Phase i safety, pharmacokinetic, and pharmacodynamic study of SAR245409 (XL765), a novel, orally administered PI3K/mTOR inhibitor in patients with advanced solid tumors

Clinical Cancer Research

Volumn 20, Issue 9, 2014, Pages 2445-2456

  Papadopoulos, Kyriakos P ^a   Tabernero, Josep ^e   Markman, Ben ^e,f   Patnaik, Amita ^a   Tolcher, Anthony W ^a   Baselga, José ^b   Shi, Weiliang ^a   Egile, Coumaran ^g   Ruiz Soto, Rodrigo ^a   Laird, A Douglas ^c   Miles, Dale ^c   Lo Russo, Patricia M ^d  

^a South Texas Accelerated Research Therapeutics ^*  (United States)

^b MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^c EXELIXIS INC   (United States)

^d WAYNE STATE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^e HOSPITAL UNIVERSITARI VALL D HEBRON   (Spain)

^f MONASH UNIVERSITY   (Australia)

^g SANOFI   (France)

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE AMINOTRANSFERASE; ASPARTATE AMINOTRANSFERASE; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; SAR 245409; UNCLASSIFIED DRUG; XL 765; ANTINEOPLASTIC AGENT; PHOSPHATIDYLINOSITOL 3 KINASE; QUINOXALINE DERIVATIVE; SULFONAMIDE; TARGET OF RAPAMYCIN KINASE; VOXTALISIB;

ADRENAL CANCER; ADULT; ADVANCED CANCER; ANTINEOPLASTIC ACTIVITY; AREA UNDER THE CURVE; ARTICLE; BASAL CELL CARCINOMA; BLADDER CANCER; CATARACT; DECREASED APPETITE; DIARRHEA; DOSE RESPONSE; DRUG BLOOD LEVEL; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG HALF LIFE; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; DYSKINESIA; ECG ABNORMALITY; ENZYME INHIBITION; ESOPHAGUS CANCER; FEMALE; HUMAN; HYPERGLYCEMIA; LIVER DYSFUNCTION; MACULOPAPULAR RASH; MAJOR CLINICAL STUDY; MALE; MAXIMUM PLASMA CONCENTRATION; MELANOMA; MESOTHELIOMA; MORNING DOSAGE; MULTICENTER STUDY; MULTIPLE CYCLE TREATMENT; NAUSEA; NEUROENDOCRINE TUMOR; PHASE 1 CLINICAL TRIAL; PRIORITY JOURNAL; PROSTATE CANCER; PRURITUS; QT PROLONGATION; RASH; SARCOMA; SMALL INTESTINE CANCER; SOLID TUMOR; TESTIS CANCER; TIME TO MAXIMUM PLASMA CONCENTRATION; UTERINE CERVIX CANCER; VOMITING; AGED; ANTAGONISTS AND INHIBITORS; CANCER STAGING; CLINICAL TRIAL; DRUG EFFECTS; DRUG MONITORING; MAXIMUM TOLERATED DOSE; METABOLISM; MIDDLE AGED; NEOPLASMS; ORAL DRUG ADMINISTRATION; PATHOLOGY; SIGNAL TRANSDUCTION; TREATMENT OUTCOME; VERY ELDERLY; YOUNG ADULT;

ADMINISTRATION, ORAL; ADULT; AGED; AGED, 80 AND OVER; ANTINEOPLASTIC AGENTS; DRUG MONITORING; FEMALE; HUMANS; MALE; MAXIMUM TOLERATED DOSE; MIDDLE AGED; NEOPLASM STAGING; NEOPLASMS; PHOSPHATIDYLINOSITOL 3-KINASES; QUINOXALINES; SIGNAL TRANSDUCTION; SULFONAMIDES; TOR SERINE-THREONINE KINASES; TREATMENT OUTCOME; YOUNG ADULT;

EID: 84899750348     PISSN: 10780432     EISSN: 15573265     Source Type: Journal    
DOI: 10.1158/1078-0432.CCR-13-2403     Document Type: Article

References (25)

1. Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. J Clin Oncol 2010;28:1075-83.
2. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004;304:554.
3. Hollander MC, BlumenthalGM,Dennis PA.PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat Rev Cancer 2011;11:289-301.
4. Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 2009; 8:627-44.
5. O'Brien NA, Browne BC, Chow L, Wang Y, Ginther C, Arboleda J, et al. Activated phosphoinositide 3-kinase/AKT signaling confers resistance to trastuzumab but not lapatinib. Mol Cancer Ther 2010; 9:1489-502.
6. Awasthi N, Yen PL, Schwarz MA, Schwarz RE. The efficacy of a novel, dual PI3K/mTOR inhibitor NVP-BEZ235 to enhance chemotherapy and antiangiogenic response in pancreatic cancer. J Cell Biochem 2012;113:784-91.
7. Priulla M, Calastretti A, Bruno P, Azzariti A, Paradiso A, Canti G, et al. Preferential chemosensitization of PTEN-mutated prostate cells by silencing the Akt kinase. Prostate 2007;67:782-9.
8. Faber AC, Li D, Song Y, Liang MC, Yeap BY, Bronson RT, et al. Differential induction of apoptosis in HER2 and EGFR addicted cancers following PI3K inhibition. Proc Natl Acad Sci U S A 2009;106: 19503-8.
9. Markman B, Dienstmann R, Tabernero J. Targeting the PI3K/Akt/ mTOR pathway-beyond rapalogs. Oncotarget 2010;1:530-43.
10. Chappell WH, Steelman LS, Long JM, Kempf RC, Abrams SL, Franklin RA, et al. Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health. Oncotarget 2011;2:135-64.
11. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006;66:1500-8.
12. Yu P, Laird AD, Du X, Wu J, Won K, Yamaguchi K, et al. Characterization of the Activity of the PI3K/mTOR Inhibitor XL765 (SAR245409) in Tumor Models with Diverse Genetic Alterations Impacting the PI3K Pathway. Mol Cancer Ther. 2014 March 7. [Epub ahead of print]
13. Markman B, Atzori F, Perez-Garcia J, Tabernero J, Baselga J. Status of PI3K inhibition and biomarker development in cancer therapeutics. Ann Oncol 2010;21:683-91.
14. Prasad G, Sottero T, Yang X, Mueller S, James CD, Weiss WA, et al. Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide. Neuro Oncol 2011; 13:384-92.
15. U.S.Department of Health and Human Services, National Cancer Institute, National Institutes of Health. Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. 2006.
16. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205-16.
17. Markman B, Tabernero J, Krop I, Shapiro GI, Siu L, Chen LC, et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors. Ann Oncol 2012; 23:2399-408.
18. Bendell C, Rodon J, Burris HA, de Jonge M, Verweij J, Birle D, et al. Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol 2012;30:282-90.
19. Arkenau H-T, Fields Jones S, Kurkjian C, Infante JR, Pant S, Burris HA, et al. The PI3K/mTOR inhibitor BEZ235 given twice daily for the treatment of patients (pts) with advanced solid tumors. J Clin Oncol 2012;30:Abstr.3097.
20. Wagner AJ, Bendell JC, Dolly S, Morgan JA, Ware JA, Fredrickson J, et al. A first-in-human phase I study to evaluate GDC-0980, an oral PI3K/mTOR inhibitor, administered QDin patients with advanced solid tumors. J Clin Oncol 2011;29:Abstr.3020.
21. Hong DS, Bowles DW, Falchook GS, Messersmith WA, George GC, O'Bryant CL, et al. A multicenter phase I trial of PX-866, an oral irreversible phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res 2012;18:4173-82.
22. Papadopoulos KP, Abrisqueta P, Chambers G, Rasco D, Patnaik A, Tabernero J, et al. A phase I dose expansion cohort study of the safety, pharmacokinetics and pharmacodynamics of SAR245409 (S09), an orally administered PI3K/mTOR inhibitor, in patients with lymphoma. Blood (ASH Annual Meeting Abstracts) 2011;118:Abstr.1608.
23. Cloughesy TF, Mischel PS, Omuro AMP, Prados M, Wen PY, Wu B, et al. Tumor pharmacokinetics (PK) and pharmacodynamics (PD) of SAR245409 (XL765) and SAR245408 (XL147) administered as single agents to patients with recurrent glioblastoma (GBM): an Ivy Foundation early-phase clinical trials consortium study. J Clin Oncol 2013;31: Abstr.2012.
24. Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 2008;118:3065-74.
25. Castellano E, Downward J. RAS Interaction with PI3K: more than just another effector pathway. Genes Cancer 2011;2:261-74.