Safety and efficacy of the MDR inhibitor incel (biricodar, VX-710) in combination with mitoxantrone and prednisone in hormone-refractory prostate cancer

Randall P. Rago, Albert Einstein, Richard Lush, Tomasz M. Beer, Yoo Joung Ko, W. David Henner, Glenn Bubley, Elizabeth A. Merica, Varun Garg, Ene Ette, Matthew W. Harding, William S. Dalton

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    32 Scopus citations

    Abstract

    Purpose: VX-710 (biricodar, Incel) restores drug sensitivity to cells expressing P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP1). MRP1 is expressed in a high proportion of prostate tumors while P-gp expression is variable. Since mitoxantrone (M) and prednisone (P) are substrates for MDR transporters, we initiated a study to evaluate the safety, pharmacokinetics, and efficacy of VX-710 plus M/P in patients with hormone-refractory prostate cancer (HRPC). Patients and methods: Eligible patients had progressive HRPC (defined as new lesions, new disease-related pain, or 50% increase in PSA within 6 weeks of entry), testosterone < 30 ng/ml, no prior chemotherapy, ECOG performance status of 0-3, and adequate organ function. Patients received VX-710 (120 mg/m2 per h) as a 72-h continuous intravenous infusion with intravenous bolus mitoxantrone (12 mg/m2) administered 4 h after VX-710 was started and prednisone (5 mg twice daily) administered throughout the study treatment. Endpoints included serum PSA response, PSA response duration, time to PSA progression, pain reduction, and quality of life measures. Results: Enrolled in the study were 40 patients and 184 courses of VX-710 plus M/P were administered. Intensive pharmacokinetics, which were performed on six patients who received one cycle of M/P alone, followed by VX-710 plus M/P for all other cycles, showed that VX-710 did not alter mitoxantrone clearance. VX-710 blood concentration at the time of mitoxantrone administration averaged 4.52 μg/ml. VX-710 plus M/P was well tolerated. Transient nausea/vomiting and mild neutropenia were the principal treatment toxicities. Five patients experienced an uncomplicated febrile neutropenic episode (12%), three had severe nausea/vomiting, and two experienced transient moderate to severe ataxia. Of the 40 patients, 12 (30%, 95% confidence interval 16-44%) had a reduction in PSA of ≥50% and 9 of the 12 patients (23% overall, 95% CI 10-35%) achieved a reduction in PSA of ≥80% that was sustained for the duration of treatment with M/P plus VX-710. The median time to PSA progression was 41 weeks (95% CI 34-68 weeks). Of the 40 patients, 15 completed treatment with stable disease and 13 had progressive disease with increasing serum PSA during study treatment. Median survival was 48 weeks for the intent-to-treat population of 40 patients. Conclusions: The addition of VX-710 to M/P therapy did not appear to increase the proportion of patients with significant serum PSA reductions compared to M/P alone. However, the duration of PSA response observed for the 12 PSA responders suggests that MDR inhibition may benefit some patients with HRPC. In addition to MRP1 or P-gp expression, other mechanisms of drug resistance are probably associated with the relative insensitivity of HRPC to cytotoxic therapy.

    Original languageEnglish (US)
    Pages (from-to)297-305
    Number of pages9
    JournalCancer Chemotherapy and Pharmacology
    Volume51
    Issue number4
    DOIs
    StatePublished - Apr 1 2003

    Keywords

    • HRPC
    • Mitoxantrone
    • Multidrug resistance
    • VX-710

    ASJC Scopus subject areas

    • Oncology
    • Toxicology
    • Pharmacology
    • Cancer Research
    • Pharmacology (medical)

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    Rago, R. P., Einstein, A., Lush, R., Beer, T. M., Ko, Y. J., Henner, W. D., Bubley, G., Merica, E. A., Garg, V., Ette, E., Harding, M. W., & Dalton, W. S. (2003). Safety and efficacy of the MDR inhibitor incel (biricodar, VX-710) in combination with mitoxantrone and prednisone in hormone-refractory prostate cancer. Cancer Chemotherapy and Pharmacology, 51(4), 297-305. https://doi.org/10.1007/s00280-003-0573-4