Dose-dense Doxorubicin/Cyclophosphamide With Intermittent Low-dose Sunitinib in Breast Cancer Patients

Summary

Background: The investigators previously studied the addition of low-dose, short-course sunitinib to pre-operative chemotherapy in the neoadjuvant setting in newly diagnosed breast cancer patients with measurable primary breast tumor in a phase Ib/II study at the National University Cancer Institute, Singapore. These data showed that the addition of sunitinib improved tumor vascularization as hypothesized with enhanced short-term treatment response. However, pathological complete response rate after 4 cycles of chemotherapy was not superior to standard chemotherapy, and may be attributed to dose delays from increased myelosuppression with the addition of sunitinib. The investigators hypothesize that this promising regimen may be further optimized with the use of growth factor support. The investigators thus plan to study the addition of low-dose, shortcourse sunitinib to dose-dense doxorubicin/cyclophosphamide (ddAC) administered every 14 days, supported by pegfilgrastim. Aim: To confirm that the addition of 12.5mg sunitinib for 5-7 days can be added before each cycle of ddAC (delivered every 14 days, supported by pegfilgrastim) without compromising dose intensity, in phase II open label single arm part of the study, followed by a phase II randomized study to compare the pathological complete response rate of ddAC versus sunitinib + ddAC in stage I-III HER2 negative breast cancer patients in the neoadjuvant setting. Methods:A single-centre study comprising two phases: a. Phase II open label single-arm study that will enroll newly diagnosed stage I-IV HER2 negative breast cancer patients receiving either neoadjuvant chemotherapy (stage I-III patients) or first-line palliative chemotherapy (stage IV patients). All patients will be treated with 4 cycles of ddAC at standard doses (60/600mg/m2) every 2 weeks, supported by subcutaneous pegfilgrastim 6mg, to be administered 24-36 hours after each dose of chemotherapy. Low dose sunitinib at 12.5mg daily orally will be administered for 7 days prior to cycle 1 ddAC, and for 5 days prior to each subsequent cycle of ddAC. b. Phase II randomized study that will enroll newly diagnosed stage I-III HER2 negative breast cancer patients receiving neoadjuvant chemotherapy before definitive breast cancer surgery. Eligible patients will be randomized 1:1 to 4 cycles of ddAC with or without intermittent sunitinib in patients with measurable primary breast cancer who are receiving preoperative chemotherapy.

Timeline

Start

2016-05

Primary completion

2020-05

Completion

2020-11

Publications

• Background Burstein HJ, Elias AD, Rugo HS, Cobleigh MA, Wolff AC, Eisenberg PD, Lehman M, Adams BJ, Bello CL, DePrimo SE, Baum CM, Miller KD. Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2008 Apr 10;26(11):1810-6. doi: 10.1200/JCO.2007.14.5375. Epub 2008 Mar 17.
• Background Duda DG, Batchelor TT, Willett CG, Jain RK. VEGF-targeted cancer therapy strategies: current progress, hurdles and future prospects. Trends Mol Med. 2007 Jun;13(6):223-30. doi: 10.1016/j.molmed.2007.04.001. Epub 2007 Apr 25.
• Background Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM, Kuzma CS, Pluard TJ, Somlo G, Port ER, Golshan M, Bellon JR, Collyar D, Hahn OM, Carey LA, Hudis CA, Winer EP. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol. 2015 Jan 1;33(1):13-21. doi: 10.1200/JCO.2014.57.0572. Epub 2014 Aug 4.
• Choo JRE, Jan YH, Ow SGW, Wong A, Lee MX, Ngoi N, Yadav K, Lim JSJ, Lim SE, Chan CW, Hartman M, Tang SW, Goh BC, Tan HL, Chong WQ, Yvonne ALE, Chan GHJ, Chen SJ, Tan KT, Lee SC. Serial Tumor Molecular Profiling of Newly Diagnosed HER2-Negative Breast Cancers During Chemotherapy in Combination with Angiogenesis Inhibitors. Target Oncol. 2022 May;17(3):355-368. doi: 10.1007/s11523-022-00886-x. Epub 2022 Jun 14.
• Yadav K, Lim J, Choo J, Ow SGW, Wong A, Lee M, Chan CW, Hartman M, Lim SE, Ngoi N, Tang SW, Ang Y, Chan G, Chong WQ, Tan HL, Tan SH, Goh BC, Lee SC. Immunohistochemistry study of tumor vascular normalization and anti-angiogenic effects of sunitinib versus bevacizumab prior to dose-dense doxorubicin/cyclophosphamide chemotherapy in HER2-negative breast cancer. Breast Cancer Res Treat. 2022 Feb;192(1):131-142. doi: 10.1007/s10549-021-06470-7. Epub 2021 Dec 20.

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