MLNM phase III-Very encouraging data.
Session Info. : Simultaneous Session: Molecular Target Based Therapy for Multiple Myeloma (10:30 AM-12:30 PM), Monday, December 09, 2002
[388] Phase I Study of the Proteasome Inhibitor Bortezomib (PS-341, velcade™) in Combination with Pegylated Liposomal Doxorubicin (Doxil®) in Patients with Refractory Hematologic Malignancies.
Robert Z. Orlowski, M. Hall, P. Voorhees, C. Hogan, E. Humes, A. Johri, H. Bell, R. Garcia, J. Adams, D. Esseltine, D. Gabriel, T. Shea, H. Van Deventer, B. Mitchell, E.C. Dees. University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA
Introduction: The proteasome, a multicatalytic proteinase complex involved in intracellular protein degradation, is a novel target for therapy of hematologic malignancies based on in vitro and in vivo preclinical models, and on Phase I and II clinical trials. In addition, proteasome inhibitors may block activation of several survival pathways, including NF-kB, that may limit the effectiveness of drugs such as anthracyclines, suggesting that such a combination might have enhanced anti-tumor efficacy. Study Aims: We sought to evaluate the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of the combination of the proteasome inhibitor bortezomib (velcade™; also known as PS-341, MLN-341) and pegylated, liposomal doxorubicin (Doxil®) in patients (pts) with refractory hematologic malignancies. Pharmacodynamic determinations of peripheral blood 20S proteasome activity and doxorubicin pharmacokinetics will be compared with toxicity and outcome, and correlative studies are planned as well. Methods: Patients receive bortezomib as an intravenous bolus on days 1, 4, 8, and 11 of a three week cycle, with planned dose levels of 0.90, 1.05, 1.20, and 1.30 mg/m2, while Doxil® is administered on day 4 at 30 mg/m2. The MTD is defined based on cycle one, while response evaluations are performed every two cycles. Patients: To date, 14 pts have been enrolled, with 6 at 0.90 mg/m2, and four each at 1.05 and 1.20 mg/m2. This population has included 11 pts with multiple myeloma (MM), 1 with acute myeloid leukemia (AML), 1 with myelodysplasia (MDS) with excess blasts, and 1 with chronic lymphocytic leukemia (CLL). Results: A mean of 3.6 cycles (range 1-8) has been administered to these pts, 12 of whom are evaluable for toxicity. At the first dose level a patient (pt) with underlying Crohn’s disease had grade 3 diarrhea, hypotension, confusion and syncope. No other DLTs were noted at this level, nor at the second and third dose steps, and the MTD has yet to be defined. All other non-hematologic toxicities during cycle 1 have been either grade 1 or 2 in intensity, with no grade 4 toxicities seen. Grade 3 toxicities in later cycles included fatigue and palmar plantar erythrodysesthesia in one pt each, and cytopenias. Eleven pts are evaluable for response, with one additional pt yet to undergo cycle 2 of therapy. Among the 8 evaluable MM pts complete responses (CR) have been observed in three, of whom one had relapsed after a previous CR to bortezomib alone, and achieved a second CR with a lower bortezomib dose and fewer cycles of this regimen than single-agent bortezomib. Two other pts have shown partial responses (PR), and two have exhibited stable disease (SD), while one progressed. Of the seven MM pts who showed evidence of a response six are receiving additional therapy. One pt with relapsed AML has shown a PR, one with CLL had a mixed response with some decreasing lymphadenopathy, while one patient with MDS exhibited SD. Conclusion: Early results suggest that bortezomib/Doxil® appears to be a well tolerated regimen with significant activity against multiple myeloma, and possibly in other refractory hematologic malignancies as well. Accrual is continuing to define the MTD and DLT of this combination.
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[5137] The Proteasome Inhibitor PS-341 Is More Cytotoxic in Myeloma Cells Adhered to Fibronectin.
Terry H. Landowski, Julian Adams, William S. Dalton. Arizona Cancer Center, University of Arizona, Tucson, AZ, USA; Millenium Pharm. Inc, Cambridge, MA, USA; H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL, USA
Resistance to chemotherapeutic drugs is the primary obstacle to the successful treatment of multiple myeloma. Recent studies have documented the contribution of the bone marrow microenvironment to the anti-apoptotic phenotype in response to both physiological mechanisms, and cytotoxic inducers of cell death. These observations suggest that the identification of specific phenotypic alterations in cells in contact with components of the microenvironment may provide molecular targets for drug therapy. The ubiquitin-proteasome system of protein degradation regulates many important cellular functions including cell cycle progression, differentiation, signal transduction and gene transcription. The proteasome inhibitor, PS-341, is a dipeptidyl boronic acid that has shown activity in clinical trials in patients with multiple myeloma. Using oligonucleotide microarray analysis, we have examined the differential gene expression profile of 8226 multiple myeloma cells treated with PS-341 in contact with the extracellular matrix (ECM) component, fibronectin compared to cells treated in suspension culture. Microarray analysis demonstrated 19 genes increased and 10 genes reduced by two fold or more in 8226 cells treated with PS-341 in suspension, compared to 51 genes increased and 39 genes reduced by two fold or more in 8226 cells treated with PS-341 on fibronectin. Most dramatically altered were the heat shock proteins, hsp70, hsp40, and the heat shock associated factor, Bag-3. Adhesion of myeloma cells to FN alone repressed the expression of these anti-apoptotic proteins by 9.8, 2.6, and 1.8 fold, respectively. Furthermore, reduced expression of the heat shock family in FN adhered cells correlated with enhanced sensitivity to PS-341. To examine the role of hsp70 in PS-341 cytoxicity, we examined the activation of the endoplasmic reticulum-stress associated caspase, caspase 12, following treatment with PS-341. We found that PS-341 preferentially activates caspase 12 in myeloma cells, suggesting that proteosomal inhibition induces ER stress mediated apoptosis in adherent cells associated with reduced hsp70.
Keywords: Proteasome inhibitor\ Cell adhesion mediated drug resistance\ Fibronectin
Session Info. : Publication Only,
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