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Thalidomide and celecoxib as potential modulators of irinotecan’s activity in cancer patients

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Abstract

Purpose: Nuclear factor-κB (NF-κB) activation induces resistance to irinotecan. Preclinically, thalidomide and COX-2 inhibitors reduce NF-κB activation. We tested the feasibility of combining irinotecan with thalidomide and thalidomide/celecoxib in patients with refractory malignancies. Patients/methods: The study was conducted in two parts. First, the optimal dose of thalidomide (400 or 200 mg daily) in combination with irinotecan 125 mg/m2 days 1 and 8 every 3 weeks was determined. In the second part, celecoxib 400 mg twice-daily was added to irinotecan/thalidomide. Pharmacokinetics of irinotecan and thalidomide alone or concurrently were evaluated. Tumor necrosis factor alpha, beta-fibroblast growth factor, and NF-κB activation were measured in blood mononuclear cells (PBMC). No CYP450 enzyme inducers/inhibitors were allowed. Results: Thirty-six patients were enrolled: Eleven received thalidomide 400 mg, 13 thalidomide 200 mg and 12 thalidomide 400 mg and celecoxib, with irinotecan. For the two-drug combination, there was a higher rate of moderate/severe diarrhea/myelosuppression with thalidomide 200 mg. Thus thalidomide 400 mg was combined with celecoxib. The triple combination resulted in similar toxicity as the doublet with the lower thalidomide dose. Concurrent administration of irinotecan/thalidomide did not influence pharmacokinetics. Anti-tumor responses occurred in two patients and prolonged stabilization in eight others. NF-κB activation increased over time. Patients experiencing tumor response or prolonged stabilization had lower NF-κB activation, albeit not statistically significant (P = 0.124). Conclusions: The combination of thalidomide/irinotecan is safe and devoid of PK interactions. Thalidomide 400 mg appeared more suitable for combination, whereas the addition of celecoxib did not improve tolerability. Tumor-specific studies in patients with lesser prior treatment will be necessary to establish the therapeutic impact of the combinations.

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Authors and Affiliations

  1. Department of Medicine, The Ohio State University College of Medicine and Public Health, B406 Starling-Loving Hall, 320 West 10th Avenue, Columbus, OH, 43210-1240, USA

    Miguel Villalona-Calero, Larry Schaaf, Gregory Otterson, Kevin Panico, Wenrui Duan & Manisha Shah

  2. OSU Center for Biostatistics, The Ohio State University College of Medicine and Public Health, B406 Starling-Loving Hall, 320 West 10th Avenue, Columbus, OH, 43210-1240, USA

    Gary Phillips & Donn Young

  3. Clinical Trials Office, The Ohio State University College of Medicine and Public Health, B406 Starling-Loving Hall, 320 West 10th Avenue, Columbus, OH, 43210-1240, USA

    Barbara Kleiber

  4. The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Wan-Hong Wu & John Kuhn

Authors
  1. Miguel Villalona-Calero
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  2. Larry Schaaf
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  3. Gary Phillips
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  7. Barbara Kleiber
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  8. Manisha Shah
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  9. Donn Young
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  10. Wan-Hong Wu
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Correspondence to Miguel Villalona-Calero.

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Villalona-Calero, M., Schaaf, L., Phillips, G. et al. Thalidomide and celecoxib as potential modulators of irinotecan’s activity in cancer patients. Cancer Chemother Pharmacol 59, 23–33 (2007). https://doi.org/10.1007/s00280-006-0249-y

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  • DOI: https://doi.org/10.1007/s00280-006-0249-y

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