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