A first-in-human phase I and pharmacokinetic study of CP-4126 (CO-101), a nucleoside analogue, in patients with advanced solid tumours.
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.
Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow, G12 0YN, UK. balajivenugopal@nhs.net.|Institute of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow, G61 1BD, UK. balajivenugopal@nhs.net.
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Venugopal
Institut Jules Bordet, Université Libre de Bruxelles, 121, Boulevard de Waterloo, 1000, Brussels, Belgium.
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Awada
Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow, G12 0YN, UK.|Institute of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow, G61 1BD, UK.
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TR
Evans
Department of Oncology, Oslo University Hospital, Oslo, Norway.
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Dueland
Institut Jules Bordet, Université Libre de Bruxelles, 121, Boulevard de Waterloo, 1000, Brussels, Belgium.
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Hendlisz
Clavis Pharma ASA, Parkveien 53 B, 0256, Oslo, Norway.
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Rasch
Clavis Pharma ASA, Parkveien 53 B, 0256, Oslo, Norway.
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Hernes
Clavis Pharma ASA, Parkveien 53 B, 0256, Oslo, Norway.
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Hagen
Department of Oncology, Oslo University Hospital, Oslo, Norway.
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Aamdal
D000293:Adolescent; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D015331:Cohort Studies; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D019008:Drug Resistance, Neoplasm; D015507:Drugs, Investigational / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D055815:Young Adult
D000964:Antimetabolites, Antineoplastic; C538828:CP 4126; D015507:Drugs, Investigational; D003841:Deoxycytidine
CO-101; CP-4126; Gemcitabine; Nucleoside transporter; Pancreatic cancer; Pharmacokinetics; hENT1