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A first-in-human phase I and pharmacokinetic study of CP-4126 (CO-101), a nucleoside analogue, in patients with advanced solid tumours

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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/m2). Dose-limiting toxicities included grade 3 anaemia, grade 3 fatigue and grade 3 elevation of transaminases. The MTD and RP2D were 1250 mg/m2 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.

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References

  1. Burris HA, Moore MJ, Andersen J et al (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15:2403–2413

    CAS  PubMed  Google Scholar 

  2. Sandler AB, Nemunaitis J, Denham C et al (2000) Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 18:122–130

    CAS  PubMed  Google Scholar 

  3. Damaraju VL, Damaraju S, Young JD et al (2003) Nucleoside anticancer drugs: the role of nucleoside transporters in resistance to cancer chemotherapy. Oncogene 22:7524–7536

    Article  CAS  PubMed  Google Scholar 

  4. Mori R, Ishikawa T, Ichikawa Y et al (2007) Human equilibrative nucleoside transporter 1 is associated with the chemosensitivity of gemcitabine in human pancreatic adenocarcinoma and biliary tract carcinoma cells. Oncol Rep 17:1201–1205

    CAS  PubMed  Google Scholar 

  5. Mackey JR, Mani RS, Selner M et al (1998) Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer Res 58:4349–4357

    CAS  PubMed  Google Scholar 

  6. Mackey JR, Yao SY, Smith KM et al (1999) Gemcitabine transport in xenopus oocytes expressing recombinant plasma membrane mammalian nucleoside transporters. J Natl Cancer Inst 91:1876–1881

    Article  CAS  PubMed  Google Scholar 

  7. Bergman AM, Adema AD, Balzarini J et al (2011) Antiproliferative activity, mechanism of action and oral antitumor activity of CP-4126, a fatty acid derivative of gemcitabine, in in vitro and in vivo tumor models. Invest N Drugs 29:456–466

    Article  CAS  Google Scholar 

  8. Venugopal B, Evans TRJ (2011) Gemcitabine elaidate. Drugs Fut 36:427

    Article  CAS  Google Scholar 

  9. Stuurman FE, Lolkema MP, Huitema AD et al. (2013) A phase 1 comparative pharmacokinetic and cardiac safety study of two intravenous formulations of CO-101 in patients with advanced solid tumors. J Clin Pharmacol 53:878–883

    Article  CAS  PubMed  Google Scholar 

  10. Therasse P, Arbuck SG, Eisenhauer EA, European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada et al (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216

    Article  CAS  PubMed  Google Scholar 

  11. Gupta N, Ahmed I, Steinberg H et al (2002) Gemcitabine-induced pulmonary toxicity: case report and review of the literature. Am J Clin Oncol 25:96–100

    Article  PubMed  Google Scholar 

  12. Maniwa K, Tanaka E, Inoue T et al (2003) An autopsy case of acute pulmonary toxicity associated with gemcitabine. Intern Med 42:1022–1025

    Article  PubMed  Google Scholar 

  13. Peters GJ, Clavel M, Noordhuis P et al. (2007) Clinical phase I and pharmacology study of gemcitabine (2′,2′-difluorodeoxycytidine) administered in a two-weekly schedule. J Chemother 19:212–221

    Article  CAS  PubMed  Google Scholar 

  14. Abbruzzese J, Grunewald R, Weeks E et al. (1991) A phase I clinical plasma and cellular pharmacology study of gemcitabine. J Clin Oncol 9:491–498

    CAS  PubMed  Google Scholar 

  15. Farrell JJ, Elsaleh H, Garcia M et al (2009) Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. Gastroenterology 136:187–195

    Article  PubMed  Google Scholar 

  16. Giovannetti E, Del Tacca M, Mey V et al (2006) Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine. Cancer Res 66:3928–3935

    Article  CAS  PubMed  Google Scholar 

  17. Poplin E, Wasan H, Rolfe L et al (2013) Randomized, multicenter, Phase II study of CO-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma: including a prospective evaluation of the role of hENT1 in gemcitabine or CO-101 sensitivity. J Clin Oncol 31:4453–4461

    Article  CAS  PubMed  Google Scholar 

  18. Li D, Pant S, Ryan DP et al (2014) A phase II, open-label, multicenter study to evaluate the antitumor efficacy of CO-1.01 as second-line therapy for gemcitabine-refractory patients with stage IV pancreatic adenocarcinoma and negative tumor hENT1 expression. Pancreatology 14:398–402

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors are grateful to the patients and their carers, who participated in this study and gratefully acknowledge the support of the study staff at the participating study sites.

Funding

The study was supported by Clavis Pharma ASA, Oslo, Norway. The Glasgow site was supported by the Glasgow ECMC (Experimental Cancer Medicine Centre), which is funded by Cancer Research UK, and the Chief Scientist’s Office, Scotland.

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Correspondence to B. Venugopal.

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Conflict of interest

B. Venugopal, A. Awada, S. Dueland, A. Hendlisz, S. Aamdal: None. T. R. J. Evans has received an honorarium for consultancy from Clovis for CO-1.01 (CP-4126) and research funding from Clavis Pharma and from Clovis Oncology for the conduct of this and subsequent studies. W. Rasch, K. Hernes and S. Hagen: Former employee at Clavis Pharma ASA.

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Venugopal, B., Awada, A., Evans, T.R.J. et al. A first-in-human phase I and pharmacokinetic study of CP-4126 (CO-101), a nucleoside analogue, in patients with advanced solid tumours. Cancer Chemother Pharmacol 76, 785–792 (2015). https://doi.org/10.1007/s00280-015-2846-0

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  • DOI: https://doi.org/10.1007/s00280-015-2846-0

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