UK#Myeloma#Research#Alliance#Clinical#Trials#Update#

Prof%Gordon%Cook%

University%of%Leeds%

“To steal ideas from one person is plagiarism, to steal from many is research”!

##

UK#Myeloma#Research#Alliance#NCRI Haemato-Oncology CSG (Myeloma Sub-group)

MUK Research Advisory

Group

Phase III Phase II

Phase IIb

Phase I Phase I/II

MUK#CTN#

United Kingdom Myeloma Forum

MUK Board

Current%UKMRA%Ac9vity%In#discussion# In#Concept# In#Set<up# Open#

TRALA# My#XIV#(FITNESS)# My#XII# My#XI+#PCL#(EMN)# RADAR# IDRIS# CARDAMON#AlloSCT# CATALYST# BUBBLE# TEAMM#

PIM#Inh#(ph#I)# MUKnine$ R2W#MM#Bone#Disease# MUKeleven$ OPTIMAL#Delay#in#diagnosis# MUKfive$

MISFIT# MUKseven$Melody# MUKeight$

MUKtwelve$MUKfourteen$

March$2016$

Myeloma%X%

4%

ISRCTN60123120##Sponsor#ID:#HM05/7287##

EudraCT#Number:#2006<005890<24##

(2014)$Vol.$15,$No.$8,$p874–885.$$$

6%6

Bortezomib, Doxorubicin & Dexamethasone (PAD) x2-4

Stem cell remobilisation

Randomisation

Melphalan 200mg/m2 IV & ASCT

Cyclophosphamide 400mg/m2 PO/week x12

n=292

Off study

PD or <2x106/kg CD34+ cells

n=110

n=174

n=89 N=85

Trial#conduct#Recruitment#from#April#2008#–#December#2012#

Response%Rate%to%ReAinduc9on%&%randomized%

Treatment%(Day+100)%

Post<randomisa\on:#≥VGPR#rate:#59_5%#aaer#salvage#ASCT#vs#47_1%#aaer#cyclophosphamide##(OR#0_38,#95%CI#0_2,0_7;#ordinal#logis\c#regression#P=0_0036)#

Cook et al, Lancet Oncology, 2014, Vol. 15, No. 8, p874–885

TimeAtoAprogression%&%PFS%(ITT)%

PFS TTP

•  Median%TTP%(ITT)%for%ASCT%is%19%mns%(95%%ci%16,%25)%vs%11mns%(95%%ci%9,%12)%for%CA

weekly%(HR%0.36%(95%%ci%0.25,%0.53);%p<0.0001)%

Cook,$ASH$2015$

PFS2%

Median PFS2 ASCT2 67m, [95%CI 52,∞] NTC/ASCT2 31m, [95%CI 23,42] NTC/noASCT 39m, [95%CI 32,47] Log Rank p<0.0001

Cook,$ASH$2015$

Overall%Survival%

Median#follow<up:#52%months%(IQR%range%41,%62)%%

75%pa9ents%(43.1%)%have%died%since%randomiza9on,%primarily%from%PD%(59.4%).%%

%

Median#survival:##ASCT2%was%67%months%(95%%CI%55,%∞)%

NTC%52%months%(95%%CI%42,60)%

Cox%propor9onal%hazards%regression%for%reduced%hazard%of%death%(ASCT2%vs%NTC)%%was%HR=0.56,#95%CI#(0.35,#0.90),#p=0.0169.%%

Log Rank p=0.022

OS by relapse therapy OS - overall

Cook,$ASH$2015$

UK%MRA%Myeloma%X%Trial%Team%

Chief Investigator •  Prof Gordon Cook, University of Leeds, UK

Clinical Investigators: •  Dr Cathy Williams , Nottingham University Hospitals, UK •  Prof Curly Morris, Queen’s University, Belfast, UK •  Prof Jamie Cavenagh, Barts & The London NHS Trust, UK •  Prof John Snowden, Royal Hallamshire Hospital, Sheffield, UK •  Dr John Ashcroft, Mid-Yorks Trust, Wakefield, UK

Central Immunology Analysis •  Prof Mark Drayson, Uni. of Birmingham, UK

Central MRD Monitoring •  Dr Roger Owen, HMDS, Leeds, UK

Statistical support •  Prof Julia Brown, CTRU, Uni. Of Leeds, UK •  Mr Alex Szubert & Mr David Cairns, CTRU, Uni. of Leeds, UK

Trial Co-ordination •  Miss Marie Fletcher, CTRU, Uni. of Leeds, UK •  Dr Sue Bell, CTRU, Uni. of Leeds, UK

What#next…….?#

ACCoRD#trial%Augmented%Condi9oning%&%Consolida9on%in%

Relapsed%Disease%UKMRA%Myeloma%XII%Relapsed%Intensive%Study%

CI:#Prof#Gordon#Cook#

Objec9ves%Primary#Objec\ve#:#• R1(ASCTCon%vs%ASCTAug):#≥VGPR%rate%• R2%(ITDCon/Ixa%main%vs%No%therapy):%ProfessionAfree%survival%(PFS)%

Secondary#Objec\ves:#• R1:%Overall%Response%Rate,%MRDnega9ve%rate%&%conversion%aher%ITD%consolida9on,%

Engrahment%kine9cs,%Safety%&%Tolerability,%Quality%of%Life%

• R2:%Overall%Response%Rate,%MRDnega9ve%rate,%TimeAtoAprogression%(TTP),%TTNT,%PFS2,%%

OS,%Safety%&%Tolerability,%Quality%of%Life%

Total%Recruitment%Target:%360%first%relapse%pa9ents%

Expected$FPFV:$Q2$2016$

Myeloma%XII:%Trial%Management%Group%•  Clinical%Inves9gators: % % %%

–  Dr%Cathy%Williams%,%Nolngham%City%Hospitals,%UK%%–  Prof%Kwee%Yong,%UCH,%London,%UK%–  Prof%Jamie%Cavenagh,%Barts%&%The%London%NHS%Trust,%UK%

–  Dr%John%Snowden,%Royal%Hallamshire%Hospital,%Sheffield,%UK%

–  Dr%John%Ashcroh,%MidAYorks%Trust,%Wakefield,%UK%

–  Dr%Mark%Cook,%University%Hospitals%Birmingham%NHS%Trust,%UK%

•  Central%Immunology%Analysis%

•  Central%MRD%Monitoring%

•  Sta9s9cal%support%–  Prof%Julia%Brown,%CTRU,%Uni.%Of%Leeds,%UK%– Mr%David%Cairns,%CTRU,%Uni.%of%Leeds,%UK%

•  Trial%CoAordina9on%– Ms%Anna%Chalmers,%CTRU,%Uni.%of%Leeds,%UK%

Myeloma%XI/XI+%

CI:#Prof#Graham#Jackson#

No further treatment

R 1:1 *

R 1:1:2

CTD Cyclophosphamide: 500mg d1,8,15 Thalidomide: 100-200mg daily Dexamethasone: 40mg d1-4,12-15 To max response/intolerance Dose reduced for TNE

CRD Cyclophosphamide: 500mg d1,8 Lenalidomide: 25mg d1-21 Dexamethasone: 40mg d1-4,12-15 To max response/intolerance Dose reduced for TNE

ASCT (TE only)

CVD Cyclophosphamide: 500mg d1,8,15 Velcade: 1.3mg/m2 d1,4,8,11 Dexamethasone: 20mg d1-2,4-5,8-9,11-12 Dose reduction for TNE

Induc\on#Consolida\on##

TE

TNE

R 1:1

CCRD Cyclophosphamide: 500mg d1,8 Carfilzomib: 20/36 mg/m2 d1-2,8-9,15-16

Lenalidomide: 25mg d1-21 Dexamethasone: 40mg d1-4,8-9,12-15 To max response/intolerance Not for TNE

TE: Transplant eligible TNE: Transplant non-eligible Decision based on individual patient factors including age, co-morbidities and patient/clinician discussion. * Patients with NC/PD response to initial IMiD all received CVD consolidation

Lenalidomide No maintenance

Maintenance##

NCRI Myeloma XI+

18%

•  Primary%endpoint%PFS/OS%–%PFS%an9cipated%mid%2016%

•  The%interim%analysis%of%the%intensive%pathway%aimed%to%assess%

tolerability%and%efficacy%in%pa9ents%receiving:%%

1)  Thalidomide%containing%triplet%(CTD)%vs%lenalidomide%

containing%triplet%(CRD)%

2)  CTD/CRD%vs%a%quadruplet%(KCRD)%3)  Sequen9al%PI%triplet%(CVD)%for%subop9mal%responders%

NCRI%Myeloma%XI%Analysis%

0#

10#

20#

30#

40#

50#

60#

70#

80#

90#

100#

CTD##(n=879)#

CRD##(n=880)#

KCRD##(n=275)#

%#of#p

a\en

ts#

Response%to%ini9al%induc9on%Lenalidomide%triplet%induces%deeper%responses%than%thalidomide%triplet%

%

19%

ORR#84%#

ORR#86%#

VGPR 46%

CR 9%

PR 30%

CR 13%

VGPR 49%

PR 24%

VGPR 57%

CR 25% Pawlyn)et)al,)ASH)2015)

0#

10#

20#

30#

40#

50#

60#

70#

80#

90#

100#

CTD##(n=879)#

CRD##(n=880)#

KCRD##(n=275)#

%#of#p

a\en

ts#

Response%to%ini9al%induc9on%Quadruplet%KCRD%induces%deeper%responses%than%triplets%

%

20%

55%#62%#

VGPR 46%

CR 9% CR 13%

VGPR 49%

VGPR 57%

CR 25%

82%#KCRD vs CTD/CRD Odds ratio: 4.40 (2.38,6.84) p < 0.001

Pawlyn)et)al,)ASH)2015)

NCRI%Myeloma%XI%

Trial%outline%

21%

R 1:1:2

CTD

CRD

ASCT

CVD Induc9on%

Pre%transplant%consolida9on%%

TE

R 1:1

R* 1:1

KCRD

No Rx

Lenalidomide

No maintenance

TE:%Transplant%eligible,%K:%Carfilzomib,%C:%Cyclophosphamide,%T:%Thalidomide%%R:%Lenalidomide,%V:%Bortezomib,%D:%dexamethasone%ASCT:%Autologous%stem%cell%transplant%

*%Pa9ents%with%NC/PD%response%to%ini9al%IMiD%all%received%CVD%consolida9on%

Improvement%in%response%with%sequencing%Sequen9al%PI%improves%a%subop9mal%response%to%ini9al%triplet%IMiD%

22%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

%#of#p

a\en

ts#

142%pa9ents%

%

MR/PR%to%

induc9on%IMiD%triplet%

%

Randomised%

to%receive%

CVD%

PR/MR 57 (40%)

CR/VGPR 67 (47%)

*%

**%

* NC/PD 3 (2%) ** Missing data 15 (11%)

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

%#of#p

a\en

ts#

Improvement%in%response%with%sequencing%Sequen9al%PI%improves%refractory%disease%following%ini9al%triplet%IMiD%

23%

63%pa9ents%

%

NC/PD%to%

induc9on%IMiD%triplet%

%

Received%CVD%

PR/MR 19 (30%)

CR/VGPR 18 (29%)

NC/PD 17 (27%)

*%

* Missing data 9 (14%)

Conclusions%

24%

%

%

•  CTD,%CRD%and%now%the%novel%quadruplet%KCRD%are%well%tolerated,%outpa9ent%delivered,%induc9on%regimens%for%NDMM.%

•  Deeper%responses%are%obtained%with%a%triplet%containing%lenalidomide%compared%to%thalidomide.%

%

•  KCRD%induces%very%high%response%rates,%significantly%deeper%and%achieved%faster,%than%either%triplet.%

•  Sequen9al%treatment%with%a%proteasome%inhibitor%in%pa9ents%with%

a%subop9mal%response%to%IMiD%triplet%improved%responses%%

% %A%but%could%not%match%the%excellent%responses%achieved% %

%with%the%quadruplet%approach.%

%

Pawlyn)et)al,)ASH)2015)

Chief Investigator: Professor Gareth Morgan Co-Investigators: Professor Graham Jackson Dr Faith Davies Professor Nigel Russell Professor Gordon Cook Immunology: Dr Mark Drayson Cellular Studies: Dr Brian Walker Dr Roger Owen Pharmacy Liaison: Ms Catherine Parbutt

Clinical Trials Research Unit, Leeds: Professor Walter Gregory Dr Jacqueline Ouzman Ms Rachel Sigsworth Mrs Corinne Collett Dr David Cairns Mr Alex Szubert Ms Ana Quartilho Ms Samantha Hinsley Ms Samantha Marshall Dr Helen Howard Ms Helen Turner Patients and staff at 112 UK centres

Myeloma XI/XI+ Trial Team

What#next…….?#

UKMRA%Myeloma%XIV%–%FITNESS%FrailtyAadjusted%therapy%In%Transplant%NonAEligible%pa9entS%with%Symptoma9c%myeloma%

Fist%line%therapy%in%the%nonAintensive%

selng%for%Myeloma%

CI:#Prof#Graham#Jackson#&#Prof#Gordon#Cook#

Frailty#Index<adjusted#Therapy#Non<adjusted#

1:1%

1:2%

CRDa% IRDa%

FIT)

%C%–%500mg%D1%&%D8%%

R%–%25mg%D1A21%%

D%–%20mg%%

I%–%4mg%weekly%

%

UNFIT) FRAIL)

1:2%

!!CRDa% !!IRDa%

1:2%

CRDa% IRDa%

1:2%

!CRDa% !IRDa%

TREAT%TO%MAXIMUM%RESPONSE%(6A8%cycles)%

FIT:$$C%–%500mg%D1%&%D8,%R%–%25mg%D1A21,%D%–%20mg/wk,%I%–%4mg/wk%UNFIT:$C%–%350mg%D1%&%D8,%R%–%15mg%D1A21,%D%–%10mg/wk,%I%–%3mg/wk%

FRAIL:$C%–%250mg%D1%&%D8,%R%–%10mg%D1A21,%D%–%10mg/wk,%I%–%3mg/wk%

1:1%

Revlimid% Ixazomib%Revlimid%M

AINTENANCE%

INDUCTION%Frailty%Indexing%(FI)%performed%in%all%pa9ents%at%baseline%

Trial#Design# Transplant%ineligible%NDMM%

Objec\ves#Primary#•  The%impact%of%IMiD/PI%–based%induc9on%regimen%%followed%by%IMiD/PI–

based%maintenance%regimen%on%PFS%auained%by%current%standard%of%care%in%previously%untreated%nonAtransplant%eligible%pa9ents.%

Secondary#•  ORR,%sCR/CR%rate%%

•  Early%mortality%(<60%days)%&%OS%

•  Clinical%u9lity%of%a%biological%risk%stra9fica9on:%the%impact%on%the%deliverability%of%upAfront%therapy%&%correla9on%with%outcomes.%

•  MRD%nega9vity%rate%

•  Safety%&%tolerability%

•  Impact%of%treatment%interven9ons%on%outcomes%in%molecular%high%risk%disease%

%

Sample#Size#IRD#vs#CRD:)1200%par9cipants%%Frailty<based#dosing:)1196%par9cipants.)Maintenance#I#vs#R)518%par9cipants.%)

Chief Investigators: Professor Graham Jackson Professor Gordon Cook Co-Investigators: Dr Jenny Bird Dr Stella Bowcock Dr Matthew Jenner Dr Kishore Bhuvan Central Assessment laboratory: Prof Mark Drayson Cellular Studies: Dr Martin Kaiser Dr Roger Owen Pharmacy Liaison:

Clinical Trials Research Unit, Leeds: Professor Walter Gregory Dr David Cairns Ms Anna Chalmers

UKMRA Myeloma XIV TMG

UKMRA%Myeloma%XV%Phase%III%study%in%NDMM%pa9ents%eligible%for%ASCT%

RADAR%(Risk%Adapted,%therapy%Directed%According%to%Response).%)

CI:#Prof#Kwee#Yong#&#Dr#Mark#Cook#

Chief%Inves9gators:%

Professor%Kwee%Yong%

Dr%Mark%Cook%

%

CoAInves9gators:%

Prof%Graham%Jackson%

Prof%Gordon%Cook%

Dr%Guy%Prau%

%

Central%Assessment%laboratory:%

Prof%Mark%Drayson%

%

Cellular%Studies:%

Dr%Mar9n%Kaiser%

Dr%Roger%Owen%

%

%

%

%

Clinical%Trials%Research%Unit,%Leeds:%

Professor%Walter%Gregory%

Dr%David%Cairns%

Ms%Anna%Waterhouse%

%

%

UKMRA Myeloma XV TMG

Tackling#Early#Morbidity#and#Mortality#in#Myeloma:#assessing#the#benefit#of#an\bio\c#prophylaxis#and#its#effect#on#

healthcare#associated#infec\ons#(TEAMM)%%

CI:#Prof#Mark#Drayson#

0%

100%

200%

300%

400%

500%

600%

700%

800%

MarA12%

JunA12%

SepA12%

DecA12%

MarA13%

JunA13%

SepA13%

DecA13%

MarA14%

JunA14%

SepA14%

DecA14%

MarA15%

JunA15%

SepA15%

Cumula\ve#Recruitment#Actual%

Target%

Leeds Clinical Trials Coordinating Office

MUK#CTN#–#therapy$accelerated$programme$

CTN Portfolio

Trial# Concept# Set#up# Recrui\ng# Closed# Target# Status#

MUK%one%98A%%

(complete)%Publica9on%in%press%Bri9sh%Journal%of%Haematology%2015%%

MUK%three% 38%Completed%recruitment%on%04Dec%2015.%%22%pts%recruited%

MUK%four% 68%Closed%early%to%recruitment.%16%pts%recruited%Abstract%presented%at%ASH%2015%

MUK%five% 300%Open%to%recruitment,%245%pts%recruited.%%37%sites%open.%Abstract%presented%at%ASH%2015%

%

MUK%six% 54%Closed%to%recruitment.%Abstract%presented%at%ASH%2015.%

MUK%seven% 250%Opened%to%recruitment%%2%March%2016,%3%centres%open%0%pats%

MUK%eight% 212%Opened%%to%recruitment%on%17%Dec%2015,%11%centres%open%and%8%pts%recruited%

MUK%nine%%%%%%HIGH%RISK% 105% Expected%to%open%Q3%2016%

MUK%11%%%%RELAPSED/REFRACTORY% 40%% Finalising%study%design,%due%to%open%late%summer%2016%

MUK%12%% 30%In%discussion%with%company%%

MUK%14% 47%In%discussion%with%company%%

MUKseven$

RRMM

PomCyDex

PomDex

Treat%un9l%PD%

Phase IIb 1:1 randomization

CI:#Dr#Mar\n#Kaiser#

•  Trial opened 2nd March 2016.

•  3 sites open to recruitment, 16 more in set up

•  No patients have yet been registered to the trial

MUKeight$

RRMM

CyDex

IxaCyDex

Treat%un9l%PD%

All#cycles#of#treatment,#28#day#cycle%IxaCyDex#Ixazomib #% %Oral %4mg %Days%1,%8%and%15%

Cyclophosphamide #Oral %500mg %Days%1,%8%and%15%

Dexamethasone #Oral %40mg%Days%1A4%and%12A15%%

#CyDex#Cyclophosphamide #Oral %500mg %Days%1,%8%and%15%

Dexamethasone #Oral %40mg%Days%1A4%and%12A15%

Phase IIb 1:1 randomization

CI:#Prof#Gordon#Cook#

MUKnine)

PD#

Lenalidomide#

Pomalidomide#

MUKeleven:#VIRel%Viral%Immunotherapy%in%Relapse/Refractory%Myeloma%

Phase%I/II%Study%Design%

D1 # ##D8# # #D15## #D22## #(each#28#day#cycle)#

Reovirus%

Immune%response%Biomarkers%Steroid#Discon\nua\on#

IMiD#con\nua\on#

CI:#Prof#Gordon#Cook#

Future Studies •  Op9mal%treatment%combina9ons%prohibi9vely%expensive%so%

considering%the%commercial%lifeAspan%of%drugs%in%the%realAworld%

selng%via%clinical%pathway%cri9que%

•  Defining%study%endApoints%that%can%change%clinical%prac9ce%but%are%realis9c%e.g.%PFS2%cf%OS%

•  Heterogeneity%of%disease%–%need%for%beuer%methodologies%to%define%

pa9ent%groups:%stra9fied/personalized/precisionAbased%therapy%

•  BiomarkersAbased%(i.e.%gene9c%subgroups)%

•  ClinicalAbased%(therapyArefractory,%elderly/frail,%renal%impairment)%

•  Drug%discovery,%development%and%reimbursement%underAperforming%

in%terms%of%access%to%novel%treatments%in%development%

•  Where%are%the%gaps%in%evidence%that%inform%clinical%prac9ce%but%are%

also%need%to%“staveAoff”%NICEAbased%restric9ons%and%NHSEngland%

treatment%algorithm%edicts%

Summary#•  To%date,%UK%myeloma%clinical%research%has%been%pivotal%to%the%evolu9on%of%clinical%prac9ce%interna9onally.%

•  “ReAbranding”%for%interna9onal%recogni9on%of%clinical%research%(MRC%cf%UKMRA).%

•  The%infraAstructure%for%the%delivery%of%research%in%this%area%con9nues%to%evolve%but%needs%to%be%more%strategic%in%its%alignment%with%healthcare%provision%and%regulatory%issues%as%well%as%new%exci9ng%developments%in%clinical%and%molecular%medicine.%

•  The%advancement%of%both%diagnos9cs%and%biological%therapies%now%proximate%more%than%ever%the%poten9al%of%a%stra9fied,%even%personalized,%medicine%approach%in%the%care%of%pa9ents%with%myeloma.%