Summary
Introduction This phase I, multicenter, open-label, single-arm, dose-escalation study evaluated the safety, pharmacokinetics and antitumor activity of APTO-253, an inducer of the transcription factor KLF4, in adults with advanced solid tumors. Methods APTO-253 was administered IV on days 1 and 2, and 15 and 16 of each 28 day cycle; the dose were escalated from 20 to 387 mg/m2 in 9 cohorts until DLT was observed. Results Thirty-two patients were treated on this trial (50 % colon cancer, 22 % other gastrointenstinal malignancies and 18 % non-small cell lung cancer). Fatigue was the only drug-related treatment-emergent adverse event to occur in >10 % of patients. Dose-limiting toxicities of hypersensitivity reaction and transient hypotension despite prophylaxis occurred at 387 mg/m2 which led to identification of 298 mg/m2 as the MTD. Only 1 patient had any drug-related treatment-emergent grade 3 adverse event at or below 229 mg/m2. A total of 21 patients underwent at least one restaging after 2 cycles; 11 patients discontinued prior to the end of cycle 2 due to adverse events (9) or disease progression (2). The best overall response was stable disease (SD) in 5 of these 21 (23.8 %) with durations ranging from 3.6 to 8.4 months. Conclusion APTO-253 was well tolerated at the Phase 2 recommended dose and produced evidence of antitumor activity in the form of stable disease in patients with advanced solid tumors. Based on the drug levels achieved and the lower frequency of treatment-emergent adverse events encountered, 229 mg/m2 was selected as the recommended Phase 2 dose. Overall APTO-253 was found to be well tolerated and to have favorable pharmacokinetics, and treatment was associated with stable disease in 5 of 21 (24 %) of patients with far advanced solid tumors.
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Funding
This study was sponsored by Aptose Biosciences. No author received financial support related to the development of this article other than Dr. Stephen Howell who served as consultant for the preparation of the manuscript.
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All authors participated in the collection and analysis of data, manuscript editing and provide final approval of the manuscript.
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P. Murray and S. Zhou are employees of Aptose Biosciences the sponsor of this trial. Dr. Stephen Howell is a consultant to Aptose Biosciences. No potential conflicts of interest were disclosed by the other authors.
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All procedures performed in these 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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Informed consent was obtained from all individual participants included in this study.
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Cercek, A., Wheler, J., Murray, P.E. et al. Phase 1 study of APTO-253 HCl, an inducer of KLF4, in patients with advanced or metastatic solid tumors. Invest New Drugs 33, 1086–1092 (2015). https://doi.org/10.1007/s10637-015-0273-z
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DOI: https://doi.org/10.1007/s10637-015-0273-z