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
• 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
Clinical
Trial
Network
Academia
Scientific
question
Pharma
Novel drug(s)
Early
Phase
Clinical
Trial
Trial
Management
Biomarker
Evaluation
Biological
Markers of
Activity
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
TYPE
ACADEMIC
1st LINE
PADIMAC
RELAPSE
MUK
6
COMMERCIAL
C16006
CARDAMON
MLN9708+MP
MUK
5
DARATUMUMAB
CVD vs
CCarD
+Rev
Dex
VTDPana
PIPELINE
+Vel
Dex
Vel Dex
±
Tabalumab
MUK 4
VelDex
+
Vorinostat
MUK
3
CHR3996
+
Tosedostat
Proteasome Inhibitors
K Anderson, ASH Education Book December 2011
New
Diagnosis
Velcade
PAD = Doxorubicin
Dexamethasone
PAD
(2-6 cycles)
<PR
≥ VGPR
PR
Re-induction
Stem cell harvest
MRD
Salvage
High Dose
Melphalan
Relapse
Observe
High Dose
Melphalan
Can we defer high dose treatment in
people that have responded well?
PADIMAC
MLN9708 with melphalan & prednisolone
(phase 1/2)
Days 1
4
8
15
22
28
INDUCTION 12 cycles
• Newly
diagnosed
• Not suitable
for ASCT
MLN9708
Melphalan
Prednisolone
Days 1
8
15
22
MAINTENANCE up to 1yr
MLN9708
28
MUK 5 (phase 2)
CVD vs CCD
Randomisation
CVD
8 cycles 21 days
• 1st relapse or
refractory to 1
line of therapy
• IMW Measurable
disease
CCarD
6 cycles 28 days
No
maintenance
Maintenance
Carfilzomib
Up to 18 months
Proteasome and HDAC Inhibition
Hideshima T et al. Mol Cancer Ther 2011;10:2034-2042
MUK 6 (Phase 1/2)
VTD-Panabinostat
Days 1
3
5
8
10
12
21
INDUCTION 16 cycles
Bortezomib
Dexamethasone
Panabinostat
Thalidomide
MAINTENANCE
Panabinostat
up to 1yr
• 1- 4 prior lines
• Prior BZ ok if
responsive
• Measurable
disease (IMW
criteria)
MUK 3 (Phase 1/2)
CHR3996 + Tosedostat
Dose Level (DL)
CHR-3996 (mg)
Tosedostat (mg)
1
20
0 (nil)
40
0 (nil)
40
60
40
120
40
240 (dose reduction of
120 after 2 cycles)
2
3
4
5
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 Sheet
Weers et al; The Journal of Immunology 2011;186(3) 1840-1848
Plesner et al., ASH 2012
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-andrefractory multiple myeloma
van der Veer M S et al. Haematologica 2011;96:284-290
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)
Pathogenesis of Lymphoma
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)
Targeting the BCR
Young & Staudt, Nature Reviews Drug Discovery 12, 229-243 (March 2013)
Weistner et al, Journal of Clinical Oncology, Vol 30, 2012
Ibrutinib & Myeloma
(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.
Edwards C M Blood 2012;120:1757-1759
Tai et al. Blood 2012;120(9):1877-1887.
Ibrutinib Combinations
Edwards C M Blood 2012;120:1757-1759
Tai et al. Blood 2012;120(9):1877-1887.
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
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