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Oral Oncol. 2016 Feb;53:74-9. doi: 10.1016/j.oraloncology.2015.11.014. Epub 2015 Dec 15.

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

Author information

1
Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States.
2
Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, CO, United States.
3
Division of Interventional Radiology, Department of Radiology, University of Colorado School of Medicine, Aurora, CO, United States.
4
Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology.
5
Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States; Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, CO, United States.
6
Department of Pathology, University of Colorado School of Medicine, Aurora, CO, United States.
7
Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States; Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology. Electronic address: antonio.jimeno@ucdenver.edu.

Abstract

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 400mg/m(2) loading dose followed by 250mg/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 160mg, 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 77days (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.

KEYWORDS:

Cetuximab; Combination therapy; Head and neck squamous cell carcinoma; Hedgehog signaling pathway; Phase 1

[Indexed for MEDLINE]
Free PMC Article

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