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 (Tom) Beer, Yoo Joung Ko, W. David Henner, Glenn Bubley, Elizabeth A. Merica, Varun Garg, Ene Ette, Matthew W. Harding, William S. Dalton

    Research output: Contribution to journalArticle

    32 Citations (Scopus)

    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
    StatePublished - Apr 1 2003

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    Mitoxantrone
    Prednisone
    Refractory materials
    Prostatic Neoplasms
    Hormones
    Safety
    P-Glycoprotein
    Pharmacokinetics
    biricodar
    Nausea
    Therapeutics
    Vomiting
    Serum
    Multidrug Resistance-Associated Proteins
    Pain
    Chemotherapy
    Ataxia
    Neutropenia
    Drug Resistance
    Intravenous Infusions

    Keywords

    • HRPC
    • Mitoxantrone
    • Multidrug resistance
    • VX-710

    ASJC Scopus subject areas

    • Cancer Research
    • Pharmacology
    • Oncology

    Cite this

    Safety and efficacy of the MDR inhibitor incel (biricodar, VX-710) in combination with mitoxantrone and prednisone in hormone-refractory prostate cancer. / Rago, Randall P.; Einstein, Albert; Lush, Richard; Beer, Tomasz (Tom); Ko, Yoo Joung; Henner, W. David; Bubley, Glenn; Merica, Elizabeth A.; Garg, Varun; Ette, Ene; Harding, Matthew W.; Dalton, William S.

    In: Cancer Chemotherapy and Pharmacology, Vol. 51, No. 4, 01.04.2003, p. 297-305.

    Research output: Contribution to journalArticle

    Rago, RP, Einstein, A, Lush, R, Beer, TT, Ko, YJ, Henner, WD, Bubley, G, Merica, EA, Garg, V, Ette, E, Harding, MW & Dalton, WS 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, vol. 51, no. 4, pp. 297-305.
    Rago, Randall P. ; Einstein, Albert ; Lush, Richard ; Beer, Tomasz (Tom) ; Ko, Yoo Joung ; Henner, W. David ; Bubley, Glenn ; Merica, Elizabeth A. ; Garg, Varun ; Ette, Ene ; Harding, Matthew W. ; Dalton, William S. / Safety and efficacy of the MDR inhibitor incel (biricodar, VX-710) in combination with mitoxantrone and prednisone in hormone-refractory prostate cancer. In: Cancer Chemotherapy and Pharmacology. 2003 ; Vol. 51, No. 4. pp. 297-305.
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    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.",
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    TY - JOUR

    T1 - Safety and efficacy of the MDR inhibitor incel (biricodar, VX-710) in combination with mitoxantrone and prednisone in hormone-refractory prostate cancer

    AU - Rago, Randall P.

    AU - Einstein, Albert

    AU - Lush, Richard

    AU - Beer, Tomasz (Tom)

    AU - Ko, Yoo Joung

    AU - Henner, W. David

    AU - Bubley, Glenn

    AU - Merica, Elizabeth A.

    AU - Garg, Varun

    AU - Ette, Ene

    AU - Harding, Matthew W.

    AU - Dalton, William S.

    PY - 2003/4/1

    Y1 - 2003/4/1

    N2 - 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.

    AB - 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.

    KW - HRPC

    KW - Mitoxantrone

    KW - Multidrug resistance

    KW - VX-710

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