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