A phase I trial of topotecan plus tivantinib in patients with advanced solid tumors
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Tyrosine kinase inhibitors (TKI) that target MET signaling have shown promise in various types of cancer, including lung cancer. Combination strategies have been proposed and developed to increase their therapeutic index. Based on preclinical synergy between inhibition of MET and topoisomerase I, a phase I study was designed to explore the combination of topotecan with the MET TKI tivantinib.
Eligible patients with advanced solid malignancies for which there was no known effective treatment received topotecan at doses of 1.0–1.5 mg/m2/day for five consecutive days in 21-day cycles with continuous, oral tivantinib given at escalating doses of 120–360 mg orally twice daily. Pharmacokinetic analyses of tivantinib were included. Circulating tumor cells (CTC) were collected serially to identify peripheral changes in MET phosphorylation.
The trial included 18 patients, 17 of whom received treatment. At the planned doses, the combination of topotecan and tivantinib was not tolerable due to thrombocytopenia and neutropenia. The addition of G-CSF to attenuate neutropenia did not improve tolerability. Greater tivantinib exposure, assessed through pharmacokinetic analysis, was associated with greater toxicity. No responses were seen. MET phosphorylation was feasible in CTC, but no changes were seen with therapy.
The combination of topotecan and oral tivantinib was not tolerable in this patient population.
KeywordsTivantinib ARQ-197 Topotecan MET phosphorylation Circulating tumor cells
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under awards UM1 CA186717, P30CA033572 (including work performed in the Biostatistics Core and the Analytical Pharmacology Core), and P30CA014089 [including work performed in the Circulating Tumor Cell (CTC) Research Core and the Biostatistics Core]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Research reported in this publication was also supported by an institutional research Grant from the American Cancer Society to the University of Southern California under award number ACS-IRG 53-5114-0188. The authors would also like to acknowledge the contributions of the additional co-investigators who contributed to the study: Dr. Anthony El-Khoueiry and Dr. Agustin Garcia.
This study was funded by the National Cancer Institute of the National Institutes of Health under awards UM1 CA186717, P30CA033572 (including work performed in the Biostatistics Core and the Analytical Pharmacology Core), and P30CA014089 (including work performed in the Circulating Tumor Cell (CTC) Research Core and the Biostatistics Core). Research reported in this publication was also supported by an institutional research Grant from the American Cancer Society to the University of Southern California under award number ACS-IRG 53-5114-0188.
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Conflict of interest
SVL reports personal fees from Takeda, AstraZeneca, Bristol-Myers Squibb, Lilly, Taiho, and Celgene; grants from Bayer, Clovis, Corvus, Esanex, Lycera, Merck, Oncomed, Threshold, and Medimmune; and grants and personal fees from Genentech, Ignyta, and Pfizer, all outside the submitted work. BJG reports personal fees from Genentech. MK reports personal fees from AstraZeneca. DRG reports personal fees from Celgene, Guardant health, Lilly, Liquid Genomics/NANT and grants and personal fees from AstraZeneca/Medimmune and Genentech. Other authors report no relevant conflicts of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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