT01132664) [homepage on the Internet]. [cited 4/3/2013]
33.
Mortazavi-Jehanno N, Giraudet AL, Champion L, Lerebours F, Le Stanc E, Edeline V et al (2012) Assessment of response to endocrine therapy using FDG PET/CT in metastatic breast cancer: a pilot study. Eur J Nucl Med Mol Imaging 39(3):450–460CrossRefPubMed
34.
Mileshkin L, Hicks RJ, Hughes BG, Mitchell PL, Charu V, Gitlitz BJ et al (2011) Changes in 18F-fluorodeoxyglucose and 18F-fluorodeoxythymidine positron emission tomography imaging in patients with non-small cell lung cancer treated with erlotinib. Clin Cancer Res 17(10):3304–3315CrossRefPubMed
35.
McArthur GA, Puzanov I, Amaravadi R, Ribas A, Chapman P, Kim KB et al (2012) Marked, homogeneous, and early [18F]fluorodeoxyglucose-positron emission tomography responses to vemurafenib in BRAF-mutant advanced melanoma. J Clin Oncol 30(14):1628–1634CrossRefPubMed
36.
Juvekar A, Burga LN, Hu H, Lunsford EP, Ibrahim YH, Balmana J et al (2012) Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for a mouse model of BRCA1-related breast cancer. Cancer Discov 2(11):1048–1063PubMedCentralCrossRefPubMed
37.
Kelly CJ, Hussien K, Muschel RJ (2012) 3D tumour spheroids as a model to assess the suitability of [18F]FDG-PET as an early indicator of response to PI3K inhibition. Nucl Med Biol 39(7):986–992CrossRefPubMed
38.
Di Nicolantonio F, Arena S, Tabernero J, Grosso S, Molinari F, Macarulla T et al (2010) Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J Clin Invest 120(8):2858–2866PubMedCentralCrossRefPubMed
39.
Rexer BN, Chanthaphaychith S, Dahlman KB, Arteaga CL (2014) Direct inhibition of PI3K in combination with dual HER2 inhibitors is required for optimal antitumor activity in HER2+ breast cancer cells. Breast Cancer Res 16(1):R9PubMedCentralCrossRefPubMed
40.
41.
Huang A, Fritsch C, Wilson C, Reddy A, Liu M, Lehar J et al (2012) Single agent activity of PIK3CA inhibitor BYL719 in a broad cancer cell line panel. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, Illinois. Philadelphia (PA): AACR Abstract nr 3749
42.
Jia S, Liu Z, Zhang S, Liu P, Zhang L, Lee SH et al (2008) Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature 454(7205):776–779PubMedCentralPubMed
43.
Wee S, Wiederschain D, Maira SM, Loo A, Miller C, de Beaumont R et al (2008) PTEN-deficient cancers depend on PIK3CB. Proc Natl Acad Sci U S A 105(35):13057–62PubMedCentralCrossRefPubMed
44.
Juric D, Baselga J (2012) Tumor genetic testing for patient selection in phase I clinical trials: the case of PI3K inhibitors. J Clin Oncol 30(8):765–766CrossRefPubMed
45.
Engelman JA (2009) Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9(8):550–562CrossRefPubMed
Metadata
Title
Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors
Authors
Jordi Rodon
Irene Braña
Lillian L Siu
Maja J De Jonge
Natasha Homji
David Mills
Emmanuelle Di Tomaso
Celine Sarr
Lucia Trandafir
Cristian Massacesi
Ferry Eskens
Johanna C Bendell
Publication date
01-08-2014
Publisher
Springer US
Published in
Investigational New Drugs / Issue 4/2014
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-014-0082-9

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