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A phase I, first in man study of OSI-7836 in patients with advanced refractory solid tumors: IND.147, a study of the Investigational New Drug Program of the National Cancer Institute of Canada Clinical Trials Group

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Abstract

Purpose: To determine the maximum tolerated dose (MTD), recommended phase II dose (RP2D), safety, tolerability, toxicity profile, dose-limiting toxicities (DLTs), anti-tumor activity and pharmacokinetics of OSI-7836 given IV on day 1 and day 8 every 3 weeks in patients with advanced incurable cancer. Methods: Twenty-seven previously treated patients with advanced or metastatic solid tumors were enrolled in this phase I study conducted by the National Cancer Institute of Canada Clinical Trial Group (NCIC CTG). OSI-7836 was administered IV on day 1 and day 8 every 3 weeks. The dose was initially escalated from 100 to 600 mg/m2 and finally de-escalated to 200 mg/m2 in seven cohorts of patients. Patients were evaluated every other cycle of treatment for radiological response. Pharmacokinetics were performed on day 1 and day 8 of cycle 1 for all patients. Results: Twenty-six patients were evaluable for toxicity. All patients experienced reversible Grade 3 lymphopenia beginning at cycle 1. The maximal delivered dose was 600 mg/m2. MTD was reached at 400 mg/m2. DLTs included fever, fatigue, rash, herpes simplex infection, nausea and vomiting. The RP2D was 200 mg/m2. No objective responses were seen in 21 evaluable patients. Pharmacokinetics were dose proportional, with a mean half-life of 46.0 min and a clearance of 34 l/(h·m2). Conclusion: OSI-7836 given at 200 mg/m2 on day 1 and day 8 every 3 weekly is associated with manageable toxicity and is recommended for further study. While no objective responses were seen, the significant treatment related lymphopenia suggests that hematologic malignancies may warrant further investigation.

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References

  1. Brand R, Capadano M, Tempero M et al (1997) A phase I trial of weekly gemcitabine administered as a prolonged infusion in patients with pancreatic cancer and other solid tumors. Invest New Drugs 15(4):331–341

    Article  PubMed  CAS  Google Scholar 

  2. British Columbia Cancer Agency: Health Professional Info- Cancer Drug Manual: BCCA Cancer Drug Manual: fludarabine and cladribine monographs. http://www.bccancer.bc.ca/HPI/DrugDatabase/DrugIndexPro

  3. Colagiovanni DB, Drolet D, Richardson FC (2002) Nonclinical toxicologic and pharmacokinetic evaluation of the nucleoside analog GS7836. In: Proceedings of the 93rd American Association of Cancer Research 43:211 Abstract 1058

  4. De Jonge MJ, O’Donnell A, Verweij J, Chick J, Hanwell J, Schothorst K et al (2003) Phase I evaluation of OSI-7836- a new nucleoside analogue- using two administration schedules. Clin Cancer Res 9:6080–6081 Abstract A48

    Google Scholar 

  5. Mani S, Kugler JW, Knost JA, Sciortino DF, Gibbons J, Garcia JC et al (1998) Phase II trial of 150-minute weekly infusion of gemcitabine in advanced colorectal cancer: minimal activity in colorectal cancer. Invest New Drugs 16(3):275–278

    Article  PubMed  CAS  Google Scholar 

  6. Moore DF Jr, Pazdur R, Daugherty K, Tarassoff P, Abbruzzeze JL (1992) Phase II study of gemcitabine in advanced colorectal adenocarcinoma. Invest New Drugs 10(4):323–325

    Article  PubMed  Google Scholar 

  7. Ototani N, Whistler RL (1974) Preparation and antitumor activity of 4′-thio analogs of 2,2′-anhydro-1-β-D-arabinofuranosylcytosine. J Med Chem 17(5):535–537

    Article  PubMed  CAS  Google Scholar 

  8. Richardson F, Black C, Richardson K, Franks A, Wells E, Karimi S et al (2005) Incorporation of OSI-7836 into DNA of Calu-6 and H460 xenograft tumors. Cancer Chemother Pharmacol 55(3):213–221

    Article  PubMed  CAS  Google Scholar 

  9. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J et al (2002) Comparison of four chemotherapy regimens for advanced non-small cell lung cancer. N Engl J Med 346:92–98

    Article  PubMed  CAS  Google Scholar 

  10. Seymour L, Eisenhauer E (2001) A review of dose-limiting events in phase I trials: antimetabolites show unpredictable relationships between dose and toxicity. Cancer Chemother Pharmacol 47(1):2–10

    Article  PubMed  CAS  Google Scholar 

  11. Simon RM, Freidlin B, Rubinstein LV et al (1997) Accelerated titration design for phase I clinical trials in oncology. J Natl Cancer Inst 89:1138–1147

    Article  PubMed  CAS  Google Scholar 

  12. Someya H, Shaddix SC, Tiwari KN, Secrist JA III, Parker WB (2003) Phosphorylation of 4′-thio-β-D-arabinofuranosylcytosine (4′-thio-ara-C) and its analogs by human deoxycytidine kinase. J Pharmacol Exp Ther 304(3):1314–1322

    Article  PubMed  CAS  Google Scholar 

  13. Sullivan MP, Buggé CJL, Espinosa OE (2003) Quantitation of OSI-7836 (4′-thio-araC) and OSI-8349 (4′-thio-araU) in human plasma using LC-MS-MS. AAPS PharmSci; 5. Abstract R6012

  14. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L et al (2000) New guidelines to evaluate the response to treatment in solid tumours (RECIST guidelines). J Natl Cancer Inst 92:205–216

    Article  PubMed  CAS  Google Scholar 

  15. Tiwari KN, Shortnacy-Fowler AT, Cappellacci L, Parker WB, Waud WR, Montgomery JA et al (2000) Synthesis of 4′-thio-β-D-arabinofuranosylcytosine and comparison of its anticancer activity with that of ara-C. Nucleosides Nucleotides Nucleic Acids 19(1–2):329–340

    PubMed  CAS  Google Scholar 

  16. Tomkinson BE, Brown E, Hennninger D, Gillette W, Emerson D (2002) The antitumor activity of GS7836 (4′-thio-araC), a nucleoside analog, in mouse xenografts: Comparison to standard cytotoxic agents and schedule dependence. In: Proceedings of the 93rd American Association for Cancer Research 43: 1094 Abstract 5418

  17. Waud WR, Gilbert KS, Shepherd RV, Montgomery JA, Secrist JA III (2003) Preclinical antitumor activity of 4′-thio-β-D-arabinofuranosylcytosine.(4′-thio-ara-C). Cancer Chemother Pharmacol 51(5):422–426

    PubMed  CAS  Google Scholar 

  18. Whistler RL, Doner LW, Nayak GU (1971) 4′-Thio-D-arabinofuranosylpyrimidine nucleosides. J Org Chem 36(1):108–110

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We would like to acknowledge Julie Wolf for her contribution with the pharmacokinetic analyses. Supported by research grant from National Cancer Institute of Canada and OSI Pharmaceuticals

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Authors and Affiliations

  1. The Ottawa Hospital Regional Cancer Centre, 501 Smyth Road, Ottawa, ON, Canada, K1H 8L6

    G. Goss, R. Goel & J. Maroun

  2. University Health Network—Princess Margaret Hospital, Toronto, ON, Canada

    L. L. Siu, E. X. Chen, A. M. Oza & M. Maclean

  3. NCIC Clinical Trials Group, Kingston, ON, Canada

    I. Gauthier, J. Powers, W. Walsh & L. K. Seymour

  4. OSI Pharmaceuticals, Inc., Boulder, CO, USA

    D. W. Drolet & J. Rusk

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  1. G. Goss
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  2. L. L. Siu
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  3. I. Gauthier
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  4. E. X. Chen
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  5. A. M. Oza
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  6. R. Goel
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  7. J. Maroun
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  8. J. Powers
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  9. W. Walsh
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  10. M. Maclean
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  11. D. W. Drolet
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  12. J. Rusk
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  13. L. K. Seymour
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Correspondence to G. Goss.

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Goss, G., Siu, L.L., Gauthier, I. et al. A phase I, first in man study of OSI-7836 in patients with advanced refractory solid tumors: IND.147, a study of the Investigational New Drug Program of the National Cancer Institute of Canada Clinical Trials Group. Cancer Chemother Pharmacol 58, 703–710 (2006). https://doi.org/10.1007/s00280-006-0201-1

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  • DOI: https://doi.org/10.1007/s00280-006-0201-1

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