Phase II study of XL184 in a cohort of patients (pts) with castration-resistant prostate cancer (CRPC) and measurable soft tissue disease.

Abstract

127 Background: XL184 is an oral, potent inhibitor of MET and VEGFR2. MET pathway activation promotes tumor growth, invasion and metastasis. Overexpression of MET and/or its ligand HGF are associated with prostate cancer metastasis. In preclinical studies, androgen ablation upregulates MET signaling. Preliminary data from the open label Lead-in Stage of an ongoing adaptive design phase II randomized discontinuation trial are presented. Methods: Eligible pts had CRPC, measurable disease with or without bone metastasis, and disease progression on ≤1 prior non-hormonal systemic treatment. XL184 was administered orally for 12 weeks (wks). Tumor (RECIST) and bone scan response (complete or partial resolution) were assessed every 6 wks. Primary endpoint is objective response rate at wk 12. Pts with SD at wk 12 will enter a placebo-controlled randomized phase. Results: As of 10/4/10, 72 pts have been enrolled. Median time on study was 50 days (range, 6+-350+ days). Median age was 69 yrs; 45% of pts were docetaxel-pretreated. All pts had measurable disease, including 69% with visceral metastases. To date, there are 24 response evaluable pts, defined as enrolled ≥12 wks prior to data cutoff. 5/24 (21%) pts had a partial response (≥30% reduction) in measurable disease with 3 responses confirmed at 12 wks and 2 unconfirmed responses ongoing. 6/24 (25%) had PSA declines of ≥50%. 13 of 15 (87%) pts with known bone metastases had either complete or partial resolution of lesions on bone scan. Bone scan responses were associated with investigator-reported improvement in bone pain in 11/15 (73%) with pain at baseline. Effects on osteoclast and osteoblast activity were observed: plasma C-telopeptide declined ≥50% in 8/12 (66%) pts and serum total alkaline phosphatase (tALP) declined ≥50% in 5/8 (63%) pts with bone metastases and baseline elevated tALP. The most common AEs ≥Grade 3 severity (related) were fatigue (10%), diarrhea (3%) and elevated AST (3%). Conclusions: XL184 results in tumor responses, partial or complete resolution of lesions on bone scan, and symptom relief in pts with metastatic CRPC, including those pretreated with docetaxel. XL184 also decreased biomarkers of both osteoblast and osteoclast activity. [Table: see text]