1. 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

2. 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

3. Single Agents in the Relapsed Setting

4. Approved Agents in Relapsed/Refractory PTCL
Belinostat
N=129
Outcomes
Romidepsin
N=131
Pralatrexate N=109 2
Median prior Rx 3
26%
ORR
25%
29%
11% CR
15% PR
18%
8.4
Median duration of response
17 months
10.1 months
1.6
Median PFS
4 months
3.5 months
O’Connor OA, et al. J Clin Oncol. 2011;29:
Coiffier B, et al. J Clin Oncol. 2012;30 :
O’Connor OA, et al. ASCO 2013

5. 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

6. Progression Free Survival: Relapsed/Refractory PTCL
BCCA by PS
Romidepsin N=130
Pralatrexate N=109
Belinostat N=129
Mak V et al. JCO 2013;31: , O’Connor OA, et al. J Clin Oncol. 2011;29: , Coiffier B, et al. J Clin Oncol. 2012;30 : , O’Connor OA et al ASCO 2013

7. Phase II Study of Pralatrexate
1.00
ORR 29%
Median duration = 10.1 months
0.75
Permanently censored (eg, transplant) (n = 8)
Continue in follow-up for response (n = 8)
Proportion
0.50
0.25 3 6 9 12 15 18
Months
O’Connor OA, et al JCO Jan 7

8. Continuous Therapy in Relapsed T-cell Lymphoma
Belinostat DoR AITL
Romidepsin PFS by Response
Median 13.6 mos

9. Pralatrexate for CTCL: Progression Free Survival
Cohort >15 mg/m2 N=41
Med PFS 388 days

10. Autologous Transplantation in Relapsed PTCL
MSKCC
CIBMTR: PFS excluding pt in CR1
(Most patients ALCL)
The Stanford Experience Auto 12 24 36 48 60 72 84 96
108
120
132
PFS ICE months
0.0
0.2
0.4
0.6
0.8
1.0 %
Median PFS 6 months
Response to ICE 70% (28/40)
Received ASCT 68% (27/40)
Benefits are unclear. Most single institution studies show low PFS rates while registry data suggests better outcomes
Smith S, et al. JCO Abstract 689; Chen AI, et al. Biol Blood Marrow Transplant. 2008;14(7): Horwitz et al, ASH 2005 .

11. Retrospective Analyses of Allogeneic Stem-cell Transplantation for PTCL
French Registry N=77
TRM 34%
MSKCC N=34
TRM 18%
5 year OS 57%
2 year OS 61%
5 year EFS 53%
Le Gouill, S. et al. J Clin Oncol; 26:
Goldberg J. et al. Leuk Lymphoma Jan 31

12. Algorithmic Approach to Patients with Relapsed PTCL (NOS, AITL, ALCL)
Allogeneic stem-cell transplantation
Transplantation soon
(Donor known; patient eligible)
Combination chemotherapy (ICE, other combinations)
Adequate response
Transplantation unclear
(Donor unknown; patient may or may not be eligible)
Clinical trial or
single agent
Donor known and eligible
No donor available
Transplantation never
(Physician or patient determines patient ineligible)
Clinical trial or
single agent
POD intolerance
Clinical trial or
single agent
Lunning et al. J Clin Oncol, 2013;31:

13. Differential resposnes ORR (%) by Lymphoma Subtype
Pralatrexate
Romidepsin
Belinostat
Brentuximab vedotin
PTCL, NOS 31 29 23 33
AITL 8 30 46 54
ALCL 24 15 86
O’Connor OA, et al. J Clin Oncol. 2011;29:
Coiffier B, et al. J Clin Oncol. 2012;30: ,
Horwitz, S et al ICML 2013,
Horwitz S M et al. Blood 2014;123:
Pro B, et al. J Clin Oncol. 2012;30:

14. Combinations

15. Year after randomization Percentage of Treatment Group
DLBCL vs. PTCL OS
100 80 60 40 20
0.5
1.0
1.5
2.0
2.5
3.0
Year after randomization
P < 0.007
CHOP plus rituximab
CHOP
Percentage of Treatment Group
PTCL
Coiffier B et al. N Engl J Med. 2002;346:
Vose et al. J Clin Oncol. 2008;26:4124–4130,

16. T-cell Lymphoma: Current approaches that may be better than CHOP
International T-cell Project (retrospective)
Anthracycline containing >85%
N=299
5 yr OS 32%
Nordic Study
CHOEP-ASCT,
N=166
5 yr OS 51%
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Better Results with more intensive therapy?
Patient selection?
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):

17. Phase II Study of Denileukin Diftitox + CHOP in PTCL: “CONCEPT” Trial Interim Results
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%)
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%
Foss et al. 10th ICML Lugano, June 5, 2008

18. Alemtuzumab (A) + Chemotherapy First-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
CHOP
80/65
43 (1 yr)
10% death
infection
Kluin-Nelemans
Annals of Oncol, 2011 10
30x3
CHOP-14
90/60
27 (2 yr)
15% EBV=LPD20% TRM
Single agent: N=14, Phase II, RR 36%, 5 deaths
Enblad et al. Blood. 2004;103:

19. AFTER the dose/age amendment
The ACT trial
AFTER the dose/age amendment
ACT-1
ACT-2
18 yrs
80 yrs
65 yrs
CHOP-14
A30 - CHOP-14
HDT R
CHOP-14
A30 - CHOP-14 R
A60
CHOP-14
A60
A60
CHOP-14
A60
CHOP-14
HDT
No ALCL cases

20. Response rates and time-related end-points
ACT-1
Response rates and time-related end-points
15 mo median follow-up
Response rates
Time-related end-points
Primary
Secondary
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)
EFS OS
End-point
1-yr (95% CI)
EFS
55% (42-67)
PFS
54% (42-67) OS
78% (67-88)
d’Amore et al, ASH 2012

21. Phase I/II Pralatrexate in Combination with Gemcitabine
The initial study design was to give pralatrexate day 1 and gemcitabine
day 2 on a weekly schedule 3 out of every 4 weeks (Cohort A); due to
hematologic toxicity observed the subsequent Cohorts received both drugs
on Q2 week schedule (Cohort B – sequential days) and (Cohort C – same
day pralatrexate followed 1h later by gemcitabine)
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
Phase I Initial Dosing
Cohort
PDX/Gem
Schedule
DLT 1
15/ 400
3/4 weeks
2/2
Neutro: Gr3,4Throm: Gr3,4 -1
10/400
Throm: Gr 3 -2
10/300
2/3
Neutro: Gr 3, Throm: Gr3
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)
Horwitz et al ASH 2009 a1674

22. CEOP-Pralatrexate PFS
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
N=33
ORR 70%
CR 52%
months
Advani et al. ASH 2013

23. Romidepsin-CHOP Dose-escalation Phase
New definition of DLTs
(amendment °1)
Cohort 6
12 mg/m2 N=3
Cohort 5
12 mg/m2 N=3
Cohort 4
10 mg/m2
N=3
Cohort 1
10 mg/m2
N=3
Cohort 2
10 mg/m2
N=3
Cohort 3
8 mg/m2
N=3
2 DLT
Nausea
DOSE USED FOR PHASE 2
1 DLT
Pulmonary edema
Gr 3
1 DLT
Syncope
Gr 3
2 DLTs
Hem Gr 3
NO DLT
NO DLT
SAEs: 2-acute myocardial infarction
1-acute pulmonary edema, all after first cycle, none fatal
Thrombocytopenia led to discontinuation of Romidepsin in 5 patients
Dupuis et al. ICML 2013

24. PFS (Median Follow-up 10 months; n=27)
Romidepsin-CHOP
PFS (Median Follow-up 10 months; n=27)
CR 15/27 (55.6%)
ORR 20/27 74%
1 year estimated PFS 63.9% (95%CI 35.4 – 82.5)
Dupuis et al. ICML 2013

25. Phase III Ro-CHOP Study
International randomized, open-label study
Principal objective: PFS improvement
Planned accrual: 420 patients 25

26. Brentuximab + CH-P Response and PFS
sALCLN (%)
Other DxN (%)
TotalN (%)
ORR
19 (100)
7 (100)
26 (100) CR
16 (84)
23 (88) PR
3 (16) --
3 (12)
PFS
N=26
Median F/U 21.4 mos
Est 1 yr PFS 71%
Fanale et al JCO epub September 2014

27. 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
BV + CH-P”
x 6-8 cycles R A N D O M I Z E
PTCL-CD30+ (> 10%)
If ALK+ ALCL IPI >2
F/U
Progression
Death
RESTAGE C4
Placebo+ CHOP”
x 6-8 cycles
N=300
Primary endpoint
PFS approx. 45% improvement

28. Phase III Trials Untreated PTCL
Intervention
Patient Population
Primary Endpoints
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
PFS, OS
Closed
Romidepsin + CHOP vs CHOP
Belinostat + CHOP or Pralatrexate + CHOP vs CHOP
Planned

29. 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