First-in-man dose escalation and pharmacokinetic study of CAP7.1, a novel prodrug of etoposide,in adults with refractory solid tumours |
| |
| Affiliation: | 1. Comprehensive Cancer Center, Campus Mitte & Campus Benjamin Franklin, Berlin, Germany;2. Institute for Medical Immunology, Campus Virchow-Klinikum, Charité University of Medicine, Berlin, Germany;3. Statistical Services, London, UK;4. M Lassus Consulting, Milan, Italy;5. Kings College, London, UK;6. LYO-X, Basel, Switzerland;7. CellAct Pharma, Dortmund, Germany;1. Breast Cancer Research Centre-Western Australia, Perth, WA, Australia;2. International Drug Development Institute, San Francisco, CA;3. I-BioStat, Hasselt University, Belgium;4. Puma Biotechnology Inc, Los Angeles, CA, USA;1. University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94115, USA;1. Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Center of Pharmacological and Toxicological Research (IFT), ICBM, Program of Molecular and Clinical Pharmacology, Faculty of Medicine, University of Chile, Santiago, Chile;2. Department of Urology, University of Chile Clinical Hospital (HCUCH), Santiago, Chile;3. National Cancer Corporation (CONAC), Santiago, Chile;4. Environmental Health Program, School of Public Health, Faculty of Medicine, University of Chile, Santiago, Chile;5. Department of Processes Management and Care, SSMOC, Santiago, Chile;1. Departments of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA;2. Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA;3. Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA;1. Department for Radiation Oncology, University Hospital Zurich, CH-8091 Zurich, Switzerland;2. Basilea Pharmaceutica International Ltd, CH-4005 Basel, Switzerland;1. NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany;2. Multiple Sclerosis Centre, Klinik Hennigsdorf, Germany |
| |
| Abstract: | ![]()
AimAn open-label, phase I dose-escalation trial was performed in adult patients with various solid cancers to identify the maximum tolerated dose (MTD), to assess the safety, pharmacokinetic profile and anti-tumour activity of the new prodrug CAP7.1. The prodrug is converted to its active moiety etoposide via carboxylesterases in selective cells leading to a better tolerability and higher efficacy in therapeutic resistance cells and children with refractory neuroblastoma.Patients and methodsEligible adult patients with advanced, refractory, solid malignancies received CAP7.1 as intravenous infusion on 5 consecutive days. Doses were escalated in four cohorts consisting of three to six patients, with a starting dose of 45 mg/m2/day. Treatment cycles were repeated in 21-day intervals in the absence of disease progression and prohibitive toxicity. The safety, pharmacokinetics and efficacy were evaluated, and the MTD and dose-limiting toxicity (DLT) were determined.ResultsNineteen patients were assigned to four CAP7.1 dose cohorts (45, 90, 150 and 200 mg/m2/day). CAP7.1 was well tolerated. Haematotoxicity was observed at the two highest dose levels including three DLTs (two febrile neutropenia and one sepsis) only and were reversible with adequate therapy. No organ toxicity was observed. Non-haematological toxicities (mild-moderate) consist mainly of nausea, fatigue, vomiting, pyrexia and alopecia. One partial response and 11 stable diseases were observed as supporting signs of efficacy.ConclusionMTD of CAP7.1 was reached at the dose of 200 mg/m2. A favourable safety profile and initial anti-tumour efficacy of CAP7.1 in therapeutic refractory tumours warrant further evaluation in clinical studies. |
| |
| Keywords: | CAP7.1 Etoposide Prodrug Solid tumours Anti-cancer drug Phase I trial |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
