A phase I study of selumetinib (AZD6244/ARRY-142866), a MEK1/2 inhibitor, in combination with cetuximab in refractory solid tumors and KRAS mutant colorectal cancer
- 14 December 2015
- journal article
- phase i-studies
- Published by Springer Science and Business Media LLC in Investigational New Drugs
- Vol. 34 (2), 168-175
- https://doi.org/10.1007/s10637-015-0314-7
Abstract
Summary Background KRAS mutations are clinically important predictors of resistance to EGFR-directed therapies in colorectal cancer (CRC). Oncogenic activation of the RAS/RAF/MEK/ERK signaling cascade mediates proliferation independent of growth factor signaling. We hypothesized that targeting MEK with selumetinib could overcome resistance to cetuximab in KRAS mutant CRC. Methods A phase I study (NCT01287130) was undertaken to determine the tolerability, and pharmacokinetic profiles of the combination of selumetinib and cetuximab, with an expanded cohort in KRAS-mutant CRC. Results 15 patients were treated in the dose escalation cohort and 18 patients were treated in the expansion cohort. Two dose-limiting toxicities were observed. One grade 3 acneiform rash and one grade 4 hypomagnesemia occurred. The most common grade 1 and 2 adverse events included rash, nausea/vomiting, diarrhea, and fatigue. The maximum tolerated dose was established at selumetinib 75 mg PO BID and cetuximab 250 mg/m2 weekly following a 400 mg/m2 load. Best clinical response in the dose escalation group included 1 unconfirmed partial response in a patient with CRC and stable disease (SD) in 5 patients (1 squamous cell carcinoma of the tonsil, 1 non-small cell lung cancer, and 3 CRC), and in the KRAS-mutant CRC dose expansion cohort, of the 14 patients who were evaluable for response, 5 patients had SD and 9 patients had progressive disease. Conclusions The combination of selumetinib and cetuximab is safe and well tolerated. Minimal anti-tumor activity was observed in KRAS-mutant refractory metastatic CRC. Further investigations might be warranted in other cancer subtypes.Keywords
Funding Information
- National Cancer Institute (U01 CA062491)
- National Cancer Institute (P30 CA014520)
This publication has 17 references indexed in Scilit:
- BRAF mutation is a powerful prognostic factor in advanced and recurrent colorectal cancerBritish Journal of Cancer, 2011
- The First-in-Human Study of the Hydrogen Sulfate (Hyd-Sulfate) Capsule of the MEK1/2 Inhibitor AZD6244 (ARRY-142886): A Phase I Open-Label Multicenter Trial in Patients with Advanced CancerClinical Cancer Research, 2010
- Stability of cetuximab and panitumumab in glass vials and polyvinyl chloride bagsAmerican Journal of Health-System Pharmacy, 2010
- Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancerBritish Journal of Cancer, 2009
- New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)European Journal of Cancer, 2009
- Wild-Type BRAF Is Required for Response to Panitumumab or Cetuximab in Metastatic Colorectal CancerJournal of Clinical Oncology, 2008
- K-rasMutations and Benefit from Cetuximab in Advanced Colorectal CancerThe New England Journal of Medicine, 2008
- Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral, Small-Molecule Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor AZD6244 (ARRY-142886) in Patients With Advanced CancersJournal of Clinical Oncology, 2008
- AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical modelsMolecular Cancer Therapeutics, 2007
- Oncogenic Activation of the RAS/RAF Signaling Pathway Impairs the Response of Metastatic Colorectal Cancers to Anti–Epidermal Growth Factor Receptor Antibody TherapiesCancer Research, 2007