Summary
Vinflunine is to date the only registered agent for second-line treatment of metastatic urothelial cell carcinoma (UCC) in Europe. However, the effect is modest. Pemetrexed has demonstrated some single-agent activity in this disease entity. In order to improve treatment possibilities for UCC patients, a phase I trial (VINTREX) was undertaken to assess the safety of vinflunine and pemetrexed in metastatic UCC patients. A dose escalation design was planned to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of a vinflunine/pemetrexed combination. Pemetrexed was added to vinflunine dosed at 280 mg/m2 on day 1 of a 21-day cycle. Three levels of pemetrexed were planned starting at 400 mg/m2. Four patients were enrolled with a mean age of 66 years and with a mean number of prior GC-cycles of 6,8. Two DLT’s were observed at the lowest dose-level in cohort 1. One patient experienced grade 4 thrombocytopenia and a second demonstrated hepatobiliary toxicity grade 3 with an increase in alanine aminotransaminase. Most common grade 3 and 4 adverse events were anemia, thrombocytopenia and neutropenia. Three out of four patients received 3 cycles of pemetrexed and vinflunine, all had progressive disease. Based on these observations and due to protocol design, the study was interrupted at dose level 1 for safety reasons. The combined therapy of vinflunine (Javlor®, Pierre Fabre Pharma) and pemetrexed (Alimta®, Eli Lilly) is poorly tolerated in metastatic UCC patients. The combination cannot be recommended for further investigations in metastatic UCC.
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This study was funded by an unrestricted grant from Pierre-Fabre.
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HP has received research grants from Roche and MSD, and has been in the advisory board for Roche. HvdM declares no conflict of interest. MA has been in the advisory board for MSD and Roche. AU has received research grants from Pierre-Fabre and Bayer, and has been in the advisory board for Roche, MSD and Pierre-Fabre.
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All procedures performed in the present study were in accordance with the ethical standards of the national research committee and with the 1964 Helsinki declaration and its later amendments.
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Informed consent was obtained from all individual participants included in the study.
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Pappot, H., von der Maase, H., Ullén, A. et al. Combined treatment with pemetrexed and vinflunine in patients with metastatic urothelial cell carcinoma after prior platinum-containing chemotherapy – results of an exploratory phase I study. Invest New Drugs 36, 615–618 (2018). https://doi.org/10.1007/s10637-017-0528-y
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DOI: https://doi.org/10.1007/s10637-017-0528-y