steven m. horwitz m.d. associate attending memorial sloan-kettering cancer center
DESCRIPTION
How do we best deploy novel agents for T cell lymphoma: What have we learned from key clinical trials and should they be employed upfront?. Steven M. Horwitz M.D. Associate Attending Memorial Sloan-Kettering Cancer Center Associate Professor Weill Cornell Medical College. 3 questions. - PowerPoint PPT PresentationTRANSCRIPT
How do we best deploy novel agents for T cell lymphoma: What have we learned from
key clinical trials and should they be employed upfront?
Steven M. Horwitz M.D.Associate Attending
Memorial Sloan-Kettering Cancer CenterAssociate Professor
Weill Cornell Medical College
3 questions
How do we best deploy novel agents for T cell lymphoma?
What have we learned from key clinical trials?
Should they be employed upfront?
Carefully and somewhat empirically
Most ORR and toxicity
Probably not routinely outside of clinical trial
Single Agents in the Relapsed Setting
Approved Agents in Relapsed/Refractory PTCL
O’Connor OA, et al. J Clin Oncol. 2011;29:1182-1189Coiffier B, et al. J Clin Oncol. 2012;30 :631-636O’Connor OA, et al. ASCO 2013
BelinostatN=129
Outcomes RomidepsinN=131
Pralatrexate N=109
2 Median prior Rx
2 3
26% ORR 25% 29%
11% CR 15% 11%
15% PR 11% 18%
8.4 Median duration of response
17 months 10.1 months
1.6 Median PFS 4 months 3.5 months
MLN8237 (Alisertib):Response (PR+CR) by Histology
Category Response n (%)*
PTCL, NOS 4/13 (31%)
Angioimmunoblastic 3/9 (33%)
Anaplastic, ALK neg 1/2 (50%)
Adult T-cell (HTLV-1) 1/4 (25%)
Extranodal NK/T-cell 0/2
Transformed MF 0/7
Barr et al. ASCO 2014
Pralatrexate N=109
Romidepsin N=130
Mak V et al. JCO 2013;31:1970-1976, O’Connor OA, et al. J Clin Oncol. 2011;29:1182-1189, Coiffier B, et al. J Clin Oncol. 2012;30 :631-636, O’Connor OA et al ASCO 2013
Belinostat N=129
Progression Free Survival: Relapsed/Refractory PTCL
BCCA by PS
Phase II Study of Pralatrexate
3 6 9 12 15 180
0
0.25
0.50
1.00
0.75
Months
Pro
po
rtio
n
ORR 29%Median duration = 10.1 months
Permanently censored (eg, transplant) (n = 8)
Continue in follow-up for response (n = 8)
O’Connor OA, et al JCO Jan 18 2011
Continuous Therapy in Relapsed T-cell Lymphoma
Belinostat DoR AITL
Median 13.6 mos
Romidepsin PFS by Response
Pralatrexate for CTCL: Progression Free Survival
Cohort >15 mg/m2 N=41
Med PFS 388 days
Autologous Transplantation in Relapsed PTCL
CIBMTR: PFS excluding pt in CR1(Most patients ALCL)
Smith S, et al. JCO 2013. Abstract 689; Chen AI, et al. Biol Blood Marrow Transplant. 2008;14(7):741-747. Horwitz et al, ASH 2005.
The Stanford Experience Auto
• Benefits are unclear. Most single institution studies show low PFS rates while registry data suggests better outcomes
MSKCC
Median PFS 6 months
Response to ICE 70% (28/40)
Received ASCT 68% (27/40)
Le Gouill, S. et al. J Clin Oncol; 26:2264-2271 2008Goldberg J. et al. Leuk Lymphoma. 2012 Jan 31
Retrospective Analyses of Allogeneic Stem-cell Transplantation for PTCL
5 year EFS 53%
5 year OS 57%
French Registry N=77TRM 34%
MSKCC N=34TRM 18%
2 year OS 61%
Algorithmic Approach to Patients with Relapsed PTCL (NOS, AITL, ALCL)
Lunning et al. J Clin Oncol, 2013;31:
Transplantation soon(Donor known; patient
eligible)
Transplantation soon(Donor known; patient
eligible)
Combination chemotherapy (ICE, other combinations)
Combination chemotherapy (ICE, other combinations)
Allogeneic stem-cell transplantation
Allogeneic stem-cell transplantation
Transplantation unclear
(Donor unknown; patient may or may not
be eligible)
Transplantation unclear
(Donor unknown; patient may or may not
be eligible)
Clinical trial or
single agent
Clinical trial or
single agent
Transplantation never(Physician or patient determines patient
ineligible)
Transplantation never(Physician or patient determines patient
ineligible)
Clinical trial or
single agent
Clinical trial or
single agent
Clinical trial or
single agent
Clinical trial or
single agent
POD intolerance
Adequate
response
Donor known and
eligible
No donor available
Differential resposnesORR (%) by Lymphoma Subtype
Subtype Pralatrexate Romidepsin BelinostatBrentuximab
vedotin
PTCL, NOS 31 29 23 33
AITL 8 30 46 54
ALCL 29 24 15 86
O’Connor OA, et al. J Clin Oncol. 2011;29:1182-1189. Coiffier B, et al. J Clin Oncol. 2012;30:631-636, Horwitz, S et al ICML 2013, Horwitz S M et al. Blood 2014;123:3095-3100Pro B, et al. J Clin Oncol. 2012;30:2190-2196.
Combinations
DLBCL vs. PTCL
Coiffier B et al. N Engl J Med. 2002;346:235-242.Vose et al. J Clin Oncol. 2008;26:4124–4130,
OS
100
80
60
40
20
00 0.5 1.0 1.5 2.0 2.5 3.0
Year after randomization
P < 0.007
CHOP plus rituximab
CHOP
Per
cen
tag
e o
f T
reat
men
t G
rou
p
PTCL
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
T-cell Lymphoma: Current approaches that may be better than CHOP
Vose et al. J Clin Oncol. 2008;26:4124–4130, International T-cell Classification Project
D’Amore, et al. J Clin Oncol. 2012;30(25):3093-3099
International T-cell Project (retrospective)Anthracycline containing >85%N=2995 yr OS 32%
Nordic StudyCHOEP-ASCT,N=1665 yr OS 51%
Better Results with more intensive therapy?Patient selection?
Phase II Study of Denileukin Diftitox + CHOP in PTCL: “CONCEPT” Trial Interim Results
Foss et al. 10th ICML Lugano, June 5, 2008
Phase II, newly diagnosed aggressive PTCL 18mcg/kg/d D1-2, CHOP D3 N=49 (80% PTCL/AITL/ALCL) CR 75.7%, ORR 86.5%
•7 D/C due to Adverse Events
•anaphylaxis
•pneumonia
•pneumonitis
•LFTs
•cardiac arrest x 2
•TLS/rhabdo
•POD-7
•Patient request
•Early Discontinuation 20 (41%)
Alemtuzumab (A) + ChemotherapyFirst-line treatment of PTCL
Citation n PTCL A dose
mg
Chemo ORR/CR % PFS/EFS
% Toxicity
Gallamani
Blood 2007
24 14 30 CHOP-28 75/71
(50% PTCL)
48 (2 yr) 17% G4 infection
Kim
Chemother Pharmacol
2007
20 30 CHOP 80/65 43 (1 yr) 10% death
infection
Kluin-Nelemans
Annals of Oncol, 2011
20 10 30x3 CHOP-14 90/60 27 (2 yr) 15% EBV=LPD20% TRM
Single agent: N=14, Phase II, RR 36%, 5 deathsEnblad et al. Blood. 2004;103:2920-2924.
CHOP-14
HDT
The ACT trial AFTER the dose/age amendment
CHOP-14
CHOP-14
CHOP-14
CHOP-14
CHOP-14
CHOP-14
A30 - CHOP-14
A30 - CHOP-14
A30 - CHOP-14
A30 - CHOP-14
HDT
R
CHOP-14
CHOP-14
CHOP-14
CHOP-14
CHOP-14
CHOP-14
A30 - CHOP-14
A30 - CHOP-14
A30 - CHOP-14
A30 - CHOP-14
CHOP-14
R
18 yrs
65 yrs
80 yrs
CHOP-14A60
A60
A60
CHOP-14A60
No ALCL cases
ACT-1 ACT-2
Time-related end-pointsResponse rates
ACT-1 Response rates and time-related end-points
Response rates N (%)
ORR 42 (67)
CR/CRu 38 (61)
PR 4 (6)
SD 3 (5)
PD 16 (25)
Not evaluable 2 (3)
Total 63 (100)
Months
Pro
po
rtio
n
0 5 10 15 20 25 30 35 40 45 50
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
OS
Months
Pro
po
rtio
n
0 5 10 15 20 25 30 35 40 45 50
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
EFS
Primary Secondary
End-point 1-yr (95% CI)
EFS 55% (42-67)
PFS 54% (42-67)
OS 78% (67-88)
15 mo median follow-up
d’Amore et al, ASH 2012
The initial study design was to give pralatrexate day 1 and gemcitabineday 2 on a weekly schedule 3 out of every 4 weeks (Cohort A); due tohematologic toxicity observed the subsequent Cohorts received both drugson Q2 week schedule (Cohort B – sequential days) and (Cohort C – sameday pralatrexate followed 1h later by gemcitabine)
The initial study design was to give pralatrexate day 1 and gemcitabineday 2 on a weekly schedule 3 out of every 4 weeks (Cohort A); due tohematologic toxicity observed the subsequent Cohorts received both drugson Q2 week schedule (Cohort B – sequential days) and (Cohort C – sameday pralatrexate followed 1h later by gemcitabine)
Phase I/II Pralatrexate in Combination with Gemcitabine
Phase I Initial Dosing
Cohort PDX/Gem Schedule DLT DLT
1 15/ 400 3/4 weeks 2/2 Neutro: Gr3,4Throm: Gr3,4
-1 10/400 3/4 weeks 2/2 Throm: Gr 3
-2 10/300 3/4 weeks 2/3 Neutro: Gr 3, Throm: Gr3
Horwitz et al ASH 2009 a1674
Initial design: pralatrexate day 1 and gemcitabine day 2 weekly 3/4 weeks (Cohort A)
Starting Doses Pralatrexate 15 mg/m2 and Gemcitabine 400 mg/m2
•Study modified to Every other Week dosing•Pralatrexate day 1 and gemcitabine day 2 (Cohort B)•Pralatrexate day 1 and gemcitabine 1 hour later (Cohort C)
CEOP-Pralatrexate PFS
N=33ORR 70%CR 52%
Advani et al. ASH 2013
Cycle A: CEOP-Cyclophosphamide 750 mg/m2 IV d1-Etoposide 100 mg/m2 IV d1-3-Vincristine 2 mg IV day 1-Prednisone 100 mg/day X 5
•Cycle B: Pralatrexate (P)- 30 mg/m2 IV d 15, 22 and 29
months
Cohort 110 mg/m2 N=3
Cohort 210 mg/m2
N=3
Cohort 38 mg/m2
N=3
Cohort 410 mg/m2 N=3
Cohort 512 mg/m2 N=3
1 DLTSyncope Gr 3
2 DLTsHem Gr 3 NO DLT
NO DLT
1 DLTPulmonary edemaGr 3
New definition of DLTs(amendment °1) Cohort 6
12 mg/m2 N=3
2 DLTNauseaDOSE USED FOR PHASE 2
Romidepsin-CHOP Dose-escalation Phase
SAEs: 2-acute myocardial infarction1-acute pulmonary edema, all after first cycle, none fatalThrombocytopenia led to discontinuation of Romidepsin in 5 patients
Dupuis et al. ICML 2013
1 year estimated PFS 63.9% (95%CI 35.4 – 82.5)
Romidepsin-CHOP PFS (Median Follow-up 10 months; n=27)
CR 15/27 (55.6%)ORR 20/27 74%
Dupuis et al. ICML 2013
Phase III Ro-CHOP Study
International randomized, open-label study Principal objective: PFS improvement Planned accrual: 420 patients
Brentuximab + CH-PResponse and PFS
sALCLN (%) Other DxN (%) TotalN (%)
ORR 19 (100) 7 (100) 26 (100)
CR 16 (84) 7 (100) 23 (88)
PR 3 (16) -- 3 (12)
Fanale et al JCO epub September 2014
PFS
N=26Median F/U 21.4 mosEst 1 yr PFS 71%
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Brentuximab Vedotin and CHP (A+CHP) Versus CHOP in the Frontline Treatment of Patients with CD30-
positive Mature T-cell Lymphomas
PTCL-CD30+ (> 10%)If ALK+ ALCL IPI >2
BV + CH-P” x 6-8 cycles
Placebo+ CHOP”
x 6-8 cycles
RANDOMIZE
RESTAGE C4
F/UProgression
Death
N=300Primary endpointPFS approx. 45% improvement
Phase III TrialsUntreated PTCL
Intervention Patient Population
Primary Endpoint
s
Status
Alemtuzumab + CHOP14 + G-CSF vs CHOP14 + G-CSF
Newly diagnosed PTCL
EFS Completed
Brentuximab vedotin + CHP vs CHOP CD30+ PTCL PFS Ongoing
CHOP pralatrexate Newly diagnosed PTCL
PFS, OS Closed
Romidepsin + CHOP vs CHOP Newly diagnosed PTCL
PFS Ongoing
Belinostat + CHOP or Pralatrexate + CHOP vs CHOP
Newly diagnosed PTCL
PFS Planned
3 questions
How do we best deploy novel agents for T cell lymphoma?
What have we learned from key clinical trials?
Should they be employed upfront?
Carefully and somewhat empirically
Most ORR and toxicity
Probably not routinely outside of clinical trial