Highlights
- •This first-in-man clinical trial established the safety, pharmacokinetics, maximum tolerated and recommended phase II dose for the doxorubicin (Dox) prodrug DTS-201 in solid tumour patients.
- •DTS-201 was administered at four dose levels ranging from 80 to 400 mg/m2, equivalent to 45–225 mg/m2 of conventional Dox per administration, resulting in high cumulative anthracycline exposure.
- •Diarrhoea, vomiting and neutropenia were dose limiting and 400 mg/m2 DTS-201 was the maximum tolerated and recommended phase II dose for the enzyme-activated prodrug.
- •DTS-201 is well tolerated and safe in solid tumour patients and is not associated with treatment-related severe cardiac adverse events, even at very high acute and cumulative anthracycline doses tested.
- •More than half of the patients derived clinical benefit during treatment with DTS-201, achieving either disease stabilisation or a confirmed partial response.
Abstract
Purpose
DTS-201 is a doxorubicin (Dox) prodrug that shows encouraging data in experimental
models in terms of both efficacy and safety compared with conventional Dox. The purpose
of this phase I study was to assess the safety profile, to establish the recommended
dose (RD) for clinical phase II studies and to assess potential anticancer activity
of the compound.
Experimental design
DTS-201 was administered as a 1-hour infusion every 3 weeks in eligible patients with
advanced solid tumours according to common clinical phase I criteria. Dose escalation
was performed according to a modified Fibonacci schema.
Results
Twenty-five patients with a median age of 58 years (range, 30–72) were enrolled in
the study. The median number of treatment cycles was 2 (range, 1–8). DTS-201 was administered
at four dose levels (DLs) ranging from 80 to 400 mg/m2, which is equivalent to 45–225 mg/m2 of conventional Dox. No dose-limiting toxicity (DLT) occurred at the first two DLs.
Three DLTs were observed at DL3 and DL4 (diarrhoea for DL3, vomiting and neutropenia
for DL4). DL4 (400 mg/m2) was considered the maximum tolerated dose. Myelosuppression was the main toxicity,
and NCI-CTC grade III–IV neutropenia was common at RD. Non-haematological adverse
reactions were mild to moderate and included nausea, anorexia, asthenia and alopecia.
No treatment-related severe cardiac adverse events were observed.
Conclusions
DTS-201 is well tolerated and safe in heavily pretreated solid tumour patients. A
high equivalent dose of Dox could be delivered without severe drug-related cardiac
events. DTS-201 showed evidence of clinical activity with a confirmed partial response
in a patient with soft-tissue sarcoma. The recommended phase II dose is 400 mg/m2.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to European Journal of CancerAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Risk factors for doxorubicin-induced congestive heart failure.Ann Intern Med. 1979; 91: 710-717
- New insight into epirubicin cardiac toxicity: competing risks analysis of 1097 breast cancer patients.J Natl Cancer Inst. 2008; 100: 1058-1067
- Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity.Phamacol Rev. 2004; 56: 185-229
- Extra-cellularly tumor-activated prodrugs for the selective chemotherapy of cancer/application to doxorubicin and preliminary in vitro and in vivo studies.Cancer Res. 2001; 61: 2843-2846
- CD10 is a key enzyme involved in the activation of tumor-activated peptide prodrug CPI-004Na and novel analogues: implications for the design of novel peptide prodrugs for the therapy of CD10+ tumors.Cancer Res. 2003; 63: 5526-5531
- Thimet oligopeptidase (EC 3.4.24.15) activates CPI-0004Na, an extra-cellularly tumor-activated prodrug of doxorubicin.Eur J Cancer. 2006; 42: 3049-3056
- Secretion of a neuropeptide-metabolizing enzyme similar to endopeptidase 22.19 by glioma C6 cells.Biochem Biophys Res Commun. 1993; 191: 275-281
- The association of metalloendopeptidase EC 3.4.24.15 at the extra-cellular surface of the AtT-20 cell plasma membrane.Brain Res. 1999; 835: 113-124
- Preclinical toxicity, toxicokinetics, and antitumor efficacy studies of DTS-201, a tumor-selective peptidic prodrug of doxorubicin.Clin Cancer Res. 2008; 14: 1258-1265
- New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.J Natl Cancer Inst. 2000; 92: 205-216
- Design and analysis of phase I clinical trials.Biometrics. 1989; 45: 925-937
- Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials.Cancer. 2003; 97: 2869-2879
- Plasma pharmacokinetics of adriamycin and its metabolites in human with normal hepatic and renal function.Cancer Res. 1977; 37: 1416-1420
- Human plasma pharmacokinetics of doxorubicin: comparison of bolus and infusional administrations.Cancer Trea Symp. 1984; 3: 77-83
- Comparative pharmacokinetic study of adriamycin and 4′-epiadriamycin after their simultaneous intravenous administration.Eur J Clin Pharmacol. 1986; 30: 629-631
- Clinical pharmacokinetics of doxorubicin.Clin Pharmacokinet. 1988; 15: 15-31
- Anthracycline-trastuzumab regimens for HER2/Neu-overexpressing breast cancer: current experience and future strategies.Ann Oncol. 2008; 19: 1530-2153
- In vivo antitumoral efficacy of PhAc-ALGP-doxorubicin, an enzyme-activated doxorubicin prodrug, in patient-derived soft tissue sarcoma xenograft models.Mol Cancer Ther. 2017 May 31; (pii: molcanther.0832.2016, [Epub ahead of print])https://doi.org/10.1158/1535-7163.MCT-16-0832
- Phase III study of aldoxorubicin vs investigators' choice as treatment for relapsed/refractory soft tissue sarcomas.in: Oral Abstract Session: Sarcoma, ASCO Annual Meeting. 2017
https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm569950.htm.
Article info
Publication history
Published online: October 19, 2017
Accepted:
September 14,
2017
Received:
September 1,
2017
Identification
Copyright
© 2017 Elsevier Ltd. All rights reserved.
