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Early Phase Myeloma Studies

Early Phase Myeloma Studies. Rakesh Popat UCL Cancer Institute & University College Hospital. Myeloma outcomes getting better…. …but not good enough. Kumar et al., Blood 2007 Kumar et al, Leukemia 2011. Why develop early phase trials in the UK?. Improve patient access to novel agents

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Early Phase Myeloma Studies

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  1. Early Phase Myeloma Studies Rakesh Popat UCL Cancer Institute & University College Hospital

  2. Myeloma outcomes getting better… …but not good enough Kumar et al., Blood 2007 Kumar et al, Leukemia 2011

  3. Why develop early phase trials in the UK? • Improve patient access to novel agents • Provide evidence to develop clinically relevant treatments for the UK • Influence drug development globally • Advance understanding of myeloma and drug resistance • Investigate treatment specific predictors and markers of response/ resistance

  4. Early phase clinical trials: the risks

  5. An approach to early phase trials Academia Scientific question Pharma Novel drug(s) Clinical Trial Network Early Phase Clinical Trial Biomarker Evaluation Trial Management Biological Markers of Activity

  6. Myeloma Treatments under evaluation Mahindra, A. et al. (2012); Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2012.15

  7. UK Myeloma Phase I/II Studies Overview TYPE ACADEMIC COMMERCIAL PIPELINE 1st LINE PADIMAC CARDAMON C16006 MLN9708+MP RELAPSE MUK 6 VTD-Pana MUK 5 CVD vs CCarD Vel Dex ± Tabalumab DARATUMUMAB MUK 4 VelDex + Vorinostat +Rev Dex +VelDex MUK 3 CHR3996+ Tosedostat

  8. Proteasome Inhibitors K Anderson, ASH Education Book December 2011

  9. New Diagnosis Velcade Doxorubicin Dexamethasone PAD = PAD (2-6 cycles) Can we defer high dose treatment in people that have responded well? ≥ VGPR <PR PR Relapse Re-induction Stem cell harvest MRD High Dose Melphalan High Dose Melphalan Salvage Observe

  10. PADIMAC

  11. MLN9708 with melphalan & prednisolone (phase 1/2) • Newly diagnosed • Not suitable for ASCT Days 1 4 8 15 22 28 INDUCTION 12 cycles MLN9708 Melphalan Prednisolone MLN9708 Days 1 8 15 22 28 MAINTENANCE up to 1yr

  12. MUK 5 (phase 2)CVD vs CCD Randomisation • 1st relapse or refractory to 1 line of therapy • IMW Measurable disease CVD 8 cycles 21 days CCarD 6 cycles 28 days Maintenance Carfilzomib Up to 18 months No maintenance

  13. Proteasome and HDAC Inhibition Hideshima T et al. Mol Cancer Ther 2011;10:2034-2042

  14. MUK 6 (Phase 1/2)VTD-Panabinostat INDUCTION 16 cycles Days 1 3 5 8 10 12 21 • 1- 4 prior lines • Prior BZ ok if responsive • Measurable disease (IMW criteria) Bortezomib Dexamethasone Panabinostat Thalidomide Panabinostat MAINTENANCE up to 1yr

  15. MUK 3 (Phase 1/2)CHR3996 + Tosedostat Faith Davies Lab

  16. Monoclonal Antibody Targets

  17. Tabalumab Neri P et al. Clin Cancer Res 2007;13:5903-5909

  18. Bortezomib +/- Tabalumab Phase 2

  19. Daratumumab Daratumumab Fact Sheet Weers et al; The Journal of Immunology 2011;186(3) 1840-1848

  20. Plesner et al., ASH 2012

  21. Daratumumab & lenalidomide GEN503: A Phase 1/2 trial investigating the safety of daratumumab in combination with lenalidomide and dexamethasone in patients with relapsed or relapsed-and-refractory multiple myeloma van der Veer M S et al. Haematologica 2011;96:284-290

  22. B Cell Receptor Signalling • Ag induced aggregation of BCR – recruitment of SYC • SYC phosphorylates BLNK – BTK – CARD11 • CD19 activates PI3K • Result activation of survival pathways Young & Staudt, Nature Reviews Drug Discovery 12, 229-243 (March 2013)

  23. Pathogenesis of Lymphoma

  24. BCR signalling in lymphoid malignancy • ABC DLBCL • FL • CLL • MCL • MAL • Burkitts • GCB DLBCL Young & Staudt, Nature Reviews Drug Discovery 12, 229-243 (March 2013)

  25. Targeting the BCR Young & Staudt, Nature Reviews Drug Discovery 12, 229-243 (March 2013) Weistner et al, Journal of Clinical Oncology, Vol 30, 2012

  26. Ibrutinib & Myeloma • directly inhibit tumor growth • directly inhibit osteoclastic bone resorption, • inhibit the release of osteoclast-derived tumor growth factors • prevent adhesion to bone marrow stromal cells (BMSCs) and release of BMSC-derived growth factors. Edwards C M Blood 2012;120:1757-1759 Tai et al. Blood 2012;120(9):1877-1887.

  27. Ibrutinib Combinations Edwards C M Blood 2012;120:1757-1759 Tai et al. Blood 2012;120(9):1877-1887.

  28. Ibrutinib Combinations • MYD88 L265P mutations cooperate with CD79B mutations to enhance BCR signaling addiction • ABC DLBCLs with CARD11 mutations or MYD88 L265P without CD79B mutation resist ibrutinib Yang, Y. et al. Cancer Cell 2012

  29. BCR inhibitor Myeloma Early Phase Trial

  30. Summary • Number of early phase myeloma studies in UK • Mix of commercial and academically sponsored • Novel drug access to patients improving • To be globally competitive: • Crucial to maintain innovative pipeline • Meet ambitious recruitment targets • Improve trial set up times

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