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Investigational New Drugs
Published in: Investigational New Drugs 6/2014

01-12-2014 | PHASE I STUDIES

Phase I dose-escalation study of cabazitaxel administered in combination with cisplatin in patients with advanced solid tumors

Authors: A. Craig Lockhart, Shankar Sundaram, John Sarantopoulos, Monica M. Mita, Andrea Wang-Gillam, Jennifer L. Moseley, Stephanie L. Barber, Alex R. Lane, Claudine Wack, Laurent Kassalow, Jean-François Dedieu, Alain C. Mita

Published in: Investigational New Drugs | Issue 6/2014

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Summary

Introduction Cabazitaxel is a second-generation taxane with in vivo activity against taxane-sensitive and -resistant tumor cell lines and tumor xenografts. Cabazitaxel/cisplatin have therapeutic synergism in tumor-bearing mice, providing a rationale for assessing this combination in patients with solid tumors. Methods The primary objectives of this study were to determine dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of a cabazitaxel/cisplatin combined regimen (Part 1) and to assess antitumor activity at the MTD (Part 2). Safety and pharmacokinetics (PK) were also examined. Results Twenty-five patients with advanced solid tumors were enrolled (10 in Part 1; 15 in Part 2). In Part 1, two dose levels were evaluated; the MTD for cabazitaxel/cisplatin (given Q3W) was 15/75 mg/m2. DLTs occurring during Cycle 1 at the maximum administered dose (20/75 mg/m2; acute renal failure and febrile neutropenia) and the MTD (febrile neutropenia and hypersensitivity despite pre-medication) were as expected for taxane/platinum combinations. For the 18 patients treated at the MTD, the most frequent possibly related non-hematologic treatment-emergent adverse events (Grade ≥3) were nausea (16.7 %), fatigue, acute renal failure and decreased appetite (each 11.1 %). Neutropenia was the most frequent treatment-emergent Grade ≥3 hematologic laboratory abnormality at the MTD (77.8 %). The best overall response at the MTD was stable disease, observed in 66.7 % of patients. PK results of the combination did not appear to differ from single-agent administration for each agent. Conclusion Combination treatment with cabazitaxel/cisplatin had a manageable safety profile; no PK interactions were evident. The recommended Phase II dose for this combination is cabazitaxel/cisplatin 15/75 mg/m2 administered every 3 weeks. Antitumor activity findings suggest that further evaluation of this combination in disease-specific trials is warranted.
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Metadata
Title
Phase I dose-escalation study of cabazitaxel administered in combination with cisplatin in patients with advanced solid tumors
Authors
A. Craig Lockhart
Shankar Sundaram
John Sarantopoulos
Monica M. Mita
Andrea Wang-Gillam
Jennifer L. Moseley
Stephanie L. Barber
Alex R. Lane
Claudine Wack
Laurent Kassalow
Jean-François Dedieu
Alain C. Mita
Publication date
01-12-2014
Publisher
Springer US
Published in
Investigational New Drugs / Issue 6/2014
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-014-0145-y

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