B Venugopal1,2, A Awada3, T R J Evans4,5, S Dueland6, A Hendlisz3, W Rasch7, K Hernes7, S Hagen7, S Aamdal6. 1. Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow, G12 0YN, UK. balajivenugopal@nhs.net. 2. Institute of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow, G61 1BD, UK. balajivenugopal@nhs.net. 3. Institut Jules Bordet, Université Libre de Bruxelles, 121, Boulevard de Waterloo, 1000, Brussels, Belgium. 4. Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow, G12 0YN, UK. 5. Institute of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow, G61 1BD, UK. 6. Department of Oncology, Oslo University Hospital, Oslo, Norway. 7. Clavis Pharma ASA, Parkveien 53 B, 0256, Oslo, Norway.
Abstract
BACKGROUND: CP-4126 (gemcitabine elaidate, previously CO-101) is a lipid-drug conjugate of gemcitabine designed to circumvent human equilibrative nucleoside transporter1-related resistance to gemcitabine. The purpose of this study was to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of CP-4126, and to describe its pharmacokinetic profile. METHODS: Eligible patients with advanced refractory solid tumours, and adequate performance status, haematological, renal and hepatic function, were treated with one of escalating doses of CP-4126 administered by a 30-min intravenous infusion on days 1, 8 and 15 of a 28-day cycle. Blood and urine samples were collected to determine the pharmacokinetics (PKs) of CP-4126. RESULTS: Forty-three patients, median age 59 years (range 18-76; male = 27, female = 16), received one of ten dose levels (30-1600 mg/m(2)). Dose-limiting toxicities included grade 3 anaemia, grade 3 fatigue and grade 3 elevation of transaminases. The MTD and RP2D were 1250 mg/m(2) on basis of the toxicity and PK data. CP-4126 followed dose-dependent kinetics and maximum plasma concentrations occurred at the end of CP-4126 infusion. Seven patients achieved stable disease sustained for ≥3 months, including two patients with pancreatic cancer who had progressed on or after gemcitabine exposure. CONCLUSIONS: CP-4126 was well tolerated with comparable toxicity profile to gemcitabine. Future studies are required to determine its anti-tumour efficacy, either alone or in combination with other cytotoxic chemotherapy regimens.
BACKGROUND: CP-4126 (gemcitabine elaidate, previously CO-101) is a lipid-drug conjugate of gemcitabine designed to circumvent human equilibrative nucleoside transporter1-related resistance to gemcitabine. The purpose of this study was to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of CP-4126, and to describe its pharmacokinetic profile. METHODS: Eligible patients with advanced refractory solid tumours, and adequate performance status, haematological, renal and hepatic function, were treated with one of escalating doses of CP-4126 administered by a 30-min intravenous infusion on days 1, 8 and 15 of a 28-day cycle. Blood and urine samples were collected to determine the pharmacokinetics (PKs) of CP-4126. RESULTS: Forty-three patients, median age 59 years (range 18-76; male = 27, female = 16), received one of ten dose levels (30-1600 mg/m(2)). Dose-limiting toxicities included grade 3 anaemia, grade 3 fatigue and grade 3 elevation of transaminases. The MTD and RP2D were 1250 mg/m(2) on basis of the toxicity and PK data. CP-4126 followed dose-dependent kinetics and maximum plasma concentrations occurred at the end of CP-4126 infusion. Seven patients achieved stable disease sustained for ≥3 months, including two patients with pancreatic cancer who had progressed on or after gemcitabine exposure. CONCLUSIONS: CP-4126 was well tolerated with comparable toxicity profile to gemcitabine. Future studies are required to determine its anti-tumour efficacy, either alone or in combination with other cytotoxic chemotherapy regimens.
Authors: Siyuan Zeng; Marina Pöttler; Bin Lan; Robert Grützmann; Christian Pilarsky; Hai Yang Journal: Int J Mol Sci Date: 2019-09-11 Impact factor: 5.923
Authors: Caixia Wang; Yuanqiang Zheng; Michael A Sand Oval; Solange A Valdes; Zhe Chen; Dharmika S Lansakara-P; Maolin Du; Yanchun Shi; Zhengrong Cui Journal: Oncotarget Date: 2017-09-23
Authors: Sarah P Blagden; Ivana Rizzuto; Puvan Suppiah; Daniel O'Shea; Markand Patel; Laura Spiers; Ajithkumar Sukumaran; Nishat Bharwani; Andrea Rockall; Hani Gabra; Mona El-Bahrawy; Harpreet Wasan; Robert Leonard; Nagy Habib; Essam Ghazaly Journal: Br J Cancer Date: 2018-09-12 Impact factor: 7.640