CORAL: COllaborative trial in Relapsed Aggressive Lymphoma R-ICE versus R-DHAP in relapsed patients...

CORAL: COllaborative trial in Relapsed Aggressive Lymphoma

R-ICE versus R-DHAP in relapsed patients with CD20 diffuse large B-cell lymphoma (DLBCL) followed by autologous stem cell

transplantation: CORAL study.

C. Gisselbrecht, B. Glass, N. Mounier, D. Gill, D. C. Linch, M. Trneny,

A. Bosly, O. Shpilberg, H. Hagberg, N. Ketterer, D. Ma, P. Gaulard,

C. Moskowitz, and N. Schmitz.

WHAT TO DO IN RELAPSING DLBLCL

Standard of care in DLBCL, failing first line chemotherapy treatment, is salvage regimen followed in chemosensitive patients with autologous stem cell transplantation (ASCT).

In the Parma study the 7 yr event free survival rate was 41% for ASCT vs 13% for conventional arm.

Before rituximab era: different salvage regimens would provide a response rate between 50% to 68% with mobilization of hematopoetic peripheral stem cell in most situation.

In the rituximab era: What is the best salvage regimen? No randomized

comparison have been made previously What is the place of rituximab after

transplantation?

CORAL Trial of RICE v DHAP

CD20+ DLBCLRelapsed/Refractory

R-ICE x 3

R-DHAP x 3

R

A

N

D

O

M

I

Z

E

R

A

N

D

O

M

I

Z

E

SD/POD → Off

PR/CR →

→A BS EC AT M

R x 6

Obs

N=400

Which salvage regimen is the best?

Place of immunotherapy post transplantation?

Orlando ASCO May 2009 / Coral study C. Gisselbrecht

CORAL StudyNCT 00137995. Eudract N°2004-002103-32

Inclusion Criteria

Diffuse large B Cell Lymphoma, CD 20+: in 1st relapse, partial response to first line treatment ≤ 65 year old Eligible for transplant Previously treated with chemotherapy

regimen containing anthracyclines with or without rituximab

PS 2 Informed consent


CORAL StudyPrimary objective : Part I: induction therapy : Overall response rate

(ORR) adjusted with successful mobilization: MARR Target difference in Response Rate 15% with 400

pts randomized Part II: maintenance therapy : Event free survival

(EFS) at 2 years post transplantation Target difference 15% with 240 patients

randomized Secondary objectives: Eligibility for transplant, toxicities with R-ICE and R-DHAP Toxicity Rituximab post transplant Time to progression or relapse Disease-free survival for complete responders overall survival.


• Patient distribution

Australasia

60

Germany

113

Cesz Republic

36

France

128

Belgium

31

Israel

13

US

9

Sweden

13

Switzerland

24

481 patients30/6/2008

Ireland

4

UK

50Thank you to all investigators and pathologists

CORAL Study


CORAL Study

Report on 400 patients included between July 24, 2003 to September 4, 2007 : First randomization: R-ICE vs R-DHAP

Second randomization : Rituximab vs no further therapy still on going (240 pts)

Stratification for subgroup analysis

i) Center, groupii) Prior treatment with Rituximab during first lineiii) Relapse < 12months and Refractory (non achieving CR 1st line treatment)


Patients randomized

N = 400

R-ICE

N = 202

R-DHAP

N = 194

Received study treatment

N = 197

Received study treatment

N = 191

Completed induction phase

N = 169

Completed induction phase

N = 161

Received BEAM+ASCT

N = 101

Received BEAM+ASCT

N = 105

Randomized in maintenance

N = 98


N = 99

Arm of treatment

AllARM A / R-

ICEARM B / R-

DHAP

N % N % N %

Response after first line

108 54 101 52 209 53COMPLETE RESPONSE

UNCONFIRMED COMPLETE RESPONSE 23 11 24 12 47 12

PARTIAL RESPONSE 40 20 37 19 77 20

STABLE DISEASE 6 3 10 5 16 4

PROGRESSIVE DISEASE 24 12 20 10 44 11

NOT EVALUATED 0 0 1 1 1 0

122 60 122 63 244 62RITUXIMAB

WHAT TYPE OF PATIENTS HAVE BEEN INCLUDED IN CORALRESPONSE AT 1ST LINE Tt


CORAL PATIENTS ITTMAIN CHARACTERISTICS AT INCLUSION

R-ICE (202) R-DHAP (194)

Median age 54 y 55 y Sex M 125 118 F 77 76

Stage I-II 81 66 Stage III-IV 119 121

ENS > 1 55 64

LDH > Nl 104 94

S-AaIPI 0-1 119 107S-AaIPI 2-3 75 74

<12 months 89 87

12 months 112 103

P=0.09


R-ICE R-DHAP

N 197 % N 191

%

Response including deaths

COMPLETE RESPONSE 48 24 53 28

UNCONFIRMED COMPLETE RESPONSE 24 12 22 12

PARTIAL RESPONSE 53 27 45 24

STABLE DISEASE 23 12 22 12

PROGRESSIVE DISEASE 38 19 35 18

DEATH 6 3 10 5

PREMATURE WITHDRAWAL / NOT EVALUATED

4 2 4 2

Total 197 100 191 100

RESPONSE AFTER INDUCTION TREATMENT INCLUDING DEATHS FOR

ALL PATIENTS (Intent To Treat)

63 .5 % 62.8 %

Arm of treatment Nb patients

Nb responders

with successful

mobilization MARR (%)

R-ICE 197 103 52.3

R-DHAP 191 104 54.5Orlando ASCO May 2009 / Coral study C. Gisselbrecht

CORAL TOXICITY R-ICE R-DHAP

Infection with neutropenia

Grade 3-4 Yes 33 (17%) 31 (16%)

Infection without neutropenia

Grade 3-4 Yes 11 (6%) 15 (8%)

Renal

Grade 3-4 Yes 2(1%) 11 (6%)

PlateletsTransfusions % pts 35% 57%

Toxic deaths 1 3

On induction safety population, in R-ICE arm 90 SAEs and in the R-DHAP arm 120 SAEs during the whole study,

concerning respectively 58 patients (29%) and 69 patients (36%).

Response p

Patients CR/Cru/PR

All patients 245 63 %

CR/CRu 147 38%

Prior Rituximab No 122 83% <0.0001

Yes 124 51%

Relapse > 12 months 140 88% <0.0001Refractory < 12 months 106 46%

s IPI < 2 160 71% <0.0002> 1 76 52%

CORAL STUDY RESPONSE RATE ACCORDING TO PROGNOSTIC FACTORS

* No difference between GELA DSHNHL ALLG** More early relapse in prior Rituximab Group


Arm of treatmentARM A /

R-ICEARM B / R-DHAP

N % N %Consolidation treatment (BEAM)

101 51 105 55YesNo 96 49 86 45

Total 197 100 191 100Transplantation

CONSOLIDATION – PATIENTS WITH BEAM AND ASCT (INDUCTION ITT)

Main Reasons for premature withdrawals:Progressive lymphoma 53%

Toxicity 7%Collection failure 10% (CD 34/kg < 2.106)

Deaths 4%


OVERALL SURVIVAL ACCORDING TO TREATMENT

ARM (INDUCTION ITT)

PROGRESSION-FREE SURVIVAL ACCORDING TO

TREATMENT ARM (INDUCTION ITT)


56%

56%

42%

45%

PROGRESSION-FREE SURVIVAL ACCORDING TO

PRIOR RITUXIMAB (INDUCTION ITT)

PROGRESSION-FREE SURVIVAL

ACCORDING TO FAILURE FROM DIAGNOSIS (INDUCTION ITT)


N=160

N=228

N=147

N=241

31%

64%

30%

62%

Failure from diagnosis =>= 12 months

EVENT-FREE SURVIVAL BY PRIOR RITUXIMAB - INDUCTION ITT

Failure from diagnosis > 12 months

Standard salvage regimen does not overcome poor prognosis of early relapse

Failure from diagnosis =< 12 months

N= 106

N= 54

N= 41

N= 187

MULTIVARIATE ANALYSIS FOR SURVIVAL

p PFS EFS OS

Prior Rituximab 0.003 0.0007 0.01

Relapse < 12 months < 0.0001< 0.0001< 0.0001

sIPI > 1 < 0.0001< 0.0004< 0.0001

Treatment Arm 0.1 0.3

0.07Prior rituximab exposure will be the rule in future study Relapses after rituximab exposure are more severe.Early relapses and failure are the main adverse prognostic factors.


PROGRESSION-FREE SURVIVAL OF PATIENTS

SUBMITTED TO ASCT from date of 1st randomization

(INDUCTION ITT)

Progression-Free Survival of maintenance ITT population

from date of 2nd randomization

R

A

N

D

O

M

I

Z

E

PR/CR →

R x 6N = 102

ObsN = 95


N = 197


N=197 pts

58%

140 events are required to conclude.Nowadays:

85 events (43%) Final analysis of

maintenance arm 2010

R-ICE and R-DHAP have similar activity and mobilization ability with less adverse events for R ICE.

Prognostic factors affecting response and survival: relapse < 12 months, secondary IPI>1, prior

rituximab exposure

A new profile of relapses and refractory patients after rituximab will come out from this trial, and will help the design of future study with new drugs.

A bio CORAL program is on going to better understand this population of poor prognosis patients

CORAL CONCLUSION

POOR RESULTS : RESPONSE RATE 50% PFS 30%

GOOD RESULTS : RESPONSE RATE 80% PFS 60%

Many Thanks again

investigatorspathologists

GELA RC

M Fournier/N. Mounier statistics

C.Pitrou/ G Chartier project leaders

L. Gérard, Data management

and all the project managers in the different countries

Thank you for their continous support: Roche, Baxter, Chugai

Date post:	18-Dec-2015
Category:	Documents
Upload:	pierce-manning
View:	232 times
Download:	0 times

CORAL: COllaborative trial in Relapsed Aggressive Lymphoma R-ICE versus R-DHAP in relapsed patients...

Documents