A Phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors

Clinical Cancer Research

Volumn 21, Issue 4, 2015, Pages 730-738

  Bedard, Philippe L ^a   Tabernero, Josep ^b   Janku, Filip ^c   A wainberg, Zev ^d   Paz Ares, Luis ^e   Vansteenkiste, Johan ^f   Cutsem, Eric Van ^f   Pérez García, José ^b   Stathis, Anastasios ^g   Britten, Carolyn D ^d   Le, Ngocdiep ^h   Carter, Kirsten ⁱ   Demanse, David ⁱ   Csonka, Denes ⁱ   Peters, Malte ⁱ   Zubel, Angela ⁱ   Nauwelaerts, Heidi ⁱ   Sessa, Cristiana ^g  

^a PRINCESS MARGARET HOSPITAL   (Canada)

^b VALL D HEBRON UNIVERSITY HOSPITAL   (Spain)

^c UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

^d UNIVERSITY OF CALIFORNIA   (United States)

^e HOSPITAL UNIVERSITARIO VIRGEN DEL ROCÍO   (Spain)

^f UNIVERSITY HOSPITALS LEUVEN   (Belgium)

^g SAN GIOVANNI HOSPITAL   (Switzerland)

^h GLAXOSMITHKLINE   (United States)

ⁱ NOVARTIS PHARMA AG   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE AMINOTRANSFERASE; ASPARTATE AMINOTRANSFERASE; B RAF KINASE; BUPARLISIB; CREATINE KINASE; MITOGEN ACTIVATED PROTEIN KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; S6 KINASE; TRAMETINIB; TRIACYLGLYCEROL LIPASE; AMINOPYRIDINE DERIVATIVE; ANTINEOPLASTIC AGENT; MORPHOLINE DERIVATIVE; NVP-BKM120; PYRIDONE DERIVATIVE; PYRIMIDINONE DERIVATIVE;

ABDOMINAL PAIN; ACNE; ADENOCARCINOMA; ADULT; ADVANCED CANCER; ALANINE AMINOTRANSFERASE BLOOD LEVEL; ANTINEOPLASTIC ACTIVITY; AREA UNDER THE CURVE; ARTICLE; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; ASTHENIA; BLOOD SAMPLING; CANCER GRADING; CANCER STAGING; CANCER SURVIVAL; CLEAR CELL CARCINOMA; COMBINATION CHEMOTHERAPY; CREATININE BLOOD LEVEL; DECREASED APPETITE; DERMATITIS; DIARRHEA; DRUG ABSORPTION; DRUG DOSE ESCALATION; DRUG RESPONSE; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; DRY SKIN; DYSGEUSIA; DYSPHAGIA; ENZYME PHOSPHORYLATION; FACE EDEMA; FATIGUE; FEMALE; GENE MUTATION; HISTOPATHOLOGY; HUMAN; HYPERGLYCEMIA; HYPERTENSION; IMMUNOHISTOCHEMISTRY; MACULOPAPULAR RASH; MAJOR CLINICAL STUDY; MALE; MAXIMUM PLASMA CONCENTRATION; MAXIMUM TOLERATED DOSE; MULTIPLE CYCLE TREATMENT; NAUSEA; NON SMALL CELL LUNG CANCER; ONCOGENE K RAS; ONCOGENE N RAS; OVARY CANCER; OVERALL SURVIVAL; PANCREAS CANCER; PERIPHERAL EDEMA; PHASE 1 CLINICAL TRIAL; PROGRESSION FREE SURVIVAL; PRURITUS; RASH; RECOMMENDED DRUG DOSE; SIDE EFFECT; SKIN FISSURE; SOLID TUMOR; STEADY STATE; STOMATITIS; THROMBOCYTOPENIA; TIME TO MAXIMUM PLASMA CONCENTRATION; TRIACYLGLYCEROL LIPASE BLOOD LEVEL; VOMITING; XEROSIS; AGED; CLINICAL TRIAL; DISEASE FREE SURVIVAL; DOSE RESPONSE; MIDDLE AGED; MORTALITY; NEOPLASMS; VERY ELDERLY;

ADULT; AGED; AGED, 80 AND OVER; AMINOPYRIDINES; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; DISEASE-FREE SURVIVAL; DOSE-RESPONSE RELATIONSHIP, DRUG; FEMALE; HUMANS; MALE; MAXIMUM TOLERATED DOSE; MIDDLE AGED; MORPHOLINES; NEOPLASMS; PYRIDONES; PYRIMIDINONES;

EID: 84923182481     PISSN: 10780432     EISSN: 15573265     Source Type: Journal    
DOI: 10.1158/1078-0432.CCR-14-1814     Document Type: Article

References (28)

1. Britten CD. PI3K and MEK inhibitor combinations: examining the evidence in selected tumor types. Cancer Chemother Pharmacol 2013;71: 1395-409.
2. Kullmann F, Hartmann A, Stohr R, Messmann H, Dollinger MM, Trojan J, et al. KRAS mutation in metastatic pancreatic ductal adenocarcinoma: results of a multicenter phase II study evaluating efficacy of cetuximab plus gemcitabine/oxaliplatin (GEMOXCET) in first-line therapy. Oncology 2011;81:3-8.
3. D'Arcangelo M, Cappuzzo F. K-Ras mutations in non-small cell lung cancer: prognostic and predictive value. ISRN Mol Biol. 2012;2012:Article ID 837306.
4. Arrington AK, Heinrich EL, Lee W, Duldulao M, Patel S, Sanchez J, et al. Prognostic and predictive roles of KRAS mutation in colorectal cancer. Int J Mol Sci 2012;13:12153-68.
5. Ascierto PA, Schadendorf D, Berking C, Agarwala SS, van Herpen CM, Queirolo P, et al. MEK162 for patients with advancedmelanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol 2013;14:249-56.
6. Vakiani E, Solit DB. KRAS and BRAF: drug targets and predictive biomarkers. J Pathol 2011;223:219-29.
7. Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, et al. Effective use of PI3K and MEK inhibitors to treat mutant KRAS G12D and PIK3CA H1047R murine lung cancers. Nat Med 2008;14:1351-6.
8. Hoeflich KP, O'Brien C, Boyd Z, Cavet G, Guerrero S, Jung K, et al. In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models. Clin Cancer Res 2009;15:4649-64.
9. Baselga J, De-Jonge MJ, Rodon J, Burris HA, Birle DC, De-Buck S, et al. A firstin- human phase I study of BKM120, an oral pan-class I PI3K inhibitor, in patients (pts) with advanced solid tumors. J Clin Oncol 2010;28 (Suppl): 3003.
10. Bendell JC, Rodon J, Burris HA, de-Jong M, Verweij J, Birle DC, 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.
11. Yamaguchi T, Yoshida T, Kurachi R, Kakegawa J, Hori Y, Nanayama T, et al. Identification of JTP-70902, a p15INK4b inductive compound, as a novel MEK1/2 inhibitor. Cancer Sci 2007;98:1809-16.
12. Abe H, Kikuchi S, Hayakawa K, Iida T, Nagahashi N, Maeda K, et al. Discovery of a highly potent and selective MEK inhibitor: GSK1120212 (JTP-74057 DMSO Solvate). ACS Med Chem Lett 2011;2:320-4.
13. Infante JR, Fecher LA, Falchook GS, Nallapareddy S, Gordon MS, Becerra C, et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol 2012;13:773-81.
14. Falchook GS, Lewis KD, Infante JR, Gordon MS, Vogelzang NJ, DeMarini DJ, et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol 2012; 13:782-9.
15. Babb J, Rogatko A, Zacks S. Cancer phase I clinical trials: efficient dose escalation with overdose control. Stat Med 1998;17:1103-20.
16. Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to phase I cancer trials. Stat Med 2008;27:2420-39.
17. Britten C, Wainberg Z, Tabernero J, Alsina-Maqueda M, Leong S, Sessa S, et al. Multi-arm phase 1 dose escalation study of safety, pharmacokinetics, and pharmacodynamics of the dual PI3K/mTOR inhibitors PF-04691502 (oral) and PF-05212384 (IV) in combination with the MEK inhibitor PD-0325901 or irinotecan in patients with advanced cancer. Eur J Cancer 2012;48:109.
18. Grilley-Olson JE, Bedard P, Fasolo A, Blackman S, Cartee L, Baker-Neblett K, et al. A phase I study of the MEK inhibitor GSK1120212 (GSK212) in combination with PI3K/mTOR inhibitor GSK2126458 (GSK458) in patients with advanced solid tumors. Mol Cancer Ther 2011;10:11.
19. Infante JR, Gandi L, Shapiro G, Rizvi N, Burris H, Bendell J, et al.Combination of the MEK inhibitor, pimasertib (MSC1936369B), and the PI3K/mTOR inhibitor, SAR245409, in patients with advanced solid tumors: results of a phase Ib dose-escalation trial [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; 2013. Abstract nr LB-147.
20. Kurzrock R, Patnaik A, Rosenstein L, Fu S, Papadopoulos KP, Smith DA, et al. Phase I dose-escalation of the oral MEK1/2 inhibitor GSK1120212 (GSK212) dosed in combination with the oral AKT inhibitor GSK2141795 (GSK795). J Clin Oncol 2011;29:215s.
21. Shapiro G, LoRusso P, Kwak EL, Cleary JM, Musib L, Jones C, et al. Clinical combination of the MEK inhibitor GDC-0973 and the PI3K inhibitor GDC-0941: a first-in-human phase Ib study testing daily and intermittent dosing schedules in patients with advanced solid tumors. J Clin Oncol 2011;29(15 suppl):3005.
22. Tolcher AW, Baird RD, Patnaik A, Moreno Garcia V, Papadopoulos KP, Garrett CR, et al. Aphase I dose-escalation study of oral MK-2206 (allosteric AKT inhibitor) with oral selumetinib (AZD6244; MEK inhibitor) in patients with advanced or metastatic solid tumors. J Clin Oncol 2011; 29:195s.
23. Farley J, Brady WE, Vathipadiekal V, Lankes HA, Coleman R, Morgan MA, et al. Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study. Lancet Oncol 2013;14:134-40.
24. Janku F, Wheler JJ, Naing A, Falchook GS, Hong DS, Stepanek VM, et al. PIK3CAmutation H1047R is associated with response to PI3K/AKT/mTOR signaling pathway inhibitors in early-phase clinical trials. Cancer Res 2013;73:276-84.
25. Ventura AP, Radhakrishnan S, Green A, Rajaram SK, Allen AN, O'Briant K, et al. Activation of the MEK-S6 pathway in high-grade ovarian cancers. Appl Immunohistochem Mol Morphol 2010;18:499-508.
26. Ihle NT, Byers LA, Kim ES, Saintigny P, Lee JJ, Blumenschein GR, et al. Effect of KRAS oncogene substitutions on protein behavior: implications for signaling and clinical outcome. J Natl Cancer Inst 2012;104: 228-39.
27. Modest DP, Brodowicz T, Stintzing S, Jung A, Neumann J, Laubender RP, et al. Impact of the specific mutation in KRAS codon 12 mutated tumors on treatment efficacy in patients with metastatic colorectal cancer receiving cetuximab-based first-line therapy: a pooled analysis of three trials. Oncology 2012;83:241-7.
28. Tejpar S, Celik I, Schlichting M, Sartorius U, Bokemeyer C, Van Cutsem E. Association of KRASG13Dtumor mutations with outcome in patients with metastatic colorectal cancer treated with first-line chemotherapy with or without cetuximab. J Clin Oncol 2012;30:357-07.