Research Article| Volume 115, ISSUE 2, P215-220, November 2009

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A phase II evaluation of bortezomib in the treatment of recurrent platinum-sensitive ovarian or primary peritoneal cancer: A Gynecologic Oncology Group study



      To determine the activity and pharmacodynamics (PD) of bortezomib in platinum-sensitive epithelial ovarian or primary peritoneal cancer (EOC/PPC).

      Patients and methods

      Eligible women with recurrent EOC/PPC progressing between 6 and 12 months after initial chemotherapy were treated with bortezomib on days 1, 4, 8, and 11 [1.5 (cohort I) and 1.3 (cohort II) mg/m2/dose]. Patients must have had initial chemotherapy only. Response Evaluation Criteria in Solid Tumors (RECIST) was assessed by computed tomography (CT) scan every 2 cycles. 20S proteasome activity was quantified in three pre-treatment and a 1-hour post-treatment (cycle one, day 1) whole blood lysates.


      Initially, 26 evaluable patients were treated at the 1.5 mg/m2/dose level. Objective response rate was 3.8% (1/26), a partial response. An additional 10 patients (38.5%) had stable disease. Given concerns that treatment discontinuations due to toxicity limited drug exposure/activity a second cohort of 29 evaluable patients was accrued at 1.3 mg/m2/dose. The 1.3 mg/m2/dose regimen is currently approved as an indication for multiple myeloma and mantle cell lymphoma. Treatment was more tolerable, although objective responses remained low at 6.9% (2/29, partial responses). Second stage accrual was not warranted at either dose. Bortezomib effectively inhibited 20S proteasome activity in whole blood lysates between 37 and 92% in 24/25 (96%) patients in cohort I, and 14–84% in 27/28 (96%) patients in cohort II who provided satisfactory pre- and post-treatment specimens for testing.


      Bortezomib has minimal activity as a single-agent in the treatment of recurrent platinum-sensitive EOC/PPC. Treatment with bortezomib at 1.5 mg/m2/dose was not feasible in this patient population due to excess toxicity. Bortezomib was well tolerated at 1.3 mg/m2/dose.


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        • Goldberg A.L.
        • Stein R.
        • Adams J.
        New insights into proteasome function: from Archaebacteria to drug development.
        Chem. Biol. 1995; 2: 503-508
        • Palombella V.J.
        • Rando O.J.
        • Goldberg A.L.
        • et al.
        The ubiquitin–proteasome pathway is required for processing the NF-κB1 precursor protein and the activation of NF-κB.
        Cell. 1994; 78: 773-785
        • Beg A.A.
        • Baltimore D.
        An essential role for NF-κB in preventing TNF-α-induced cell death.
        Science. 1996; 274: 782-784
        • Van Antwerp D.J.
        • Martin S.J.
        • Kafri T.
        • et al.
        Suppression of TNF-α-induced apoptosis by NF-κB.
        Science. 1996; 274: 787-789
        • Wang C.Y.
        • Mayo M.W.
        • Baldwin A.S.
        TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-κB.
        Science. 1996; 274: 784-787
        • Chu Z.L.
        • Mckinsey T.A.
        • Liu L.
        • et al.
        Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-κB control.
        Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 10057-10062
        • Zetter B.R.
        Adhesion molecules in tumor metastasis.
        Semin. Cancer Biol. 1993; 4: 219-229
        • Read M.A.
        • Neish A.S.
        • Luscinskas F.W.
        • et al.
        The protesome pathway is required for cytokine-induced endothelial-leukocyte adhesion molecule expression.
        Immunity. 1995; 2: 493-506
        • Benyi L.
        • Ping Dou Q.
        Bax degradation by the ubiquitin/proteasome-dependent pathway: involvement in tumor survival and progression.
        Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 3850-3855
        • An B.
        • Goldfarb R.H.
        • Siman R.
        Novel dipeptidyl proteasome inhibitors overcome Bcl-2 protective function and selectively accumulate the cyclin-dependent kinase inhibitor p27 and induce apoptosis in transformed, but not normal, human fibroblasts.
        Cell Death Diff. 1998; 5: 1062-1075
        • Herrmann J.L.
        • Briones F.
        • Brisbay S.
        • et al.
        Prostate carcinoma cell death resulting from inhibition of proteasome activity is independent of functional Bcl-2 and p53.
        Oncogene. 1998; 17: 2889-2899
        • Jemal A.
        • Siegel R.
        • Ward E.
        • et al.
        Cancer statistics, 2008.
        CA Cancer J. Clin. 2008; 58: 71-96
        • Ozols R.F.
        • Schwartz P.E.
        • Eifel P.J.
        Ovarian cancer, fallopian tube carcinoma, and peritoneal carcinoma.
        in: DeVita VT Hellman S Rosenberg RA Cancer: principles and practice of oncology, sixth ed. Lippincott Williams and Wilkins. 2001: 1597-1632
        • Cusack J.C.
        Rationale for the treatment of solid tumors with the proteasome inhibitor bortezomib.
        Cancer Treat. Rev. 2001; 29: 21-31
        • Lightcap E.S.
        • McCormack T.A.
        • Pien C.S.
        • et al.
        Proteasome inhibition measurements: clinical application.
        Clin. Chem. 2000; 46: 673-683
        • Ma M.H.
        • Yang H.H.
        • Parker K.
        • et al.
        The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents.
        Clin. Cancer Res. 2003; 9: 1136-1144
        • Mitsiades N.
        • Mitsiades C.S.
        • Richardson P.G.
        • et al.
        The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications.
        Blood. 2003; 101: 2377-2380
        • Chen T.T.
        • Ng T.
        Optimal flexible designs in phase II clinical trials.
        Stat. Med. 1998; 17: 2301-2312
        • Gordon A.N.
        • Fleagle J.T.
        • Guthrie D.
        • et al.
        Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan.
        J. Clin. Oncol. 2001; 19: 3312-3322
        • Ling Y.H.
        • Liebes L.
        • Ng B.
        • et al.
        PS-341, a novel proteasome inhibitor, induces Bcl-2 phosphorylation and cleavage in association with G2-M phase arrest and apoptosis.
        Mol. Cancer Ther. 2002; 1: 841-849
        • Loo T.W.
        • Clarke D.M.
        Superfolding of the partially unfolded core-glycosylated intermediate of human P-glycoprotein into the mature enzyme is promoted by substrate-induced transmembrane domain interactions.
        J. Biol. Chem. 1998; 273: 14671-14674
        • Loo T.W.
        • Clarke D.M.
        The human multi-drug resistance P-glycoprotein is inactive when its maturation is inhibited: potential for a role in cancer chemotherapy.
        FASEB J. 1999; 7: 1724-1732
        • DeMartino G.N.
        • Slaughter C.A.
        The proteasome, a novel protease regulated by multiple mechanisms.
        J. Biol. Chem. 1999; 274: 22123-22126
        • Adams J.
        The development of proteasome inhibitors as anticancer drugs.
        Cancer Cell. 2004; 5: 417-421
        • Adams J.
        The proteasome: structure, function, and role in the cell.
        Cancer Treat. Rev. 2003; 29: 3-9
        • Adams J.
        • Kauffman M.
        Development of the proteasome inhibitor (Velcade ™ (Bortezomib).
        Cancer Invest. 2004; 22: 304-311
        • Aghajanian C.
        • Dizon D.S.
        • Sabbatini P.
        • et al.
        Phase I trial of bortezomib and carboplatin in recurrent ovarian or primary peritoneal cancer.
        J. Clin. Oncol. 2005; 23: 5943-5949
        • Messersmith W.A.
        • Baker S.D.
        • Lassiter L.
        • et al.
        Phase I trial of bortezomib in combination with docetaxel in patients with advanced solid tumors.
        Clin. Cancer Res. 2006; 12: 1270-1275
        • Ryan D.P.
        • O'Neil B.H.
        • Supko J.G.
        • et al.
        A phase I study of bortezomib plus irinotecan in patients with advanced solid tumors.
        Clin. Cancer Res. 2006; 12: 1270-1275
        • Berenson J.R.
        • Yang H.H.
        • Sadler K.
        • et al.
        Phase I/II trial assessing bortezomib and melphalan combination therapy for the treatment of patients with relapsed or refractory multiple myeloma.
        J. Clin. Oncol. 2006; 24: 937-944
        • Orlowski R.Z.
        • Voorhees P.M.
        • Garcia R.A.
        • et al.
        Phase I trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies.
        Blood. 2005; 105: 3058-3065
        • Barlogie B.
        • Shaughnessy J.D.
        • Tricot G.
        • et al.
        Treatment of multiple myeloma.
        Blood. 2004; 103: 20-32
        • Ma C.
        • Mandrekar S.J.
        • Albersts S.R.
        • et al.
        A phase I and pharmacologic study of sequences of the proteasome inhibitor, bortezomib (PS-341, Velcade), in combination with paclitaxel and carboplatin in patients with advanced malignancies.
        Cancer Chemother. Pharmacol. 2007; 59: 207-215
        • Voortman J.
        • Smit E.F.
        • Honeywell R.
        • et al.
        A parallel dose-escalation study of weekly and twice weekly bortezomib in combination with gemcitabine and cisplatin in the first-line treatment of patients with advanced solid tumors.
        Clin. Cancer Res. 2007; 13: 3642-3651
        • Biehn S.E.
        • Moore D.T.
        • Voorhees P.M.
        • et al.
        Extended follow-up of outcome measures in multiple myeloma patients treated on a phase I study with bortezomib and pegylated liposomal doxorubicin.
        Ann. Hematol. 2007; 86: 211-216
        • Orlowski R.Z.
        • Nagler A.
        • Sonneveld P.
        • et al.
        Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in refractory multiple myeloma: combination therapy improves time to progression.
        J. Clin. Oncol. 2007; 25: 3892-3901
        • Rosen P.J.
        • Gordon M.
        • Lee P.N.
        • et al.
        Phase II results of study PX-171-007: A phase Ib/II study of carfilzomib (CFZ), a selective proteasomes inhibitor, in patients with selected advanced metastatic solid tumors.
        J. Clin. Oncol. 2009; 27 (Abstract 3515): 149s
        • Hamlin P.A.
        • Aghajanian C.
        • Younes A.
        • et al.
        First-in human phase I study of the novel structure proteasomes inhibitor NPI-0052.
        J. Clin. Oncol. 2009; 27 (Abstract 3516): 150s