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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
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Abstract
Purpose: MAPK and PI3K/AKT/mTOR pathways play important roles in many tumors. In this study, safety, antitumor activity, and pharmacokinetics of buparlisib (pan class PI3K inhibitor) and trametinib (MEK inhibitor) were evaluated. Experimental Design: This open-label, dose-finding, phase Ib study comprised dose escalation, followed by expansion part in patients with RAS- or BRAF-mutant non–small cell lung, ovarian, or pancreatic cancer. Results: Of note, 113 patients were enrolled, 66 and 47 in dose-escalation and -expansion parts, respectively. MTD was established as buparlisib 70 mg + trametinib 1.5 mg daily [5/15, 33% patients with dose-limiting toxicities (DLT)] and recommended phase II dose (RP2D) buparlisib 60 mg + trametinib 1.5 mg daily (1/10, 10% patients with DLTs). DLTs included stomatitis (8/103, 8%), diarrhea, dysphagia, and creatine kinase (CK) increase (2/103, 2% each). Treatment-related grade 3/4 adverse events (AEs) occurred in 73 patients (65%); mainly CK increase, stomatitis, AST/ALT (aspartate aminotransferase/alanine aminotransferase) increase, and rash. For all (21) patients with ovarian cancer, overall response rate was 29% [1 complete response, 5 partial responses (PR)], disease control rate 76%, and median progression-free survival was 7 months. Minimal activity was observed in patients with non–small cell lung cancer (1/17 PR) and pancreatic cancer (best overall response was SD). Relative to historical data, buparlisib exposure increased and trametinib exposure slightly increased with the combination. Conclusions: At RP2D, buparlisib 60 mg + trametinib 1.5 mg daily shows promising antitumor activity for patients with KRAS-mutant ovarian cancer. Long-term tolerability of the combination at RP2D is challenging, due to frequent dose interruptions and reductions for toxicity. Clin Cancer Res; 21(4); 730–8. ©2014 AACR.
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“Despite attempts to verify the efficacy of combined inhibition of PI3K and MEK, no desirable clinical result has been achieved for mutant-RAS tumors, and none of the approved PI3K inhibitors is adapted to treat them.620–622”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [621]
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Engelman, J. A., Chen, L., Tan, X., Crosby, K., Guimaraes, A. R., Upadhyay, R., Maira, M., McNamara, K., Perera, S. A., Song, Y., et al. (2008) · Nature Medicine · doi:10.1038/nm.1890 · Cited by 1,330
Bendell, J. C., Rodon, J. A., Burris, H. A., de Jonge, M. J. A., Verweij, J., Birle, D. C., Demanse, D., Buck, S. S. D., Ru, Q. C., Peters, M., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2011.36.1360 · Cited by 703
Self-citationAscierto, P. A., Schadendorf, D., Berking, C., Agarwala, S. S., van Herpen, C. M., Queirolo, P., Blank, C. U., Hauschild, A., Beck, J. T., St-Pierre, A., et al. (2013) · The Lancet Oncology · doi:10.1016/s1470-2045(13)70024-x · Cited by 640
Self-citationFalchook, G. S., Lewis, K. D., Infante, J. R., Gordon, M. S., Vogelzang, N. J., DeMarini, D. J., Sun, P. G., Moy, C. H., Szabo, S. A., Roadcap, L., et al. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70269-3 · Cited by 557
Self-citationInfante, J. R., Fecher, L. A., Falchook, G. S., Nallapareddy, S., Gordon, M. S., Becerra, C., DeMarini, D. J., Cox, D. S., Xu, Y., Morris, S. R., et al. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70270-x · Cited by 552
Self-citationIhle, N. T., Byers, L. A., Kim, E. S., Saintigny, P., Lee, J. J., Blumenschein, G. R., Tsao, A., Liu, S., Larsen, J. E., Wang, J., et al. (2012) · JNCI: Journal of the National Cancer Institute · doi:10.1093/jnci/djr523 · Cited by 532
Hoeflich, K. P., O'Brien, C. L., Boyd, Z. S., Cavet, G., Guerrero, S., Jung, K., Januario, T., Savage, H. M., Punnoose, E. A., Truong, T., et al. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-0317 · Cited by 474
Critical aspects of the Bayesian approach to phase I cancer trials
Neuenschwander, B. E., Branson, M., & Gsponer, T. (2008) · Statistics in Medicine · doi:10.1002/sim.3230 · Cited by 448
Farley, J. H., Brady, W. E., Vathipadiekal, V., Lankes, H. A., Coleman, R. L., Morgan, M. A., Mannel, R. S., Yamada, S. D., Mutch, D. G., Rodgers, W. H., et al. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70572-7 · Cited by 417
Tejpar, S., Celik, I., Schlichting, M., Sartorius, U., Bokemeyer, C., & Van Cutsem, E. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2012.42.2592 · Cited by 353
Jankú, F., Wheler, J. J., Naing, A., Falchook, G. S., Hong, D. S., Stepanek, V. M. T., Fu, S., Piha-Paul, S. A., Lee, J. J., Luthra, R., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-1726 · Cited by 303
Biganzoli, E. M., Boracchi, P., Mariani, L., & Marubini, E. (1998) · Statistics in Medicine · doi:10.1002/(sici)1097-0258(19980530)17:10 · Cited by 274
Prognostic and Predictive Roles of KRAS Mutation in Colorectal Cancer
Arrington, A. K., Heinrich, E. L., Lee, W., Duldulao, M., Patel, S., Sanchez, J., Garcia-Aguilar, J., & Kim, J. (2012) · International Journal of Molecular Sciences · doi:10.3390/ijms131012153 · Cited by 244
PI3K and MEK inhibitor combinations: examining the evidence in selected tumor types
Britten, C. D. (2013) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-013-2121-1 · Cited by 215
Self-citationDiscovery of a Highly Potent and Selective MEK Inhibitor: GSK1120212 (JTP-74057 DMSO Solvate)
Abé, H., Kikuchi, S., Hayakawa, K., Iida, T., Nagahashi, N., Maeda, K., Sakamoto, J., Matsumoto, N., Miura, T., Matsumura, K., et al. (2011) · ACS Medicinal Chemistry Letters · doi:10.1021/ml200004g · Cited by 202
KRAS and BRAF: drug targets and predictive biomarkers
Vakiani, E., & Solit, D. B. (2010) · The Journal of Pathology · doi:10.1002/path.2796 · Cited by 164
Identification of JTP‐70902, a p15INK4b‐inductive compound, as a novel MEK1/2 inhibitor
Yamaguchi, T., Yoshida, T., Kurachi, R., Kakegawa, J., Hori, Y., Nanayama, T., Hayakawa, K., Abe, H., Takagi, K., Matsuzaki, Y., et al. (2007) · Cancer Science · doi:10.1111/j.1349-7006.2007.00604.x · Cited by 54
Baselga, J. M., Jonge, M. J. D., Rodon, J. A., Burris, H. A., Birle, D. C., Buck, S. S. D., Demanse, D., Ru, Q. C., Goldbrunner, M., & Bendell, J. C. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2010.28.15_suppl.3003 · Cited by 53
Self-citationKullmann, F., Hartmann, A., Stöhr, R., Messmann, H., Dollinger, M. M., Trojan, J., Fuchs, M., Hollerbach, S., Harder, J., Troppmann, M., et al. (2011) · Oncology · doi:10.1159/000330194 · Cited by 46
Shapiro, G. I., LoRusso, P. M., Kwak, E. L., Cleary, J. M., Musib, L. C., Jones, C. B., de Crespigny, A. J., Belvin, M. P., McKenzie, M., Gates, M. R., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2011.29.15_suppl.3005 · Cited by 44
Tolcher, A. W., Baird, R. D., Patnaik, A., Garcia, V. M., Papadopoulos, K. P., Garrett, C. R., Olmos, D., Shannon, K., Zazulina, V., Rubin, E. H., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2011.29.15_suppl.3004 · Cited by 35
K-Ras Mutations in Non-Small-Cell Lung Cancer: Prognostic and Predictive Value
D’Arcangelo, M., & Cappuzzo, F. (2012) · ISRN Molecular Biology · doi:10.5402/2012/837306 · Cited by 35
Hannigan, A., Qureshi, M. A., Nixon, C., Tsimbouri, P. M., Jones, S., Philbey, A., & Wilson, J. B. (2011) · Molecular Cancer · doi:10.1186/1476-4598-10-11 · Cited by 30
Modest, D. P., Brodowicz, T., Stintzing, S., Jung, A., Neumann, J. H. L., Laubender, R. P., Ocvirk, J., Kurteva, G. P., Pápai, Z., Knittelfelder, R., et al. (2012) · Oncology · doi:10.1159/000339534 · Cited by 28
Kurzrock, R., Patnaik, A., Rosenstein, L., Fu, S. W., Papadopoulos, K. P., Smith, D. A., Falchook, G. S., Chambers, G., Gauvin, J., Naing, A., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2011.29.15_suppl.3085 · Cited by 28
Self-citationInfante, J. R., Gandi, L., Shapiro, G. I., Rizvi, N. A., Burris, H. A., Bendell, J. C., Baselga, J. M., Hsu, K., von Richter, O., Locatelli, G., et al. (2013) · Cancer Research · doi:10.1158/1538-7445.am2013-lb-147 · Cited by 18
Activation of the MEK–S6 Pathway in High-grade Ovarian Cancers
Ventura, A. P., Radhakrishnan, S. V., Green, A. F., Rajaram, S. K., Allen, A. N., O'Briant, K. C., Schummer, M., Karlan, B. Y., Urban, N. D., Tewari, M., et al. (2010) · Applied immunohistochemistry & molecular morphology · doi:10.1097/pai.0b013e3181e53e1c · Cited by 14
Britten, C. D., Wainberg, Z. A., Tabernero, J. M., Alsina, M., Leong, S., Sessa, C., Millham, R., Gallo, J. D., Siu, L. L., & Braña, I. (2012) · European Journal of Cancer · doi:10.1016/s0959-8049(12)72156-1 · Cited by 10
Self-citationGrilley‐Olson, J. E., Bedard, P., Fasolo, A., Blackman, S. C., Cartee, L., Baker-Neblett, K. L., Sun, P. G., & Infante, J. R. (2011) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.targ-11-b155 · Cited by 2
Self-citationPress, M. F., Gordon, M. A., & Slamon, D. J. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2011.35.1023 · Cited by 2
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Yang, J., Nie, J., Ma, X., Wei, Y., Peng, Y., & Wei, X. (2019) · Molecular Cancer · doi:10.1186/s12943-019-0954-x · Cited by 1,581
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Rodon, J. A., Dienstmann, R., Serra, V., & Tabernero, J. M. (2013) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2013.10 · Cited by 787
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Metadata
- Authors
- Bedard, P. L., Tabernero, J., Janku, F., Wainberg, Z. A., Paz-Ares, L., Vansteenkiste, J., Van Cutsem, E., Pérez-García, J., Stathis, A., Britten, C. D., Le, N., Carter, K., Demanse, D., Csonka, D., Peters, M., Zubel, A., Nauwelaerts, H., & Sessa, C.
- Affiliations
- Princess Margaret Cancer Centre (CA)
- Universitat Autònoma de Barcelona (ES)
- 3The University of Texas MD Anderson Cancer Center, Houston, Texas.
- University of California, Los Angeles (US)
- Hospital Universitario Virgen del Rocío (ES)
- Universitair Ziekenhuis Leuven (BE)
- 7Digestive Oncology, University Hospital KU Leuven, Leuven, Belgium.
- Istituto Oncologico della Svizzera Italiana (CH)
- GlaxoSmithKline (United States) (US)
- Novartis (Switzerland) (CH)
- 10Novartis Pharma AG, Basel, Switzerland.
- Corresponding author
- Sessa, Cristiana
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2015-02-15
- Volume
- 21
- Issue
- 4
- Pages
- 730-738
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W1988878042
- Cited by
- 324
- References
- 30
- Citations by year
- 2026: 11 · 2025: 18 · 2024: 23 · 2023: 25 · 2022: 22 · 2021: 50 · 2020: 32 · 2019: 39 · 2018: 27 · 2017: 29 · 2016: 25 · 2015: 20
- FWCI
- 10.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Lirias (submittedVersion, other-oa)
- Funders
- GlaxoSmithKline
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Oncology › Advanced Breast Cancer Therapies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- buparlisib, trametinib, PI3K/AKT/mTOR inhibition, MEK1/2 inhibition, MAPK signaling, combination therapy, dose-limiting toxicity, maximum tolerated dose, recommended phase 2 dose, pharmacokinetics, ovarian cancer, non-small cell lung cancer, pancreatic cancer, stomatitis
- MeSH terms
- Adult, Aged, Aged, 80 and over, Aminopyridines, Antineoplastic Combined Chemotherapy Protocols, Dose-Response Relationship, Drug, Female, Humans, Male, Middle Aged, Morpholines, Neoplasms, Pyridones, Pyrimidinones, Disease-Free Survival, Maximum Tolerated Dose
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