Purpose Osteoclast mediated bone resorption through src kinase releases growth factors, sustaining bone metastases. This trial determined the recommended phase 2 dose (RP2D) and clinical efficacy of the src-kinase inhibitor dasatinib combined with zoledronic acid (ZA) in bone predominant, HER2-negative breast cancer metastases. Experimental Design A 3+3 lead in phase I design confirmed the recommended phase 2 dose (RP2D) allowing activation of the single arm, phase II trial. ZA was administered IV on day 1 and dasatinib was given po once daily for 28 days each cycle as twice daily administration caused dose limiting toxicity. Response was assessed every 3 cycles. N-telopeptide (NTx) was serially measured. Results 25 patients were enrolled. No DLTs were noted at the RP2D of dasatinib=100 mg/day. Common adverse events (AEs) were grade 1-2: rash (9/25, 36%), fatigue (9/25, 36%), pain (9/25, 36%), nausea (6/25, 20%). The objective response rate in bone was 5/22 (23%), all partial responses (PRs). The clinical benefit rate (PRs + stable disease (SD) > 6 months) in bone was 8/22 (36%). Median time to treatment failure was 2.70 months (95% CI: 1.84 - 5.72) in the general cohort, 3.65 months (95% CI: 1.97 - 7.33) in patients with hormone receptor (HR)-positive breast cancer and 0.70 months (95% CI: 0.30 - NA) in those with HR-negative disease. Factors associated with response in bone included lower tumor grade, HR positive status, and pre-treatment high NTx levels. Conclusion Combination therapy was well tolerated, and produced responses in bone in patients with HR-positive tumors.
- Received November 23, 2015.
- Revision received April 26, 2016.
- Accepted May 2, 2016.
- Copyright ©2016, American Association for Cancer Research.