Transcript How do we best deploy novel agents for T cell lymphoma

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
How do we best deploy novel agents for T cell lymphoma?
Carefully and somewhat empirically
What have we learned from key clinical trials?
Most ORR and toxicity
Should they be employed upfront?
Probably not routinely outside of clinical trial
Single Agents in the Relapsed Setting
Approved Agents in Relapsed/Refractory
PTCL
Belinostat
N=129
Outcomes
Romidepsin
N=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
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
MLN8237 (Alisertib):Response (PR+CR) by
Histology
Category
PTCL, NOS
Response n (%)*
Angioimmunoblastic
4/13 (31%)
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
Progression Free Survival: Relapsed/Refractory PTCL
BCCA by PS
Pralatrexate N=109
Romidepsin N=130
Belinostat N=129
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
Phase II Study of Pralatrexate
1.00
ORR 29%
Median duration = 10.1 months
Proportion
0.75
Permanently censored (eg, transplant) (n = 8)
Continue in follow-up for response (n = 8)
0.50
0.25
0
0
3
6
9
Months
12
15
18
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)
The Stanford
Experience Auto
MSKCC
Median PFS 6
months
1.0
0.8
0.6
%
0.4
0.2
0.0
0
12
24
36
48
60
72
84
96 108 120 132
PFS ICE 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 2013. Abstract 689; Chen AI, et al. Biol Blood Marrow Transplant. 2008;14(7):741-747.
Horwitz et al, ASH 2005
Retrospective Analyses of Allogeneic Stem-cell
Transplantation for PTCL
French Registry N=77
TRM 34%
5 year OS 57%
5 year EFS 53%
Le Gouill, S. et al. J Clin Oncol; 26:2264-2271 2008
Goldberg J. et al. Leuk Lymphoma. 2012 Jan 31
MSKCC N=34
TRM 18%
2 year OS 61%
Algorithmic Approach to Patients with
Relapsed PTCL (NOS, AITL, ALCL)
Transplantation soon
(Donor known; patient
eligible)
Combination
chemotherapy (ICE,
other combinations)
Transplantation
unclear
(Donor unknown;
patient may or may not
be eligible)
Clinical trial
or
single agent
Transplantation never
(Physician or patient
determines patient
ineligible)
Clinical trial
or
single agent
Lunning et al. J Clin Oncol, 2013;31:
Allogeneic stem-cell
transplantation
POD
intolerance
Clinical trial
or
single agent
Differential resposnes
ORR (%) by Lymphoma Subtype
Subtype
PTCL, NOS
Brentuximab
Pralatrexate Romidepsin Belinostat
vedotin
33
31
29
23
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;123:3095-3100
Pro B, et al. J Clin Oncol. 2012;30:2190-2196.
Combinations
DLBCL vs. PTCL
OS
Percentage of Treatment Group
100
CHOP plus rituximab
80
60
CHOP
40
PTCL
20
P < 0.007
0
0
0.5
1.0
1.5
2.0
2.5
3.0
Year after randomization
Coiffier B et al. N Engl J Med. 2002;346:235-242.
Vose et al. J Clin Oncol. 2008;26:4124–4130,
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%
1.0
0.9
0.8
0.7
Nordic Study
CHOEP-ASCT,
N=166
5 yr OS 51%
0.6
0.5
0.4
0.3
0.2
0.1
0.0
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):3093-3099
Phase II Study of Denileukin Diftitox + CHOP in
PTCL: “CONCEPT” Trial Interim Results




•7 D/C due to Adverse Events
•anaphylaxis
Phase II, newly diagnosed aggressive PTCL
•pneumonia
18mcg/kg/d D1-2, CHOP D3
•pneumonitis
N=49 (80% PTCL/AITL/ALCL)
•LFTs
CR 75.7%, ORR 86.5%
•cardiac arrest x 2
•TLS/rhabdo
•POD-7
•Patient request
•Early Discontinuation 20 (41%)
Foss et al. 10th ICML Lugano, June 5, 2008
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
30
CHOP
80/65
43 (1 yr)
10%
death
infection
KluinNelemans
Annals of
Oncol, 2011
20
90/60
27 (2 yr)
15%
EBV=LPD
20% TRM
10
30x3 CHOP-14
Single agent: N=14, Phase II, RR 36%, 5 deaths
Enblad et al. Blood. 2004;103:2920-2924.
The ACT trial
AFTER the dose/age amendment
ACT-1
ACT-2
18 yrs
80 yrs
65 yrs
R
R
CHOP-14
A30 - CHOP-14
CHOP-14
A30 - CHOP-14
CHOP-14
A30 - CHOP-14
CHOP-14
A30 - CHOP-14
CHOP-14
A30 - CHOP-14
CHOP-14
A30 - CHOP-14
CHOP-14
A30 - CHOP-14
CHOP-14
A30 - CHOP-14
CHOP-14
A60 CHOP-14
CHOP-14
A60 CHOP-14
CHOP-14
A60 CHOP-14
CHOP-14
A60 CHOP-14
HDT
HDT
No ALCL cases
ACT-1
Response rates and time-related end-points
15 mo median follow-up
Response rates
Time-related end-points
Primary
1.0
CR/CRu
42 (67)
38 (61)
EFS
0.9
0.9
0.8
0.8
0.7
0.7
Proportion
ORR
N (%)
Proportion
Response rates
0.6
0.5
0.4
4 (6)
OS
0.6
0.5
0.4
0.3
0.3
0.2
0.2
0.1
0.1
PR
Secondary
1.0
0.0
0.0
0
0
5
10
15
20
25
30
35
40
45
5
10
15
20
25
30
35
40
45
50
50
Months
Months
SD
3 (5)
PD
Not evaluable
Total
End-point
1-yr (95% CI)
16 (25)
EFS
55% (42-67)
2 (3)
PFS
54% (42-67)
63 (100)
OS
78% (67-88)
d’Amore et al, ASH 2012
Phase I/II Pralatrexate in Combination with 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
The initial study design was to give pralatrexate day 1 and gemcitabine
Cohort
PDX/Gem
DLT(Cohort A); due to
DLT
day
2 on a weekly
schedule 3Schedule
out of every 4 weeks
hematologic
toxicity
the weeks
subsequent Cohorts
received
drugs
1
15/ 400observed 3/4
2/2
Neutro: both
Gr3,4Throm:
Gr3,4
on Q2
B –weeks
sequential days)
C – same
-1 week schedule
10/400 (Cohort3/4
2/2 and (Cohort Throm:
Gr 3
day pralatrexate followed 1h later by gemcitabine)
-2
10/300
3/4 weeks
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
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
Romidepsin-CHOP Dose-escalation Phase
New definition of DLTs
(amendment °1)
Cohort 1
10 mg/m2
N=3
Cohort 5
12 mg/m2
N=3
Cohort 6
12 mg/m2
N=3
Cohort 4
10 mg/m2
N=3
Cohort 2
10 mg/m2
N=3
Cohort 3
8 mg/m2
N=3
1 DLT
Syncope
Gr 3
2 DLTs
Hem Gr 3
NO DLT
NO DLT
1 DLT
Pulmonary
edema
Gr 3
2 DLT
Nausea
DOSE USED
FOR PHASE 2
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
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
Phase III Ro-CHOP Study
 International randomized, open-label study
 Principal objective: PFS improvement
 Planned accrual: 420 patients
Brentuximab + CH-P
Response 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)
PFS
N=26
Median F/U 21.4 mos
Est 1 yr PFS 71%
Fanale et al JCO epub
September 2014
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 CD30positive Mature T-cell Lymphomas
PTCL-CD30+ (> 10%)
If ALK+ ALCL IPI >2
R
A
N
D
O
M
I
Z
E
N=300
Primary endpoint
PFS approx. 45% improvement
BV + CH-P”
x 6-8 cycles
RESTAGE
C4
Placebo+
CHOP”
x 6-8 cycles
F/U
Progression
Death
Phase III Trials
Untreated 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?
Carefully and somewhat empirically
What have we learned from key clinical trials?
Most ORR and toxicity
Should they be employed upfront?
Probably not routinely outside of clinical trial