TY - JOUR
T1 - A pilot study of cetuximab and the hedgehog inhibitor IPI-926 in recurrent/metastatic head and neck squamous cell carcinoma
AU - Bowles, Daniel W.
AU - Keysar, Stephen B.
AU - Eagles, Justin R.
AU - Wang, Guoliang
AU - Glogowska, Magdalena J.
AU - McDermott, Jessica D.
AU - Le, Phuong N.
AU - Gao, Dexiang
AU - Ray, Charles E.
AU - Rochon, Paul J.
AU - Roop, Dennis R.
AU - Tan, Aik Choon
AU - Serracino, Hilary S.
AU - Jimeno, Antonio
N1 - Funding Information:
This work was supported by R21DE019712 (A.J.), the Daniel and Janet Mordecai Foundation (A.J.), the Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology , and the University of Colorado Cancer Center Support Grant ( P30CA046934 ).
Funding Information:
This work was supported by R21DE019712 (A.J.), the Daniel and Janet Mordecai Foundation (A.J.), the Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology, and the University of Colorado Cancer Center Support Grant (P30CA046934). A. Jimeno has received laboratory research support from Infinity. No other authors report conflicts of interest.
Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.All rights reserved.
PY - 2016/2/1
Y1 - 2016/2/1
N2 - 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/m2 loading dose followed by 250 mg/m2 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.
AB - 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/m2 loading dose followed by 250 mg/m2 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.
KW - Cetuximab
KW - Combination therapy
KW - Head and neck squamous cell carcinoma
KW - Hedgehog signaling pathway
KW - Phase 1
UR - http://www.scopus.com/inward/record.url?scp=84953358346&partnerID=8YFLogxK
U2 - 10.1016/j.oraloncology.2015.11.014
DO - 10.1016/j.oraloncology.2015.11.014
M3 - Article
C2 - 26705064
AN - SCOPUS:84953358346
VL - 53
SP - 74
EP - 79
JO - Oral Oncology
JF - Oral Oncology
SN - 1368-8375
ER -