A pilot study of cetuximab and the hedgehog inhibitor IPI-926 in recurrent/metastatic head and neck squamous cell carcinoma. (February 2016)

• Record Type: Journal Article
• Authors: Bowles, Daniel W.; Keysar, Stephen B.; Eagles, Justin R.; Wang, Guoliang; Glogowska, Magdalena J.; McDermott, Jessica D.; Le, Phuong N.; Gao, Dexiang; Ray, Charles E.; Rochon, Paul J.; Roop, Dennis R.; Tan, Aik-Choon; Serracino, Hilary S.; Jimeno, Antonio
• Is Part Of: Oral oncology. Volume 53(2016:Feb.)
• Page Start: 74
• Page End: 79
• Publication Date: 2016-02
• Subjects: Hedgehog signaling pathway -- Phase 1 -- Cetuximab -- Combination therapy -- Head and neck squamous cell carcinoma; Mouth -- Cancer -- Periodicals; Mouth -- Tumors -- Periodicals; Mouth Diseases -- Periodicals; Mouth Neoplasms -- Periodicals; Bouche -- Cancer -- Périodiques; Bouche -- Tumeurs -- Périodiques; Tumeurs -- Périodiques; Electronic journals; 616.9943105
• DOI: 10.1016/j.oraloncology.2015.11.014
• Languages: English
• ISSNs: 1368-8375

Abstract

Highlights: Hedgehog and EGFR pathway interact in head and neck squamous carcinomas (HNSCC). We combined a Hedgehog inhibitor (IPI-926) and cetuximab in incurable HNSCC. The combination was safe. Serial tumor biopsies were feasible. Efficacy was correlated with Hedgehog and EGFR pathway inhibition. Summary: 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-naïve 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.