TY - JOUR
T1 - TBCRC-010
T2 - Phase I/II study of dasatinib in combination with zoledronic acid for the treatment of breast cancer bone metastasis
AU - Mitri, Zahi
AU - Nanda, Rita
AU - Blackwell, Kimberly
AU - Costelloe, Colleen M.
AU - Hood, Ilona
AU - Wei, Caimiao
AU - Brewster, Abenaa M.
AU - Ibrahim, Nuhad K.
AU - Koenig, Kimberly B.
AU - Hortobagyi, Gabriel N.
AU - Van Poznak, Catherine
AU - Rimawi, Mothaffar F.
AU - Moulder-Thompson, Stacy
N1 - Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-15-2845
DO - 10.1158/1078-0432.CCR-15-2845
M3 - Article
C2 - 27166393
AN - SCOPUS:85006310608
SN - 1078-0432
VL - 22
SP - 5706
EP - 5712
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 23
ER -