“To steal ideas from one person is plagiarism, to steal ... · PIM#Inh#(ph#I)# MUKnine$ R2W#...
Transcript of “To steal ideas from one person is plagiarism, to steal ... · PIM#Inh#(ph#I)# MUKnine$ R2W#...
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$2016$
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
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%
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
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%
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#
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.%