Cited by 324PI3K/AKT/mTOR signaling in cancerAdvanced Breast Cancer TherapiesMelanoma and MAPK Pathways

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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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Bedard, Philippe L., Tabernero, Josep, Janku, Filip, Wainberg, Zev A., Paz-Ares, Luis, Vansteenkiste, Johan, Van Cutsem, Eric, Pérez-García, José, Stathis, Anastasios, Britten, Carolyn D., Le, Ngocdiep, Carter, Kirsten, Demanse, David, Csonka, Denes, Peters, Malte, Zubel, Angela, Nauwelaerts, Heidi, Sessa, Cristiana·2015·Clinical Cancer Research

DOI 10.1158/1078-0432.ccr-14-1814

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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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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: Bedard, Philippe L.
Tabernero, Josep
Wainberg, Zev A.
Paz-Ares, Luis
Pérez-García, José
Stathis, Anastasios
Demanse, David
Sessa, Cristiana
Venue: Clinical Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2015-02-15
Volume: 21
Issue: 4
Pages: 730-738
ISSN: 1078-0432 (ISSN-L)
1557-3265
DOI: 10.1158/1078-0432.ccr-14-1814
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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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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