A dose-ranging study of cabozantinib in men with castration-resistant prostate cancer and bone metastases

Abstract

Background: Cabozantinib is an oral MET/VEGFR2 inhibitor. A recent phase II study of cabozantinib (100 mg daily) showed improved bone scans in subjects with metastatic castration-resistant prostate cancer (mCRPC), but adverse events (AE) caused frequent dose reductions. This study was designed to determine the efficacy and tolerability of cabozantinib at lower starting doses.

Experimental design: An adaptive design was used to determine the lowest active daily dose among 60, 40, and 20 mg. The primary endpoint was week 6 bone scan response, defined as ≥30% decrease in bone scan lesion area. The secondary endpoint was change in circulating tumor cells (CTC).

Results: Among 11 evaluable subjects enrolled at 40 mg, there were 9 partial responses (PR), 1 complete response, and 1 stable disease (SD). Of 10 subjects subsequently enrolled at 20 mg, there were 1 PR, 5 SDs, and 4 with progressive disease. Among 13 subjects enrolled on the 40 mg expansion cohort, there were 6 PRs and 7 SDs. No subjects required dose reduction or treatment interruption at 6 or 12 weeks; 3 subjects at dose level 0 discontinued due to AEs by 12 weeks. At 40 mg, median treatment duration was 27 weeks. 58% of subjects with ≥5 CTCs/7.5 mL at baseline converted to <5.

Conclusions: Cabozantinib 40 mg daily was associated with a high rate of bone scan response. Cabozantinib 40 mg daily was associated with better tolerability than previously reported for cabozantinib 100 mg daily. These observations informed the design of phase III studies of cabozantinib in mCRPC.

Trial registration: ClinicalTrials.gov NCT01347788.

Conflict of interest statement

Conflicts of Interest: RJL: research support from Exelixis, Inc. JGG: founder of MedQIA LLC. MRS: research support from Exelixis, Inc. and consultant for Exelixis, Inc. All remaining authors have declared no conflicts of interest.

©2013 AACR

Figures

Fig. 1

Adaptive response design (17).

Fig. 2

Representative bone scan changes in two subjects from cohort 1 (40mg daily). The left panel of each pair represents the baseline bone scan; the right panel is the scan from week 6. BSLA change was −100% for subject 1 (CR) and −97% for subject 2 (PR).

Fig. 3

Waterfall plot of BSLA change at 6 weeks compared with baseline. BSR is defined as ≥ 30% decrease in BSLA. A. Cohort 1, 40mg daily. Asterisks indicate subjects with confirmed BSR at 12 weeks. B. Cohort 2, 20mg daily. Asterisks indicate subjects who achieved BSR at 12 weeks after dose-escalation to dose level +2. C. Expansion cohort, 40mg daily. Asterisks indicate subjects with BSR at 12 weeks.

Fig. 4

Waterfall plot of BSLA change and PSA change at 6 weeks compared with baseline, in subjects treated at 40mg daily (cohort 1 and expansion cohort). Each pair of bars represents one subject. Blue bars indicate BSLA change; red bars indicate PSA change. Thirteen of 24 evaluable subjects demonstrated discordance of bone scan and PSA change.

Fig. 5

Waterfall plot of CTC change by 12 weeks in subjects with unfavorable CTC levels at baseline. Green bars indicate subjects whose CTCs converted to favorable levels at 6 weeks; blue bars indicate subjects whose CTCs did not convert.