A Phase 2 Study of Bortezomib in Relapsed, Refractory Myeloma

Transcription

1 A Phase 2 Study of Bortezomib in Relapsed, Refractory Myeloma Paul G. Richardson, M.D., Bart Barlogie, M.D., Ph.D., James Berenson, M.D., Seema Singhal, M.D., Sundar Jagannath, M.D., David Irwin, M.D., S. Vincent Rajkumar, M.D., Gordan Srkalovic, M.D., Melissa Alsina, M.D., Raymond Alexanian, M.D., David Siegel, M.D., Robert Z. Orlowski, M.D., David Kuter, M.D., Ph.D., Steven A. Limentani, M.D., Stephanie Lee, M.D., Teru Hideshima, M.D., Ph.D., Dixie-Lee Esseltine, M.D., Michael Kauffman, M.D., Ph.D., Julian Adams, Ph.D., David P. Schenkein, M.D., and Kenneth C. Anderson, M.D.

2 Myeloma Multiple myeloma accounts for approximately 14,600 new cases of cancer and 10,800 deaths annually in the United States. Although conventional chemotherapy and highdose therapy with hematopoietic stem-cell rescue can prolong survival, few, if any, patients are cured. Salvage therapies for relapsed disease are equally disappointing, and although thalidomide has shown promise, new treatments are urgently needed.

3 Bortezomib (PS-341) PS-341 is a peptidyl boronic acid Novel inhibitor of the chymotryptic site (β5*) within the 20S proteasome Induces activation of the tryptic (β2*) catalytic activity within the 20S proteasome

4 Proteosome Two functional components: 20S core catalytic complex 19S regulatory subunit Ubiquitinated proteins are recognized by 19S, deubiquitinated, and denatured Proteolized into 3-22 residues in length by 20S

5 Targeting NF-κB NFkB normally counteracts chemo- and radio-therapy against cancer by responding with survival and proliferation mechanisms. Inhibiting IkB proteosomal degradation would prevent this effect.

6 Preliminary Studies of PS-341 Induces apoptosis Down-regulates the expression of adhesion molecules Inhibits cell-adhesion mediated drug resistance Decreases transcription and secretion of cytokines Entail more than NFkB inhibition Inhibited tumor-cell growth

7 Methods 202 patients with relapsed myeloma that was refractory to the therapy Patients received 1.3 mg of bortezomib per square meter of body-surface area twice weekly for 2 weeks, followed by 1 week without treatment, for up to eight cycles (24 weeks) In patients with a suboptimal response, oral dexamethasone (20 mg daily, on the day of and the day after bortezomib administration) was added to the regimen

8 Endpoints Primary end point was the overall rate of response to bortezomib Complete response: Negative immunofixation Absence of soft-tissue plasmacytomas Normal serum calcium concentration Stable skeletal disease < 5 percent plasma cells in the marrow Near-complete (immunofixationpositive): Absence of myeloma protein on electrophoresis Stable bone disease Normal serum calcium concentration.

9 Base-Line Patient Characteristics 84% had advanced disease myeloma at diagnosis 20% had functionality performance-status score of 70 or less 80% percent had symptoms of peripheral neuropathy at enrollment 178 previously treated 3of the major classes of agents for myeloma Other 15 received either 2 of the major classes of agents or a stem-cell transplant.

10 Results Median time to first response was 1.3 months Median duration of response was 12 months In 6 of these 13 patients who had a minimal to partial response to combination therapy, the disease responded to therapy to which it had previously been refractory

11 Responses to Bortezomib

12 Drug-Related Adverse Events The most clinically significant adverse event was cumulative, dose-related peripheral sensory neuropathy

13 Conclusions Bortezomib, a novel proteasome inhibitor, induces clinically significant responses in patients with relapsed multiple myeloma that is refractory to conventional chemotherapy.

14 Targeted Therapeutics p27kip1 is a cyclin dependent kinase (CDK) inhibitor which is involved in inducing G1 cell cycle arrest Jab1 binds p27 in the nucleus and regulates its degradation in the cytoplasmic 26S proteosome Cycle arrested cells may be rescued by co-expression of Jab1, and is nullified by proteosome inhibitors