Abstract A065: Neoadjuvant phase II trial with eribulin and carboplatin in patients with triple-negative breast cancer
Authors: Giordano Sara Barnato , Rao Shreyas , Hamdan Randala , Jeruss Jacqueline , Bethke Kevin , Hansen Nora , Khan Seema , Roenn Jamie Von , Rosen Steven , Gradishar William J. , Siziopikou Kalliopi , Meservey Caitlin , Kaklamani Virginia 
Published: May 2015

Background: Several neoadjuvant trials have been conducted directed at treating triple negative breast cancer (TNBC) patients with platinum agents with pathologic complete response (pCR) rates ranging from 16%-32%. Eribulin mesylate, a nontaxane microtubule dynamics inhibitor with a novel mechanism of action, has clinical activity as monotherapy in breast cancer and other solid tumors. A recent phase I trial found that the combination of eribulin mesylate with carboplatin was well tolerated and showed activity in advanced solid tumors. The recommended dose for future trials was eribulin mesylate 1.1 mg/m2 and carboplatin AUC6. We proposed a neoadjuvant phase II trial with the combination of carboplatin and eribulin in patients with TNBC. CDK inhibition has also recently shown efficacy in the treatment of TNBC in vivo. Thus we proposed correlative studies examining the impact of eribulin/carboplatin in conjunction with CDK inhibition.

Methods: 30 patients were enrolled between November 2011 and February 2013. Patients received eribulin at 1.4 mg/m2 (intravenously over 2-5 minutes) on days 1 and 8 followed by carboplatin AUC=6 (intravenously over 30 minutes) on day 1 every 21 days for a total of 4 cycles. Definitive surgery was performed 3-8 weeks after completion of therapy, which concluded the duration of the study.

Our primary endpoint was to determine the pCR in TNBC patients treated with the combination of carboplatin and eribulin. Secondary objectives included determination of the clinical response rate, toxicity evaluation, in addition to correlative markers including TLE3, Smad3, cyclins/CDKs, and PIN1. Additionally, we examined the effect of eribulin in combination with a CDK2 inhibitor on proliferation and the expression levels of phosphorylated Smad3 (p-Smad3-179) in vitro using TNBC MDA-MB-231 cells.

Results: There was an initial safety run-in to evaluate the appropriate dose of eribulin in the study population. After the 10th patient, the study was temporarily suspended; toxicity was assessed for the first 10 patients (cycle 1 only) to assess whether eribulin at 1.4mg/m2 or a dose reduction to 1.1 mg/m2 would be required for the remaining patients. Of the first 10 patients, only 2 of 10 experienced grade 3 or 4 neutropenia, and 0 of 10 patients experienced grade 3 or 4 peripheral neuropathy. Therefore, the study was continued for the remaining 20 patients with eribulin dosed at 1.4 mg/m2 and carboplatin AUC=6.

Thirty of the planned 30 patients have been enrolled to date. Of the 30 patients, 24 have completed therapy and 6 are currently on study. Of the 24 patients who have completed therapy, 11 have achieved a pCR (45.83%). All patients are scheduled to complete therapy by August 2013.

Furthermore, the combination of eribulin and carboplatin was well tolerated with a predictable side effect profile. Of the 24 patients who have completed therapy, 8 (33%) required a dose reduction in eribulin for grade 3 or 4 neutropenia and 1 for neutropenic fever. There were no dose reductions for thrombocytopenia thus far.

Combination studies with eribulin and CDK2 inhibition showed synergistic effects at concentrations of 3 μM and 1 nM for CDK2 inhibitor and eribulin respectively as tested by an MTS assay. Further, in comparison to the control, both treatments alone and in combination resulted in a decrease in the expression levels of p-Smad3-179 as examined using western blotting. Preliminary results using a transcription factor array showed that Eribulin treatment activates p53/73 and Smad3/4 transcription factors, with examination of additional factors in progress.

Conclusion: The combination of carboplatin and eribulin in the neoadjuvant setting appears to be a safe and very promising treatment for TNBC. Also, preliminary in vitro data using the eribulin/CDK2 inhibitor combination suggests a potential therapeutic effect regulated, in part, by downstream TGFβ signaling factors. Statistical analysis re outcomes for the entire study population and correlative study results on pre- and post-treatment tissues are forthcoming.

Citation Format: Sara Barnato Giordano, Shreyas Rao, Randala Hamdan, Jacqueline Jeruss, Kevin Bethke, Nora Hansen, Seema Khan, Jamie Von Roenn, Steven Rosen, William J. Gradishar, Kalliopi Siziopikou, Caitlin Meservey, Virginia Kaklamani. Neoadjuvant phase II trial with eribulin and carboplatin in patients with triple-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A065.