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TKI-258 Clinical Trial After Lenalidomide/Dex

TKI-258 Clinical Trial After Lenalidomide/Dex. Sundar Jagannath, MD St. Vincent's Comprehensive Cancer Center New York, NY. Thalidomide/Dexamethasone (Thal/Dex) as Primary Induction Therapy. ECOG phase 3 clinical trial (EA100) 207 newly diagnosed MM patients Response rate: Thal/dex: 63%

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TKI-258 Clinical Trial After Lenalidomide/Dex

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  1. TKI-258 Clinical Trial After Lenalidomide/Dex Sundar Jagannath, MDSt. Vincent's Comprehensive Cancer CenterNew York, NY

  2. Thalidomide/Dexamethasone (Thal/Dex) as Primary Induction Therapy • ECOG phase 3 clinical trial (EA100) • 207 newly diagnosed MM patients • Response rate: • Thal/dex: 63% • Dex alone: 41% • p=0.0017 ECOG = Eastern Cooperative Oncology Group; MM = multiple myeloma;Thal = thalidomide 200 mg po qd; Dex = 40 mg po d1-4, 9-12,17-20 Rajkumar et al. J Clin Oncol. 2006;24(3):431-436.

  3. Thalidomide/Dexamethasone as Primary Induction Therapy • Incidence of DVT: • Thal/dex: 17% • Dex alone: 3% • DVT prophylaxis not included in trial design • Thal/dex did not compromise successful harvest of stem cells DVT = deep vein thrombosis Rajkumar et al. J Clin Oncol. 2006;24(3):431-436.

  4. 1.0 0.8 0.6 0.4 0.2 0 6 12 18 24 30 Thal/Dex as Initial TherapyTime-to-Progression (TTP) Thalidomide/dexamethasone Median TTP: not reached Dexamethasone alone Median TTP: 8.1 months Proportion of Patients p<0.0001 Time-to-Progression (months) Rajkumar et al. ASCO 2006, Abstract 7517.

  5. High-dose Therapy WithAutologous Stem Cell Transplant • Treatment of choice for patients with refractory disease • Likelihood of long-term remission is low

  6. Patient Has Poor Prognostic Indicators • IgA isotype • del(13q) • t(4;14) IgA = immunoglobulin A; del(13q) = deletion of the long arm of chromosome 13

  7. Treatment Options for Relapsed/Refractory Disease • Participation in a clinical trial • Allogeneic stem cell transplant • Morbidity/early mortality rates high • Combination therapy with bortezomib • Patient had relapsed after 8 cycles • Lenalidomide/dexamethasone is a viable option* * Patients who have received at least one prior therapy

  8. Len/Dex vs Dex Alone Phase 3 Trial(MM-009): Response 59.4%* Response Rate (%) * p<0.001 21.1%* Bladè Criteria Weber et al. ASCO 2006, Abstract 7521.

  9. 0 6 12 18 24 30 Time-to-Progression (months) MM-009: Interim AnalysisTime-to-Progression 1.0 Len/Dex Dex/Placebo 0.8 0.6 Med. 11.1 mo Proportion of Patients 0.4 p<0.0001 0.2 Med. 4.7 mo 0.0 Weber et al. ASCO 2006, Abstract 7521.

  10. 0 6 12 18 24 30 Overall Survival (months) MM-009: Overall Survival 1.0 LEN/DEX Med OS 29.6 mo 0.8 0.6 Proportion of Patients DEX/PLACEBO 0.4 p<0.0001 Med OS 20.2 mo 0.2 0.0 Weber et al. ASCO 2006, Abstract 7521.

  11. Len/Dex Is More Effective Than Dex/Placebo Regardless of Prior Thalidomide TTP=Time-to-progression, OR=Overall Response, L=Lenalidomide, D=Dexamethasone Wang et al. ASCO 2006, Abstract 7522.

  12. Len/Dex Grade 1-2 Len/Dex Grade 3-4 Dex Gr 1-4 Len/Dex (MM-009): Common Adverse Events Constipation Diarrhea Nausea URI Pneumonia Neutropenia Anemia Thrombocytopenia Fatigue Hyperglycemia DVT/PE Per. Neuropathy 0 10 20 30 40 50 60 70 % Patients Weber et al. ASCO 2006, Abstract 7521.

  13. Treatment Recommendation • Lenalidomide/dexamethasone • Dosing schedule • Lenalidomide 25 mg, Days 1 to 21 • High-dose dexamethasone (40 mg)*, Days 1 to 4, 9 to 12, and 17 to 20 • Cycle repeated every 28 days * After 4 cycles, dex schedule reduced to 40 mg on Days 1 to 4 per cycle.

  14. Treatment Alternatives • Re-induction with DCEP • Likelihood of achieving a durable remission is low • Second autologous SCT • Meaningful remission unlikely • High potential morbidity • Enrollment in a clinical trial for FGFR3 inhibitor DCEP = dexamethasone, cyclophosphamide, etoposide, and cisplatin SCT = stem cell transplant

  15. Phase 1 TKI-258 (CHIR-258) Study • TKI-258 • Small-molecule inhibitor of FGFR3 and other receptor tyrosine kinases (RTKs) • FGFR3 is constitutively activated in patients with t(4;14) FGFR3 = fibroblast growth factor receptor 3 Trudel et al. Blood. 2005;105(7):2941-2048; ClinicalTrials.gov, http://clinicaltrials.gov/ct/gui/show/NCT00243763?order=1?

  16. FGFR3 in Multiple Myeloma • Role of activated FGFR3 in myeloma: • Promotes proliferation and survival of myeloma cells • Subsequent acquisition of activating FGFR3 mutations is associated with progression to late-stage myeloma • Can impart chemoresistance • TKI-258 may be an appropriate choice Trudel et al. Blood. 2005;105(7):2941-2048

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