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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
- Source :
- Investigational New Drugs. 34:168-175
- Publication Year :
- 2015
- Publisher :
- Springer Science and Business Media LLC, 2015.
-
Abstract
- 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.
- Subjects :
- Adult
Male
0301 basic medicine
Oncology
medicine.medical_specialty
Maximum Tolerated Dose
Colorectal cancer
Cetuximab
medicine.disease_cause
Article
Proto-Oncogene Proteins p21(ras)
03 medical and health sciences
0302 clinical medicine
Internal medicine
Antineoplastic Combined Chemotherapy Protocols
medicine
Humans
Pharmacology (medical)
Protein Kinase Inhibitors
neoplasms
Aged
Aged, 80 and over
Mitogen-Activated Protein Kinase Kinases
Pharmacology
Dose-Response Relationship, Drug
business.industry
Cancer
Middle Aged
medicine.disease
Rash
digestive system diseases
Treatment Outcome
030104 developmental biology
Tolerability
030220 oncology & carcinogenesis
Mutation
Selumetinib
Benzimidazoles
Female
KRAS
medicine.symptom
Colorectal Neoplasms
business
Progressive disease
medicine.drug
Subjects
Details
- ISSN :
- 15730646 and 01676997
- Volume :
- 34
- Database :
- OpenAIRE
- Journal :
- Investigational New Drugs
- Accession number :
- edsair.doi.dedup.....6792b5e4f72e0a87c20b09374ee79058