GDC-0449 in patients with advanced chondrosarcomas: A French Sarcoma Group (FSG)/French and U.S. National Cancer Institutes phase II collaborative study.

Abstract

10005 Background: Chondrosarcomas (CS) exhibit a strong activation of hedgehog (Hh) signaling which plays a crucial role in cartilage tumorigenesis. Preclinical data show that hedgehog blockade reduces strongly chondrosarcoma cell proliferation and tumour size. GDC-0449 is a small-molecule antagonist of the Hh pathway. Methods: This is a multicentric single-arm phase 2 clinical trial based on two-stage Simon’s design which assesses safety and efficacy of GDC-0449 in patients (pts) with advanced CS. All pts had to have documented progressive disease (PD) as per RECIST 1.1 before study entry. Pts receive GDC-0449 150mg (oral route), daily until PD or unacceptable toxicity. The primary endpoint is the 6-month non-PD rate according to RECIST. Based on the following hypotheses: 20% 6-month non-PD rate (H0), 40% acceptable 6-month non-PD rate (H1), 10% type I error rate, 90% power, a total of 37 assessable pts are necessary (17 for the first stage + 20 for the second stage). Following the inclusion of the first 17 pts, if ≥ four pts are progression-free at 6 months, the accrual will continue. In order to account for not assessable pts (+/- 10%), 41 pts will be recruited. Accrual started in February 2011 in six centers of the FSG. Results: As of January 24 2012, 40 pts (28 males, 12 females) have been included in the study. Median age is 59 years (30-86). The most frequent histological subtype is conventional CS (n=32). Twenty eight pts (70%) had grade 1 or 2 adverse events (AE) possibly related to the drug whereas 3 pts (7.5%) had grade 3 or 4 AE. The planned interim statistical analysis performed after central histological and radiological review showed that four patients out of the first 17 evaluable patients had stable disease indicating that GDC-0449 had reached the primary endpoint to justify continuing accrual after the 1st step of the study. 15 pts are still on treatment. Molecular analyses are available for 21 pts. No mutation of SMO was detected. qRT-PCR experiments and PTCH sequencing are ongoing. Conclusions: GDC-0449 is well tolerated and shows some activity in a subset of pts with advanced CS. Final clinical and molecular data will be presented at the meeting.