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Phase I study of nelfinavir in liposarcoma

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Abstract

Purpose

HIV protease inhibitors are associated with HIV protease inhibitor–related lipodystrophy syndrome. We hypothesized that liposarcomas would be similarly susceptible to the apoptotic effects of an HIV protease inhibitor, nelfinavir.

Methods

We conducted a phase I trial of nelfinavir for liposarcomas. There was no limit to prior chemotherapy. The starting dose was 1,250 mg twice daily (Level 1). Doses were escalated in cohorts of three to a maximally evaluated dose of 4,250 mg (Level 5). One cycle was 28 days. Steady-state pharmacokinetics (PKs) for nelfinavir and its primary active metabolite, M8, were determined at Levels 4 (3,000 mg) and 5.

Results

Twenty subjects (13 males) were enrolled. Median (range) age was 64 years (37–81). One subject at Level 1 experienced reversible, grade 3 pancreatitis after 1 week and was replaced. No other dose-limiting toxicities were observed. Median (range) number of cycles was 3 (0.6–13.5). Overall best responses observed were 1 partial response, 1 minor response, 4 stable disease, and 13 progressive disease. Mean peak plasma levels and AUCs for nelfinavir were higher at Level 4 (7.3 mg/L; 60.9 mg/L × h) than 5 (6.3 mg/L; 37.7 mg/L × h). The mean ratio of M8:nelfinavir AUCs for both levels was ~1:3.

Conclusions

PKs demonstrate auto-induction of nelfinavir clearance at the doses studied, although the mechanism remains unclear. Peak plasma concentrations were within range where anticancer activity was demonstrated in vitro. M8 metabolite is present at ~1/3 the level of nelfinavir and may also contribute to the anticancer activity observed.

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Acknowledgments

Grant support for this trial was provided by Pfizer Inc. and the FDA Orphan Products Development Grants Program (R01FD003006).

Conflict of interest

None.

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Authors and Affiliations

  1. Department of Medical Oncology, City of Hope, 1500 E. Duarte Rd., Duarte, CA, 91010, USA

    Janet Pan, Rachel Magnusson & Warren A. Chow

  2. Department of Molecular Pharmacology, Beckman Research Institute of City of Hope, Duarte, CA, USA

    Bixin Xi, Min Guan, Kristen Fousek, Timothy Synold & Warren A. Chow

  3. Department of Hematology/HCT, City of Hope, Duarte, CA, USA

    Michelle Mott & Ernestine Hepner

  4. Clinical Trials Office, City of Hope, Duarte, CA, USA

    Raechelle Tinsley

  5. Department of Medical Oncology, University of Miami, Miami, FL, USA

    Frances Valdes

  6. Department of Information Sciences, City of Hope, Duarte, CA, USA

    Paul Frankel

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  1. Janet Pan
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  2. Michelle Mott
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  3. Bixin Xi
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  4. Ernestine Hepner
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  7. Rachel Magnusson
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  9. Frances Valdes
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  10. Paul Frankel
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  11. Timothy Synold
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  12. Warren A. Chow
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Correspondence to Warren A. Chow.

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Pan, J., Mott, M., Xi, B. et al. Phase I study of nelfinavir in liposarcoma. Cancer Chemother Pharmacol 70, 791–799 (2012). https://doi.org/10.1007/s00280-012-1961-4

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  • DOI: https://doi.org/10.1007/s00280-012-1961-4

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