GDC-0449 in patients with advanced chondrosarcomas: a French Sarcoma Group/US and French National Cancer Institute Single-Arm Phase II Collaborative Study

• Published in: Annals of oncology Vol. 24; no. 11; pp. 2922 - 2926
• Main Authors: Italiano, A., Le Cesne, A., Bellera, C., Piperno-Neumann, S., Duffaud, F., Penel, N., Cassier, P., Domont, J., Takebe, N., Kind, M., Coindre, J.-M., Blay, J.-Y., Bui, B.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.11.2013; Oxford University Press
• Subjects: Adult; Aged; Aged, 80 and over; Anilides - administration & dosage; Antineoplastic agents; Biological and medical sciences; chondrosarcoma; Chondrosarcoma - drug therapy; Chondrosarcoma - genetics; Chondrosarcoma - pathology; Disease-Free Survival; Diseases of the osteoarticular system; Drug-Related Side Effects and Adverse Reactions - classification; Drug-Related Side Effects and Adverse Reactions - pathology; Female; France; GDC-0449; Gene Expression Regulation, Neoplastic; Hedgehog pathway; Hedgehog Proteins - biosynthesis; Hedgehog Proteins - genetics; Humans; Male; Medical sciences; Middle Aged; Original; Pharmacology. Drug treatments; Pyridines - administration & dosage; treatment; Tumors of striated muscle and skeleton; France; GDC-0449; chondrosarcoma; treatment; Hedgehog pathway; Human; Chondrosarcoma; Sarcoma; Toxicity; Diseases of the osteoarticular system; Malignant tumor; Cartilage; Treatment; Hedgehog protein; Phase II trial; Advanced stage; Inhibitor; Cancer
• ISSN: 0923-7534; 1569-8041; 1569-8041
• DOI: 10.1093/annonc/mdt391

Pre-clinical data have suggested a therapeutic role of Hedgehog (Hh) pathway inhibitors in chondrosarcoma. This phase II trial included patients with progressive advanced chondrosarcoma. They received GDC-0449 150 mg/day (days 1–28, 28-day cycle). The primary end point was the 6-month clinical benefit rate (CBR) defined as the proportion of patients with non-progressive disease at 6 months. A 6-month CBR of 40% was considered as a reasonable objective to claim drug efficacy. Between February 2011 and February 2012, 45 patients were included. Twenty had received prior chemotherapy. Thirty-nine were assessable for efficacy. The 6-month CBR was 25.6% (95% confidence interval 13.0–42.1). All stable patients had grade 1 or 2 conventional chondrosarcoma with documented progression within the 6 months before inclusion. All but one with available data also had overexpression of the Hh ligand. Median progression-free and overall survivals were 3.5 and 12.4 months, respectively. The most frequent adverse events were grade 1 or 2 myalgia, dysgeusia and alopecia. GDC-0449 did not meet the primary end point of this trial. Results suggest some activity in a subset of patients with progressive grade 1 or 2 conventional chondrosarcoma. Further studies assessing its role in combination with chemotherapy are warranted. NCT01267955.