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
Pharmaco vig
Biomarker Evaluation
Trial Management
Biological
Markers of
Activity

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

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

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

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

10. PADIMAC

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

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

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

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

15. MUK 3 (Phase 1/2) CHR3996 + Tosedostat
Dose Level (DL)
CHR-3996 (mg)
Tosedostat (mg) 1 20
0 (nil) 2 40 3 60 4
120 5
240 (dose reduction of 120 after 2 cycles)
Faith Davies Lab

16. Monoclonal Antibody Targets

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

18. Bortezomib +/- Tabalumab Phase 2

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

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:

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, (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, (March 2013)

25. Targeting the BCR
Young & Staudt, Nature Reviews Drug Discovery 12, (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:
Tai et al. Blood 2012;120(9):

27. Ibrutinib Combinations
Edwards C M Blood 2012;120:
Tai et al. Blood 2012;120(9):

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