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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.

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slide1

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
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

approved agents in relapsed refractory ptcl
Approved Agents in Relapsed/Refractory PTCL

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

slide6

Progression Free Survival: Relapsed/Refractory PTCL

BCCA by PS

Romidepsin N=130

Pralatrexate N=109

Belinostat N=129

Mak V et al. JCO 2013;31:1970-1976, 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
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

0

0

3

6

9

12

15

18

Months

O’Connor OA, et al JCO Jan 18 2011

continuous therapy in relapsed t cell lymphoma
Continuous Therapy in Relapsed T-cell Lymphoma

Belinostat DoR AITL

Romidepsin PFS by Response

Median 13.6 mos

slide9

Pralatrexate for CTCL:

Progression Free Survival

Cohort >15 mg/m2 N=41

Med PFS 388 days

slide10

Autologous Transplantation in Relapsed PTCL

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

MSKCC

The Stanford Experience Auto

CIBMTR: PFS excluding pt in CR1

(Most patients ALCL)

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 2013. Abstract 689; Chen AI, et al. Biol Blood Marrow Transplant. 2008;14(7):741-747. Horwitz et al, ASH 2005

.

slide11

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; 26:2264-2271 2008

Goldberg J. et al. Leuk Lymphoma. 2012 Jan 31

algorithmic approach to patients with relapsed ptcl nos aitl alcl
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

Donor known and eligible

Transplantation unclear

(Donor unknown; patient may or may not be eligible)

Clinical trial

or

single agent

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:

differential resposnes orr by lymphoma subtype
Differential resposnesORR (%) by Lymphoma Subtype

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.

dlbcl vs ptcl
DLBCL vs. PTCL

OS

100

CHOP plus rituximab

80

60

Percentage of Treatment Group

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,

slide16

T-cell Lymphoma: Current approaches that may be better than CHOP

Nordic Study

CHOEP-ASCT,

N=166

5 yr OS 51%

1.0

International T-cell Project (retrospective)

Anthracycline containing >85%

N=299

5 yr OS 32%

0.9

0.8

0.7

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
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

alemtuzumab a chemotherapy first line treatment of ptcl
Alemtuzumab (A) + ChemotherapyFirst-line treatment of PTCL

Single agent: N=14, Phase II, RR 36%, 5 deaths

Enblad et al. Blood. 2004;103:2920-2924.

slide19

The ACT trial

AFTER the dose/age amendment

R

R

A30- CHOP-14

A30 - CHOP-14

CHOP-14

CHOP-14

A30 - CHOP-14

CHOP-14

A30- CHOP-14

CHOP-14

CHOP-14

CHOP-14

A30 - CHOP-14

A30 - CHOP-14

CHOP-14

A30- CHOP-14

CHOP-14

A30 - CHOP-14

CHOP-14

CHOP-14

CHOP-14

CHOP-14

CHOP-14

HDT

ACT-1

ACT-2

18 yrs

80 yrs

65 yrs

CHOP-14

A60

A60

A60

CHOP-14

CHOP-14

A60

HDT

No ALCL cases

slide20

ACT-1

Response rates and time-related end-points

15 mo median follow-up

Time-related end-points

Response rates

Primary

Secondary

EFS

OS

d’Amore et al, ASH 2012

phase i ii pralatrexate in combination with gemcitabine
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

  • 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
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

slide23

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 2

10 mg/m2

N=3

Cohort 1

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

slide24

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
Phase III Ro-CHOP Study

International randomized, open-label study

Principal objective: PFS improvement

Planned accrual: 420 patients

brentuximab ch p response and pfs
Brentuximab + CH-PResponse and PFS

PFS

N=26

Median F/U 21.4 mos

Est 1 yr PFS 71%

Fanale et al JCO epub September 2014

slide27

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

3 questions1
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