TBCRC-010: Phase I/II Study of Dasatinib in Combination with Zoledronic Acid for the Treatment of Breast Cancer Bone Metastasis
Mené sur 25 patientes atteintes d'un cancer métastatique du sein HER2-, cet essai de phase I évalue la dose maximale tolérée et l'efficacité clinique du dasatinib en combinaison avec l'acide zolédronique
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.
Clinical Cancer Research , résumé, 2016