Dose-confirmation Study of ASLAN001 Combined With Weekly Paclitaxel and Carboplatin in Advanced Solid Tumours, Followed by a Study in Patients With Stage I-III HER2 Positive Breast Cancer

Summary

The current standard of care for stage I-III HER2-positive breast cancer is adjuvant chemotherapy combined with 1 year of adjuvant trastuzumab. Neoadjuvant chemotherapy in early stage breast cancer has the advantages of i) tumour downsizing, ii) higher breast conservation rates, and iii) enabling the evaluation of tumour biology. Pathologic complete response following neoadjuvant chemotherapy has been shown to be an independent, strong predictor of outcome in operable HER2-positive breast cancer. The addition of neoadjuvant anti-HER2 therapy to chemotherapy results in a 2-3 fold increase in pCR rates in operable HER2-positive breast cancer. However, the optimal neoadjuvant regimen has not been defined in HER2-positive breast cancer. The investigators recently completed a phase II study of neoadjuvant lapatinib combined with weekly paclitaxel/ carboplatin in stage I-III HER2-positive breast cancer. Preliminary analysis suggested that the utility of the regimen might have been limited by its unfavourable efficacy/ toxicity ratio. ASLAN001 is a small molecule tyrosine kinase inhibitor against HER1, HER2, and HER4. Preclinical data have shown ASLAN001 to be more potent than lapatinib and neratinib in inhibiting HER1 and HER2, and early phase clinical studies have demonstrated superior pharmacokinetics and pharmacodynamic target inhibition compared to lapatinib. Furthermore, ASLAN001 has demonstrated a better safety profile than lapatinib in early phase studies. • The investigators hypothesize that ASLAN001 combined with paclitaxel/carboplatin will induce favorable pathological complete response (of at least 30%) in stage I-III HER2 positive breast cancer, with a more favourable safety profile than lapatinib combined with paclitaxel/carboplatin.

Timeline

Start

2015-03

Primary completion

2018-03

Completion

2019-03

Publications

• Background Wong A, Tan SH, Soh T, Tan CS. Phase II study of neoadjuvant weekly paclitaxel and carboplatin with lapatinib in HER2+ breast cancer. J Clin Oncol 32:5s, (suppl; abstr 619), 2014.
• Background Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1673-84. doi: 10.1056/NEJMoa052122.
• Background Perez EA, Romond EH, Suman VJ, Jeong JH, Davidson NE, Geyer CE Jr, Martino S, Mamounas EP, Kaufman PA, Wolmark N. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol. 2011 Sep 1;29(25):3366-73. doi: 10.1200/JCO.2011.35.0868. Epub 2011 Jul 18.
• Lee MX, Wong ALA, Ow S, Sundar R, Tan DSP, Soo RA, Chee CE, Lim JSJ, Yong WP, Lim SE, Goh BC, Wang L, Lee SC. Phase Ib Dose-Finding Study of Varlitinib Combined with Weekly Paclitaxel With or Without Carboplatin +/- Trastuzumab in Advanced Solid Tumors. Target Oncol. 2022 Mar;17(2):141-151. doi: 10.1007/s11523-022-00867-0. Epub 2022 Feb 23.

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Indications