Please use this identifier to cite or link to this item: https://doi.org/10.1007/s11523-022-00867-0
Title: Phase Ib Dose-Finding Study of Varlitinib Combined with Weekly Paclitaxel With or Without Carboplatin +/- Trastuzumab in Advanced Solid Tumors
Authors: Lee, Matilda Xinwei
Wong, Andrea LA 
Ow, Samuel
Sundar, Raghav 
Tan, David SP 
Soo, Ross A 
Chee, Cheng Ean 
Lim, Joline SJ 
Yong, Wei Peng 
Lim, Siew Eng
Goh, Boon Cher 
Wang, Lingzhi 
Lee, Soo Chin 
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
HER2-POSITIVE BREAST-CANCER
KINASE INHIBITOR
TYROSINE KINASES
5-YEAR ANALYSIS
DOUBLE-BLIND
OPEN-LABEL
LAPATINIB
EGFR
PERTUZUMAB
THERAPY
Issue Date: 23-Feb-2022
Publisher: SPRINGER
Citation: Lee, Matilda Xinwei, Wong, Andrea LA, Ow, Samuel, Sundar, Raghav, Tan, David SP, Soo, Ross A, Chee, Cheng Ean, Lim, Joline SJ, Yong, Wei Peng, Lim, Siew Eng, Goh, Boon Cher, Wang, Lingzhi, Lee, Soo Chin (2022-02-23). Phase Ib Dose-Finding Study of Varlitinib Combined with Weekly Paclitaxel With or Without Carboplatin +/- Trastuzumab in Advanced Solid Tumors. TARGETED ONCOLOGY 17 (2) : 141-151. ScholarBank@NUS Repository. https://doi.org/10.1007/s11523-022-00867-0
Abstract: Background: Varlitinib is a highly potent, small-molecule, pan-HER inhibitor targeting HER1, HER2, and HER4. It has demonstrated activity in gastric, biliary tract, and breast cancers. Objective: We conducted a phase Ib dose confirmation study to determine safety and early efficacy signals of varlitinib in combination with chemotherapy (paclitaxel ± carboplatin) ± subcutaneous trastuzumab. Methods: Eligible patients had advanced or metastatic solid tumors. A 3+3 dose de-escalation study design was used and pharmacokinetic analyses of varlitinib and paclitaxel were performed. Results: Thirty-seven patients were enrolled into eight cohorts with median 4 (0–14) prior lines of palliative systemic therapies. Carboplatin area under the curve 1.5 and paclitaxel 80 mg/m2 weekly with varlitinib 500 mg twice daily continuously was de-escalated over four dose levels to 300 mg twice daily intermittently (4 days on, 3 days off) due to dose-limiting toxicities, most commonly neutropenia, febrile neutropenia, and electrolyte disturbances, with the triplet combination deemed intolerable and unable to be developed further. Varlitinib was then combined with paclitaxel alone; the recommended phase II dose of varlitinib was 300 mg twice daily intermittently. The addition of subcutaneous trastuzumab 600 mg was safe with no dose-limiting toxicities. Thirty-one patients were evaluable for response: 35.5% partial response, 41.9% stable disease. Twenty patients had HER2+ metastatic breast cancer with a median of 4 (0–14) treatment lines, 8/20 continued on single-agent varlitinib after completing chemotherapy for a median of 5.1 (range 2.0–13.3) months. A pharmacokinetic analysis showed that plasma exposure of varlitinib was dose dependent. Varlitinib administration did not significantly affect the maximum concentration or area under the curve of paclitaxel. Conclusions: The recommended phase II dose of varlitinib with paclitaxel is 300 mg twice daily intermittently dosed. This is active in HER2+ metastatic breast cancer. Subcutaneous trastuzumab can be added safely to varlitinib and paclitaxel. This combination is currently being evaluated as neoadjuvant therapy in HER2+ breast cancer (NCT02396108). Clinical Trial Registration: NCT02396108, date of registration: 25 March, 2015.
Source Title: TARGETED ONCOLOGY
URI: https://scholarbank.nus.edu.sg/handle/10635/228500
ISSN: 1776-2596
1776-260X
DOI: 10.1007/s11523-022-00867-0
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