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A phase I clinical trial of FOLFIRI in combination with the pan-cyclin-dependent kinase (CDK) inhibitor flavopiridol

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Abstract

Background

The cyclin-dependent kinase inhibitor flavopiridol increases irinotecan- and fluorouracil-induced apoptosis. We conducted a phase I trial of FOLFIRI + flavopiridol in patients with advanced solid tumors.

Design

FOLFIRI + flavopiridol were administered every 2 weeks. Based on sequence-dependent inhibition, flavopiridol was given 3 h after irinotecan but before 5-FU. Two maximum tolerated doses were determined, one with flavopiridol administered over 1 h, and one with flavopiridol split as a 30-min bolus followed by a 4-h infusion.

Results

A total of 74 patients were enrolled and 63 were evaluable. The MTD with FOLFIRI was flavopiridol 80 mg/m2 over 1 h or 35 mg/m2 bolus + 35 mg/m2 over 4 h. Dose-limiting toxicities were diarrhea, fatigue, neutropenia, and neuropathy. Clinical activity included 2 partial responses in small bowel cancer and bladder cancer and 1 complete response in mucosal melanoma. Stable disease was seen in 22 patients. Pharmacokinetic studies showed increasing Cmax with increasing flavopiridol dose. Clinical benefit was correlated with the presence of wild-type p53. Of 25 patients with colorectal cancer, 11 had as best response SD for >3 m (median 6 m, range 4.2–15.4 m), despite failing ≥1 irinotecan-containing regimen.

Conclusions

Treatment with flavopiridol and FOLFIRI is a safe and effective regimen. Concentrations of flavopiridol that enhance the effects of FOLFIRI can be achieved. Clinical activity is encouraging and includes prolonged stable disease in patients with irinotecan-refractory colorectal cancer.

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Acknowledgments

This work was supported by the National Cancer Institute at the US National Institutes of Health [R01CA67819 to GKS].

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Authors and Affiliations

  1. Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA

    Mark A. Dickson, Richard D. Carvajal, Lauren M. Cane, Heather J. Dials & Gary K. Schwartz

  2. Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Manish A. Shah & Archie Tse

  3. Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Dana Rathkopf

  4. Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Nian Wu

  5. Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Robert A. Lefkowitz

  6. Biostatistics Service, Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Mithat Gonen

Authors
  1. Mark A. Dickson
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  2. Manish A. Shah
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  3. Dana Rathkopf
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  4. Archie Tse
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  5. Richard D. Carvajal
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  6. Nian Wu
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  7. Robert A. Lefkowitz
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  8. Mithat Gonen
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  9. Lauren M. Cane
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  10. Heather J. Dials
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  11. Gary K. Schwartz
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Corresponding author

Correspondence to Gary K. Schwartz.

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Dickson, M.A., Shah, M.A., Rathkopf, D. et al. A phase I clinical trial of FOLFIRI in combination with the pan-cyclin-dependent kinase (CDK) inhibitor flavopiridol. Cancer Chemother Pharmacol 66, 1113–1121 (2010). https://doi.org/10.1007/s00280-010-1269-1

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  • DOI: https://doi.org/10.1007/s00280-010-1269-1

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