TBCRC-010: Phase I/II Study of Dasatinib in Combination with Zoledronic Acid for the Treatment of Breast Cancer Bone Metastasis.

Abstract

PURPOSE:

Osteoclast-mediated bone resorption through src kinase releases growth factors, sustaining bone metastases. This trial determined the recommended phase II dose (RP2D) and clinical efficacy of the src kinase inhibitor dasatinib combined with zoledronic acid in bone predominant, HER2-negative breast cancer metastases.

EXPERIMENTAL DESIGN:

A 3+3 lead in phase I design confirmed the RP2D allowing activation of the single-arm, phase II trial. Zoledronic acid was administered intravenously on day 1, and dasatinib was given orally once daily for 28 days each cycle as twice daily administration caused dose-limiting toxicity (DLT). Response was assessed every three cycles. N-telopeptide (NTx) was serially measured.

RESULTS:

A total of 25 patients were enrolled. No DLTs were noted at the RP2D of dasatinib = 100 mg/d. Common adverse events 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 (PR). 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% confidence interval (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 pretreatment high NTx levels.

CONCLUSIONS:

Combination therapy was well tolerated and produced responses in bone in patients with HR-positive tumors. Clin Cancer Res; 22(23); 5706-12. ©2016 AACR.

• Authors: Zahi Mitri, Rita Nanda, Kimberly Blackwell, Colleen M Costelloe, Ilona Hood, Caimiao Wei, Abenaa M Brewster, Nuhad K Ibrahim, Kimberly B Koenig, Gabriel N Hortobagyi, Catherine Van Poznak, Mothaffar F Rimawi, Stacy Moulder-Thompson, Translational Breast Cancer Research Consortium
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 22 Issue 23 Pg. 5706-5712 (Dec 01 2016) ISSN: 1557-3265 [Electronic] United States
• PMID: 27166393 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Bone Density Conservation Agents
• Diphosphonates
• Imidazoles
• Zoledronic Acid
• Receptor, ErbB-2
• src-Family Kinases
• Dasatinib

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Bone Density Conservation Agents (therapeutic use)
• Bone Neoplasms (drug therapy, metabolism, secondary)
• Breast (drug effects)
• Breast Neoplasms (drug therapy, metabolism)
• Dasatinib (therapeutic use)
• Diphosphonates (therapeutic use)
• Female
• Humans
• Imidazoles (therapeutic use)
• Middle Aged
• Receptor, ErbB-2 (metabolism)
• Zoledronic Acid
• src-Family Kinases (metabolism)