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Phase I safety and pharmacokinetic study of YM155, a potent selective survivin inhibitor, in combination with erlotinib in patients with EGFR TKI refractory advanced non-small cell lung cancer.
- Source :
-
Cancer Chemotherapy & Pharmacology . Aug2020, Vol. 86 Issue 2, p211-219. 9p. - Publication Year :
- 2020
-
Abstract
- <bold>Purpose: </bold>This phase I study was conducted to evaluate the safety and pharmacokinetics of YM155, a potent, selective survivin inhibitor, in combination with erlotinib in patients with EGFR TKI refractory advanced non-small cell lung cancer (NSCLC).<bold>Methods: </bold>The pimary objectives were to evaluate the safety and tolerability of YM155 at escalating doses (3.6, 4.8, 6.0, and 8.0 mg/m2/days) administered every 3 weeks as continuous intravenous infusion over 168 h in combination with erlotinib at a fixed dose (150 mg, once a day). Secondary objectives were to assess the pharmacokinetics of YM155, antitumor activity, and the relationship between biomarkers and efficacy. The changes in survivin expression in biopsied tumor pre- and post-YM155 administration and serum cytokine levels were also analyzed.<bold>Results: </bold>Fifteen patients were treated. The most common YM155-related adverse event was the presence of urine microalbumin, whereas grades 3/4 toxicities were rare. One patient who received 4.8  mg/m2/days YM155 developed a dose-limiting grade 2 serum creatinine elevation. YM155 exposure in plasma showed dose proportionality across all dose ranges tested. No pharmacokinetic interaction occurred between YM155 and erlotinib. The serum cytokines IL-8, G-CSF, and MIP-1b showed decreasing trends in patients who achieved progression-free survival of ≥ 12 weeks. Durable stable disease for ≥ 24 weeks was observed in two patients.<bold>Conclusion: </bold>Up to 8.0 mg/m2/days YM155 administered every 3 weeks in combination with erlotinib exhibited a favorable safety profile and moderate clinical efficacy. These results suggest that inhibiting survivin is a potential therapeutic strategy for select patients with EGFR TKI refractory NSCLC.<bold>Trial Registration: </bold>UMIN000031912 at UMIN Clinical Trials Registry (UMIN-CTR). [ABSTRACT FROM AUTHOR]
- Subjects :
- *NON-small-cell lung carcinoma
*PEMETREXED
*CLINICAL trial registries
*PHARMACOKINETICS
*THERAPEUTIC use of antineoplastic agents
*LUNG cancer
*QUINONE
*RESEARCH
*PROTEIN kinase inhibitors
*RESEARCH methodology
*LUNG tumors
*CELL receptors
*PROGNOSIS
*EVALUATION research
*MEDICAL cooperation
*IMIDAZOLES
*COMPARATIVE studies
*RESEARCH funding
*DRUG resistance in cancer cells
*LONGITUDINAL method
*PHARMACODYNAMICS
Subjects
Details
- Language :
- English
- ISSN :
- 03445704
- Volume :
- 86
- Issue :
- 2
- Database :
- Academic Search Index
- Journal :
- Cancer Chemotherapy & Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 145053878
- Full Text :
- https://doi.org/10.1007/s00280-020-04112-1