Investigator-sponsored trial of efficacy and tolerability of cabozantinib (cabo) at lower dose: A dose-finding study in men with castration-resistant prostate cancer (CRPC) and bone metastases.

Abstract

4566 Background: Cabo (XL184) is an oral inhibitor of MET and VEGFR2. In a randomized discontinuation trial of cabo 100mg daily, 76% of men with CRPC and bone metastases had partial or complete resolution of bone scan lesions as early as week (wk) 6. However, treatment was limited by adverse events (AEs), with dose reductions in 51% of patients (pts), and discontinuations in 10%. The current study was designed to determine the efficacy and tolerability of cabo at lower starting doses. Methods: An adaptive response scheme was used to determine the lowest active daily cabo dose among dose levels +1 (60mg), 0 (40mg), and -1 (20mg). The primary endpoint was wk 6 bone scan response (BSR) assessed with an automated FDA 510(k) approved computer-aided detection system. A ≥30% decrease in total bone scan lesion area (BSLA) was defined as a response. The first cohort was treated at dose level 0. The number of responses (≥8 vs. <8 among 11 evaluable pts) was used to select the dose level (-1 vs. +1) for the second cohort. Based on the observed BSR rate in the second cohort of 11 pts, a dose was selected for expansion to treat 13 more pts. Results: The study completed planned enrollment of 36 pts. Median age was 66; 44% were docetaxel-pretreated. Among 12 pts enrolled at dose level 0, there were 10 BSRs at wk 6 including 1 complete response (CR), and 1 pt with stable disease (SD). The median decrease in BSLA was 62%. Ten pts evaluated at wk 12 included 9 BSRs (3 CRs), and 1 sustained SD. Among 11 pts then treated at dose level -1, 10 pts were evaluable at wk 6: 1 BSR, 5 SD, and 4 had progressive disease. No pts in the 2 cohorts required dose reduction or treatment interruption at 12 wks; 1 pt discontinued due to grade 3 AEs (anorexia, fatigue). 6/12 pts with ≥6 months follow-up remain on study. 5/5 pts enrolled at 40mg with CTCs ≥5 per 7.5mL converted to <5. Thirteen pts accrued to the expansion cohort at 40mg daily had confirmed high BSR rate. Conclusions: Cabo 40mg daily achieves a high BSR rate in men with CRPC and bone metastases, and is associated with better tolerability than previously reported for cabo 100mg daily.