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Early Phase Myeloma Studies
Rakesh Popat
UCL Cancer Institute & University College Hospital
Myeloma outcomes getting better…
Kumar et al., Blood 2007Kumar et al, Leukemia 2011
…but not good enough
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
Early phase clinical trials: the risks
An approach to early phase trials
Early Phase
Clinical Trial
Academia
Scientific question
Pharma
Novel drug(s)
Biomarker Evaluation
Biological
Markers of
Activity
Trial Management
Clinical Trial
Network
Myeloma Treatments under evaluation
Mahindra, A. et al. (2012); Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2012.15
UK Myeloma Phase I/II Studies Overview
ACADEMIC PIPELINECOMMERCIAL
C16006MLN9708+MP
MUK 6
VTD-Pana
MUK 3
CHR3996+
Tosedostat
TY
PE
1st L
INE
RE
LA
PS
E
MUK 5
CVD vsCCarD
PADIMAC CARDAMON
DARATUMUMAB
+Rev Dex
+Vel Dex
MUK 4VelDex
+Vorinostat
Vel Dex±
Tabalumab
Proteasome Inhibitors
K Anderson, ASH Education Book December 2011
Can we defer high dose treatment in people that have responded well?
New Diagnosis
PAD (2-6 cycles)
≥ VGPRPR
High Dose Melphalan
High Dose Melphalan
Observe
Relapse
VelcadeDoxorubicinDexamethasone
PAD =
<PR
Salvage
Re-inductionStem cell harvestMRD
PADIMAC
MLN9708 with melphalan & prednisolone (phase 1/2)
INDUCTION 12 cyclesINDUCTION 12 cycles
Days 1 4 8 15 22 28
MLN9708
Melphalan
Prednisolone
MAINTENANCE up to 1yrMAINTENANCE up to 1yr
Days 1 8 15 22 28
• Newly diagnosed
• Not suitable for ASCT
• Newly diagnosed
• Not suitable for ASCT
MLN9708
MUK 5 (phase 2)CVD vs CCD
Randomisation
CVD8 cycles 21 days
CCarD6 cycles 28 days
MaintenanceCarfilzomib
Up to 18 months
No maintenance
• 1st relapse or refractory to 1 line of therapy
• IMW Measurable disease
• 1st relapse or refractory to 1 line of therapy
• IMW Measurable disease
Proteasome and HDAC Inhibition
Hideshima T et al. Mol Cancer Ther 2011;10:2034-2042
MUK 6 (Phase 1/2)VTD-Panabinostat
INDUCTION 16 cyclesINDUCTION 16 cycles
Days 1 3 5 8 10 12 21
Bortezomib
Dexamethasone
Panabinostat
Thalidomide
Panabinostat
MAINTENANCE up to 1yrMAINTENANCE up to 1yr
• 1- 4 prior lines• Prior BZ ok if
responsive• Measurable
disease (IMW criteria)
• 1- 4 prior lines• Prior BZ ok if
responsive• Measurable
disease (IMW criteria)
MUK 3 (Phase 1/2)CHR3996 + Tosedostat
Faith Davies Lab
Monoclonal Antibody Targets
Tabalumab
Neri P et al. Clin Cancer Res 2007;13:5903-5909
Bortezomib +/- Tabalumab Phase 2
Daratumumab
Daratumumab Fact SheetWeers et al; The Journal of Immunology 2011;186(3) 1840-1848
Plesner et al., ASH 2012
Daratumumab & lenalidomide
van der Veer M S et al. Haematologica 2011;96:284-290
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
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
B Cell Receptor Signalling
Young & Staudt, Nature Reviews Drug Discovery 12, 229-243 (March 2013)
• Ag induced aggregation of BCR – recruitment of SYC• SYC phosphorylates BLNK – BTK – CARD11• CD19 activates PI3K• Result activation of survival pathways
Pathogenesis of Lymphoma
BCR signalling in lymphoid malignancy
Young & Staudt, Nature Reviews Drug Discovery 12, 229-243 (March 2013)
• ABC DLBCL• FL• CLL• MCL• MAL
• Burkitts• GCB DLBCL
Targeting the BCR
Weistner et al, Journal of Clinical Oncology, Vol 30, 2012Young & Staudt, Nature Reviews Drug Discovery 12, 229-243 (March 2013)
Ibrutinib & Myeloma
Edwards C M Blood 2012;120:1757-1759Tai et al. Blood 2012;120(9):1877-1887.
(1) directly inhibit tumor growth(2) directly inhibit osteoclastic bone resorption, (3) inhibit the release of osteoclast-derived tumor
growth factors(4) prevent adhesion to bone marrow stromal cells
(BMSCs) and release of BMSC-derived growth factors.
Ibrutinib Combinations
Edwards C M Blood 2012;120:1757-1759Tai et al. Blood 2012;120(9):1877-1887.
Ibrutinib Combinations
Yang, Y. et al. Cancer Cell 2012
• 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
• 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
BCR inhibitor Myeloma Early Phase Trial
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