期刊
ORAL ONCOLOGY
卷 53, 期 -, 页码 74-79出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.oraloncology.2015.11.014
关键词
Hedgehog signaling pathway; Phase 1; Cetuximab; Combination therapy; Head and neck squamous cell carcinoma
资金
- Daniel and Janet Mordecai Foundation
- Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology
- University of Colorado Cancer Center [P30CA046934]
- [R21DE019712]
Background: This phase 1, dose-finding study determined the safety, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), antitumor activity, and molecular correlates of IPI-926, a Hedgehog pathway (HhP) inhibitor, combined with cetuximab in patients with relapsed/metastatic squamous cell carcinoma of the head and neck. Patients and methods: Cetuximab was given with a 400 mg/m(2) loading dose followed by 250 mg/m(2) weekly. IPI-926 was given daily starting two weeks after cetuximab initiation. A 3 + 3 study design was used. Prior therapy with cetuximab was allowed. Tumor biopsies occurred prior to cetuximab initiation, prior to IPI-926 initiation, and after treatment with both drugs. Results: Nine patients were enrolled. The RP2D was 160 mg, the same as the single-agent IPI-926 MTD. Among 9 treated, 8 evaluable patients, the best responses were 1 partial response (12.5%), 4 stable disease (50%), and 3 disease progressions (37.5%). The median progression free survival was 77 days (95% confidence interval 39-156). Decreases in tumor size were seen in both cetuximab-naive patients (one HPV-positive, one HPV-negative). The most frequent treatment-emergent adverse events were fatigue, muscle cramps, and rash. No DLTs were observed. Tumor shrinkage and progression free survival were associated with intra-tumoral ErbB and HhP gene expression down-regulation during therapy, supporting the preclinical hypothesis. Conclusion: Treatment with IPI-926 and cetuximab yielded expected toxicities with signs of anti-tumor activity. Serial tumor biopsies were feasible and revealed proof-of-concept biomarkers. (C) 2015 Elsevier Ltd. All rights reserved.
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