A Phase Ib, open-label, dose-finding study of alpelisib in combination with paclitaxel in patients with advanced solid tumors

Jordi Rodon, Giuseppe Curigliano, Jean-Pierre Delord, Wael Harb, Analia Azaro, Yu Han, Celine Wilke, Valerie Donnet, Dalila Sellami, Thaddeus Beck, Jordi Rodon, Giuseppe Curigliano, Jean-Pierre Delord, Wael Harb, Analia Azaro, Yu Han, Celine Wilke, Valerie Donnet, Dalila Sellami, Thaddeus Beck

Abstract

Phosphatidylinositol 3-kinase (PI3K) pathway activation is associated with resistance to paclitaxel in solid tumors. We assessed the safety and activity of alpelisib, an oral, selective PI3K p110α inhibitor, plus paclitaxel in patients with advanced solid tumors. This Phase Ib, multicenter, open-label, dose-finding study, with a planned dose-expansion phase of alpelisib once daily (QD) plus fixed-dose paclitaxel, recruited patients with advanced solid tumors. For the dose-finding phase, the primary objective was determination of maximum tolerated and/or recommended Phase II dose of alpelisib plus paclitaxel, and the secondary objectives included the assessment of safety for this combination. From March 2014 to August 2016, 19 patients with advanced solid tumors were treated with alpelisib QD (300 mg, n=6; 250 mg, n=4; 150 mg, n=9) plus paclitaxel (80 mg/m2, per standard of care). During dose finding, five of 12 (41.7%) evaluable patients for MTD determination experienced dose-limiting toxicities: alpelisib 300 mg, Grade 2 hyperglycemia (n=1); alpelisib 250 mg, Grade 2 hyperglycemia (n=1), Grade 4 hyperglycemia and Grade 3 acute kidney injury (n=1); and alpelisib 150 mg, Grade 2 hyperglycemia (n=1) and Grade 4 leukopenia (n=1). The MTD of alpelisib when administered with paclitaxel was 150 mg QD. Most frequent all-grade AEs were diarrhea (73.7%; Grade 3/4 10.5%) and hyperglycemia (57.9%; Grade 3/4 31.6%). The planned dose-expansion phase was not initiated. Alpelisib plus paclitaxel has a challenging safety profile in patients with advanced solid tumors. This study was closed following the completion of the dose-finding phase.

Clinical trial registration: ClinicalTrials.gov NCT02051751.

Keywords: PIK3CA protein; breast neoplasms; chemotherapy; drug resistance; human.

Conflict of interest statement

CONFLICTS OF INTEREST JR reports personal fees for advisory boards from Novartis, Lily, Orion, Servier, and Peptomyc; and grant funding from Bayer and Novartis. YH, CW, VD and DS are employees of Novartis Pharmaceuticals Corporation. CW and DS also report stock ownership from Novartis Pharmaceuticals Corporation. GC, J-P D, WH, AA, and TB declare no competing interest.

Figures

Figure 1. Geometric mean and arithmetic mean…
Figure 1. Geometric mean and arithmetic mean (SD) concentration-time profiles (pharmacokinetic analysis set)
(A) paclitaxel by visit and (B) plasma alpelisib by dose level at Cycle 1 Day 8. QD, every day. Data cut-off: August 19, 2016.
Figure 2. Waterfall plot of tumor responses
Figure 2. Waterfall plot of tumor responses
Best percentage change from baseline in sum of longest diameters and best overall response per local investigator assessment. PD, progressive disease; PR, partial response; QD, every day; QW, every week; SD, stable disease. *One patient who did not have any target lesion at baseline has been excluded from the graph. Missing bar denotes a missing percentage change from baseline. Data cut-off: August 19, 2016.

References

    1. Bristol-Myers Squibb Company Taxol® Prescribing information. 2015.
    1. Orr GA, Verdier-Pinard P, McDaid H, Horwitz SB. Mechanisms of taxol resistance related to microtubules. Oncogene. 2003;22:7280–7295.
    1. Wang Z. Taxane resistance in breast cancer. Cancer Cell Microenviron. 2014;1:e126.
    1. Du F, Wu X, Liu Y, Wang T, Qi X, Mao Y, Jiang L, Zhu Y, Chen Y, Zhu R, Han X, Jin J, Ma X, Hua D. Acquisition of paclitaxel resistance via PI3Kdependent epithelialmesenchymal transition in A2780 human ovarian cancer cells. Oncol Rep. 2013;30:1113–1118.
    1. Hu L, Hofmann J, Lu Y, Mills GB, Jaffe RB. Inhibition of phosphatidylinositol 3′-kinase increases efficacy of paclitaxel in in vitro and in vivo ovarian cancer models. Cancer Res. 2002;62:1087–1092.
    1. Liu Z, Zhu G, Getzenberg RH, Veltri RW. The upregulation of PI3K/Akt and MAP kinase pathways is associated with resistance of microtubule-targeting drugs in prostate cancer. J Cell Biochem. 2015;116:1341–1349.
    1. Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009;8:627–644.
    1. Network CG. Cancer Genome Atlas Network Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61–70.
    1. Banerji S, Cibulskis K, Rangel-Escareno C, Brown KK, Carter SL, Frederick AM, Lawrence MS, Sivachenko AY, Sougnez C, Zou L, Cortes ML, Fernandez-Lopez JC, Peng S, et al. Sequence analysis of mutations and translocations across breast cancer subtypes. Nature. 2012;486:405–409.
    1. Levine DA, Bogomolniy F, Yee CJ, Lash A, Barakat RR, Borgen PI, Boyd J. Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clinical cancer research: an official journal of the American Association for Cancer Research. 2005;11:2875–2878.
    1. Lui VW, Hedberg ML, Li H, Vangara BS, Pendleton K, Zeng Y, Lu Y, Zhang Q, Du Y, Gilbert BR, Freilino M, Sauerwein S, Peyser ND, et al. Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discov. 2013;3:761–769.
    1. Network, CG. Cancer Genome Atlas Network Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–337.
    1. Fritsch C, Huang A, Chatenay-Rivauday C, Schnell C, Reddy A, Liu M, Kauffmann A, Guthy D, Erdmann D, De Pover A, Furet P, Gao H, Ferretti S, et al. Characterization of the novel and specific PI3Kalpha inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials. Mol Cancer Ther. 2014;13:1117–1129.
    1. Maira SM, Pecchi S, Huang A, Burger M, Knapp M, Sterker D, Schnell C, Guthy D, Nagel T, Wiesmann M, Brachmann S, Fritsch C, Dorsch M, et al. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol Cancer Ther. 2012;11:317–328.
    1. Juric DB, Schuler M, Schellens J, Berlin J, Seggewis-Bernhardt R. Phase I study of the PI3K-alpha inhibitor BYL719, as a single agent in patients with advanced solid tumors (sAT) Ann Oncol. 2014;25:iv146–64.
    1. Juric D, Rodon J, Tabernero J, Janku F, Burris HA, Schellens JH, Middleton MR, Berlin J, Schuler M, Gil-Martin M, Rugo HS, Seggewiss-Bernhardt R, Huang A, et al. Phosphatidylinositol 3-Kinase α-Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study. J Clin Oncol. 2018;36:1291–99.
    1. Karlan BY, Oza AM, Richardson GE, Provencher DM, Hansen VL, Buck M, Chambers SK, Ghatage P, Pippitt CH, Jr, Brown JV, 3rd, Covens A, Nagarkar RV, Davy M, et al. Randomized, double-blind, placebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients with recurrent ovarian cancer. J Clin Oncol. 2012;30:362–371.
    1. Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to phase I cancer trials. Stat Med. 2008;27:2420–2439.
    1. Busaidy NL, Farooki A, Dowlati A, Perentesis JP, Dancey JE, Doyle LA, Brell JM, Siu LL. Management of metabolic effects associated with anticancer agents targeting the PI3K-Akt-mTOR pathway. J Clin Oncol. 2012;30:2919–2928.
    1. Perez EA, Vogel CL, Irwin DH, Kirshner JJ, Patel R. Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol. 2001;19:4216–4223.
    1. Sharma P, Abramson VG, O’Dea A, Lewis S, Scott JN, Ward J, De Jong JA, Lehn C, Brown AR, Williamson SK, Perez RP, Komiya T, Godwin AK, et al. Safety and efficacy results from phase I study of BYL 719 plus nab-paclitaxel in HER 2 negative metastatic breast cancer. P6-11-08 Cancer Res 2017 American Association for Cancer Research. 2017;77
    1. Janku F, Juric D, Cortes J, Rugo H, Burris HA, Schuler M, Deschler-Baier B, Middleton MR, Gil-Martin M, Berlin J, Winer E, Bootle D, Blumenstein L, et al. Phase I study of the PI3Kα inhibitor BYL719 plus fulv estrant in patients with PIK3CA-altered and wild type ER+/HER2- locally advanced or metastatic breast cancer. Cancer Res. 2015;75:PD5–5.
    1. Juric D, André F, Rugo H, Mayer I, Loibl S, Sheng Q. Combined alpelisib (BYL719) and fulvestrant in PIK3CA mutant or wild-type estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. 33rd Annual Miami Breast Cancer Conference 2016; 2016. Abstract 334.

Source: PubMed

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