Efficacy, safety, pharmacokinetics and pharmacodynamics of SAR245409 (voxtalisib, XL765), an orally administered phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor: A phase 1 expansion cohort in patients with relapsed or refractory lymphoma

Leukemia and Lymphoma

Volumn 56, Issue 6, 2015, Pages 1763-1770

  Papadopoulos, Kyriakos P ^a   Egile, Coumaran ^b   Ruiz Soto, Rodrigo ^c   Jiang, Jason ^b   Shi, Weiliang ^c   Bentzien, Frauke ^d   Rasco, Drew ^a   Abrisqueta, Pau ^e   Vose, Julie M ^f   Tabernero, Josep ^e  

^a South Texas Accelerated Research Therapeutics   (United States)

^b SANOFI   (France)

^c USA svenjager sanoficom   (United States)

^d EXELIXIS INC   (United States)

^e HOSPITAL UNIVERSITARI VALL D HEBRON   (Spain)

^f UNIVERSITY OF NEBRASKA MEDICAL CENTER   (United States)

Author keywords

Lymphoma; MTOR; Pharmacodynamics; Pharmacokinetics; PI3K; Signaling therapies

Indexed keywords

VOXTALISIB; MTOR PROTEIN, HUMAN; PHOSPHATIDYLINOSITOL 3 KINASE; QUINOXALINE DERIVATIVE; SULFONAMIDE; TARGET OF RAPAMYCIN KINASE;

ACCUMULATION RATIO; ADULT; AGED; ANEMIA; AREA UNDER THE CURVE; ARTICLE; ASTHENIA; CANCER CHEMOTHERAPY; CANCER FATIGUE; CANCER GRADING; CANCER RECURRENCE; CANCER STAGING; CLINICAL ARTICLE; COHORT ANALYSIS; CONTROLLED STUDY; DIARRHEA; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG ERUPTION; DRUG HALF LIFE; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; DRY SKIN; FEMALE; FEVER; FOLLICULAR LYMPHOMA; HEART FAILURE; HODGKIN DISEASE; HUMAN; HYPERGLYCEMIA; LARGE CELL LYMPHOMA; LYMPHOCYTOPENIA; LYMPHOMA; MALE; MANTLE CELL LYMPHOMA; MAXIMUM PLASMA CONCENTRATION; MUCOSA INFLAMMATION; MULTIPLE CYCLE TREATMENT; NAUSEA; OPEN STUDY; PHASE 1 CLINICAL TRIAL; PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; PRURITUS; THROMBOCYTOPENIA; TIME TO MAXIMUM PLASMA CONCENTRATION; TREATMENT DURATION; TREATMENT RESPONSE; VOMITING; ANTAGONISTS AND INHIBITORS; CHEMICALLY INDUCED; CLINICAL TRIAL; DRUG EFFECTS; DRUG RESISTANCE; METABOLIC CLEARANCE RATE; MIDDLE AGED; ORAL DRUG ADMINISTRATION; PATHOLOGY; RASH; REMISSION; SIGNAL TRANSDUCTION; TREATMENT OUTCOME; TUMOR RECURRENCE; VERY ELDERLY; YOUNG ADULT;

ADMINISTRATION, ORAL; ADULT; AGED; AGED, 80 AND OVER; ANEMIA; AREA UNDER CURVE; DIARRHEA; DRUG RESISTANCE, NEOPLASM; EXANTHEMA; FEMALE; HUMANS; LYMPHOMA; MALE; MAP KINASE SIGNALING SYSTEM; METABOLIC CLEARANCE RATE; MIDDLE AGED; NAUSEA; NEOPLASM RECURRENCE, LOCAL; PHOSPHATIDYLINOSITOL 3-KINASES; QUINOXALINES; REMISSION INDUCTION; SULFONAMIDES; TOR SERINE-THREONINE KINASES; TREATMENT OUTCOME; YOUNG ADULT;

EID: 84932147143     PISSN: 10428194     EISSN: 10292403     Source Type: Journal    
DOI: 10.3109/10428194.2014.974040     Document Type: Article

References (43)

1. Leslie LA, Younes A. Targeting oncogenic and epigenetic survival pathways in lymphoma. Leuk Lymphoma 2013; 54: 2365-2376.
2. Xu ZZ, Xia ZG, Wang AH, et al. Activation of the PI3K/AKT/mTOR pathway in diffuse large B cell lymphoma: clinical significance and inhibitory effect of rituximab. Ann Hematol 2013; 92: 1351-1358.
3. Hasselblom S, Hansson U, Olsson M, et al. High immunohistochemical expression of p-AKT predicts inferior survival in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Br J Haematol 2010; 149: 560-568.
4. Abubaker J, Bavi PP, Al Harbi S, et al. PIK3CA mutations are mutually exclusive with PTEN loss in diffuse large B-cell lymphoma. Leukemia 2007; 21: 2368-2370.
5. Pfeifer M, Grau M, Lenze D, et al. PTEN loss defines a PI3K/AKT pathway-dependent germinal center subtype of diffuse large B-cell lymphoma. Proc Natl Acad Sci USA 2013; 110: 12420-12425.
6. Zhao M Y, A uerbach A, D' C osta A M, et al. P hospho-p70S6K/p85S6K and cdc2/cdk1 are novel targets for diffuse large B-cell lymphoma combination therapy. Clin Cancer Res 2009; 15: 1708-1720.
7. Psyrri A, Papageorgiou S, Liakata E, et al. Phosphatidylinositol 3 '-kinase catalytic subunit alpha gene amplification contributes to the pathogenesis of mantle cell lymphoma. Clin Cancer Res 2009; 15: 5724-5732.
8. Young R M, Staudt L M. T argeting pathological B cell receptor signalling in lymphoid malignancies. Nat Rev Drug Discov 2013; 12: 229-243.
9. Markman B, Dienstmann R, Tabernero J. Targeting the PI3K/Akt/ mTOR pathway-beyond rapalogs. Oncotarget 2010; 1: 530-543.
10. Chappell WH, Steelman LS, Long JM, 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: 135-164.
11. Walsh K, McKinney MS, Love C, et al. PAK1 mediates resistance to PI3K inhibition in lymphomas. Clin Cancer Res 2013; 19: 1106-1115.
12. Bhende PM, Park SI, Lim MS, et al. The dual PI3K/mTOR inhibitor, NVP-BEZ235, is efficacious against follicular lymphoma. Leukemia 2010; 24: 1781-1784.
13. Mark A, Hajdu M, Varadi Z, et al. Characteristic mTOR activity in Hodgkin-lymphomas offers a potential therapeutic target in high risk disease- A combined tissue microarray, in vitro and in vivo study. BMC Cancer 2013; 13: 250.
14. Fang X, Jiang Y, Feng L, et al. Blockade of PI3K/AKT pathway enhances sensitivity of Raji cells to chemotherapy through downregulation of HSP70. Cancer Cell Int 2013; 13: 48.
15. Qiao Q, Jiang Y, Li G. I nhibition of the PI3K/AKT-NF-kappaB pathway with curcumin enhanced radiation-induced apoptosis in human Burkitt's lymphoma. J Pharmacol Sci 2013; 121: 247-256.
16. Gopal AK, Kahl BS, De Vos S, et al. PI3K inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 2014; 370: 1008-1018.
17. Horwitz SM, Flinn I, Patel MR, et al. Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-, in patients with relapsed/refractory lymphoma. J Clin Oncol 2013; 31(Suppl.1): Abstract 8518.
18. Dreyling M, Morschhauser F, Bron D, et al. Preliminary results of a phase II study of single agent bay 80-6946, a novel PI3K inhibitor, in patients with relapsed/refractory, indolent or aggressive lymphoma. Blood 2013; 122(Suppl. 1): Abstract 87.
19. Kahl BS, Spurgeon SE, Furman RR, et al. A phase 1 study of the PI3K inhibitor idelalisib in patients with relapsed/refractory mantle cell lymphoma (MCL). Blood 2014; 123: 3398-3405.
20. Flinn IW, Kahl BS, Leonard JP, et al. Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase as therapy for previously treated indolent non-Hodgkin lymphoma. Blood 2014; 123: 3406-3413.
21. Hess G, Herbrecht R, Romaguera J, et al. Phase III study to evaluate temsirolimus compared with investigator ' s choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol 2009; 27: 3822-3829.
22. Smith S M, v an Besien K, Karrison T, et al. T emsirolimus has activity in non-mantle cell non-Hodgkin's lymphoma subtypes: The University of Chicago phase II consortium. J Clin Oncol 2010; 28: 4740-4746.
23. Witzig TE, Reeder CB, LaPlant BR, et al. A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma. Leukemia 2011; 25: 341-347.
24. Renner C, Zinzani P L, Gressin R, et al. A multicenter phase II trial (SAKK 36/06) of single- Agent everolimus (RAD001) in patients with relapsed or refractory mantle cell lymphoma. Haematologica 2012; 97: 1085-1091.
25. Iyengar S, Clear A, Bodor C, et al. P110alpha-mediated constitutive PI3K signaling limits the efficacy of p110delta-selective inhibition in mantle cell lymphoma, particularly with multiple relapse. Blood 2013; 121: 2274-2284.
26. Muller A, Zang C, Chumduri C, et al. C oncurrent inhibition of PI3K and mTORC1/mTORC2 overcomes resistance to rapamycin induced apoptosis by down-regulation of Mcl-1 in mantle cell lymphoma. Int J Cancer 2013; 133: 1813-1824.
27. O' R eilly K E, Rojo F, She Q B, et al. m TOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006; 66: 1500-1508.
28. Yu P, Laird AD, Du X, et al. Characterization of the activity of the PI3K/mTOR inhibitor XL765 (SAR245409) in tumor models with diverse genetic alterations affecting the PI3K pathway. Mol Cancer Th er 2014; 13: 1078-1091.
29. Cloughesy TF, Mischel PS, Omuro AMP, 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 earlyphase clinical trials consortium study. J Clin Oncol 2013; 31(Suppl.): Abstract 2012.
30. Prasad G, Sottero T, Yang X, et al. I nhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide. Neuro-oncology 2011; 13: 384-392.
31. Ghadimi M P, Lopez G, Torres K E, et al. T argeting the PI3K/mTOR axis, alone and in combination with autophagy blockade, for the treatment of malignant peripheral nerve sheath tumors. Mol Cancer Th er 2012; 11: 1758-1769.
32. Papadopoulos K, Tabernero J, Markman B, et al. Phase I safety, pharmacokinetic and pharmacodynamic study of SAR245409 (XL765), a novel, orally administered PI3K/mTOR inhibitor in patients with advanced solid tumors. Clin Cancer Res 2014; 20: 2445-2456.
33. National Cancer Institute. C ommon Terminology Criteria for Adverse Events (CTCAE) version 3.0. 2006. Available from: http://www. ctep.cancer.gov/protocolDevelopment/electronic- Applications/docs/ ctcaev3.pdf
34. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007; 25: 579-586.
35. Bea S, Valdes-Mas R, Navarro A, et al. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proc Natl Acad Sci USA 2013; 110: 18250-18255.
36. Markman B, Tabernero J, Krop I, 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: 2399-2408.
37. Bendell C, Rodon J, Burris HA, 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: 282-290.
38. Arkenau H-T, Fields Jones S, Kurkjian C, et al. The PI3K/mTOR inhibitor BEZ235 given twice daily for the treatment of patients (pts) with advanced solid tumors. J Clin Oncol 2 012; 3 0(Suppl.): A bstract 3 097.
39. Wagner AJ, Bendell JC, Dolly S, et al. Afirst-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 2011; 29(Suppl.): Abstract 3020.
40. Hong DS, Bowles DW, Falchook GS, 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: 4173-4182.
41. Will M, Qin AC, Toy W, et al. Rapid induction of apoptosis by PI3K inhibitors is dependent upon their transient inhibition of RAS-ERK signaling. Cancer Discov 2014; 4: 334-347.
42. Kahl B, Byrd JC, Flinn IW, et al. Clinical safety and activity in a Phase 1 study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110, in patients with relapsed or refractory non-hodgkin lymphoma. Blood 2010; 116(Suppl. 1): Abstract 1777.
43. Brown JR, Hamadani M, Arnason J, et al. SAR245409 monotherapy in relapsed/refractory follicular lymphoma: preliminary results from the phase II ARD12130 study. Blood 2013; 122(Suppl. 1): Abstract 86.