Abstract A90: Efficacy and tolerability of cabozantinib at lower dose: A dose finding study in men with castration-resistant prostate cancer and bone metastases.
Authors: Lee Richard J.B. , Michaelson M. Dror , Saylor Philip , Gurski Carol , Goldin Jonathan G. , Smith Matthew R. 
Published: June 2012

Abstract
Background: Cabozantinib is an orally available inhibitor of MET and VEGFR2. In a randomized discontinuation trial of cabozantinib (100 mg daily), 86% of men with mCRPC and bone metastases had partial or complete resolution of lesions on bone scan as early as week 6; dose reductions for AEs occurred in 51% of pts, and discontinuations in 10%.[1] The current study is designed to determine the efficacy and safety of cabozantinib at lower doses.
Methods: The study uses an adaptive response scheme based on Sargent one-stage design [2] to determine the lowest effective cabozantinib dose among three dose levels: dose level +1 (60 mg daily), dose level 0 (40 mg daily), and dose level −1 (20 mg daily). Bone scan responses were assessed by comparison of baseline and week 6 bone scans using an automated FDA 510(k) approved computer-aided detection (CAD) system.[3] A decrease in total bone scan lesion area of ≥ 30% was defined as a response The first cohort was treated at dose level 0 (40 mg po QD). Using the adaptive design, the number of bone scan responses at dose level 0 (≥8 responses versus &lt;8 responses among 11 evaluable subjects) was used to select the dose level (−1 versus +1) for the second cohort. By this design, subjects will be treated at two of the three dose levels (dose level 0 and −1, or dose level 0 and +1). Based on the observed bone scan response rate in the second cohort of 11 subjects, a dose level will be selected for expansion to treat an additional 13 subjects.
Results: The study has enrolled a total of 23 subjects. Twelve subjects were enrolled in the first study cohort and treated with cabozantinib 40 mg daily. Median followup is 14 weeks. One subject discontinued the study at week 2 because of anorexia and fatigue. Another subject discontinued at week 6 after experiencing a hip fracture. The remaining 10 subjects remain on treatment without dose reduction. Baseline and week 6 bone scans have been centrally reviewed for the first 10 evaluable subjects. There were 9 confirmed bone scan responses at week 6 including complete response. Median decrease in bone lesion area at week 6 was 69%. Eleven subjects were accrued to the second cohort and treated with cabozantinib 20 mg daily; all subjects remain on study.
Conclusions: Cabozantinib 40 mg daily results in high rates of bone scan response in men with CRPC and bone metastases. Cabozantinib 40 mg daily is associated with improved tolerability compared to cabozantinib 100 mg daily. Evaluation of the efficacy and tolerability of cabozantinib 20 mg daily is ongoing.
References:
1. Hussain, M., Smith M.R., Sweeney C., et al. Cabozantinib (XL184) in metastatic castration-resistant prostate cancer (mCRPC): Results from a phase II randomized discontinuation trial. Proc ASCO 2011 (Abstract 4516)
2. Sargent DJ, Chan V, Goldberg RM. A three-outcome design for phase II clinical trials. Control Clin Trials 2001;22:117–25.
3. Chu G. H., Brown M.S., Kim H.J., et al. Initial analytic validation of automated bone scan measures for treatment response assessment in patients with metastatic castration-resistant prostate cancer (CRPC). J Clin Oncol 29: 2011 (suppl; abstr e15174).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A90.