An Update from ASCO 2009 F B Hagemeister, MD Professor of Medicine - - PowerPoint PPT Presentation

Therapy for Lymphomas: An Update from ASCO 2009

F B Hagemeister, MD Professor of Medicine Department of Lymphoma/Myeloma M D Anderson Cancer Center

Aggressive Lymphomas

• 1. # 8506: R-CHOP-21 vs R-CHOP-14 for Untreated

DLBCL (Cunningham)

• 2. # 8508: ER-CHOP Phase II Trial of ER-CHOP for

Untreated DLBCL (Micallef)

• 3. # 8509: R-ICE vs R-DHAP followed by SCT for

Relapsed/Refractory DLBCL (Gisselbrecht)

Aggressive Lymphomas

• 1. # 8506: R-CHOP-21 vs R-CHOP-14 for Untreated

DLBCL (Cunningham)

• 2. # 8508: ER-CHOP Phase II Trial of ER-CHOP for

Untreated DLBCL (Micallef)

• 3. # 8509: R-ICE vs R-DHAP followed by SCT for

Relapsed/Refractory DLBCL (Gisselbrecht)

How Might We Further Improve Initial Therapy of DLBCL

• Dose Density Therapy - CHOP (R) - 14
• Dose Intensity - AuSCT in First Remission
• Other Regimens (+/- rituximab)

– CHOEP, EPOCH, ACVBP

• Addition of new agents to CHOP (R)

– BCL-2 antisense, anti-CD22, anti-VEGF, bortezomib, idiotype vaccination, RIT

• Improved “risk-adapted therapy”

– Gene expression profiling, PET

CHOP -14 vs CHOP-21 vs CHOEP-14 vs CHOEP-21 for Patients > 60 with DLBCL: Event-Free Survival

90 80 70 60 50 40 30 20 10 1.0 .9 .8 .7 .6 .5 .4 .3 .2 .1 0.0 Months

56% 48 %

Pfreundschuh et al. Blood 104: 634-642, 2004 42%

34 %

CHOEP-14 (n=169) CHOEP-21 (n=170) CHOP-21 (n=178) CHOP-14 (n=172)

CHOP-21 CHOP-14

90 80 70 60 50 40 30 20 10 1.0 .9 .8 .7 .6 .5 .4 .3 .2 .1 0.0

CHOEP-14 (n=177) CHOEP-21 (n=185) CHOP-21 (n=176) CHOP-14 (n=172)

Months

72 % 58 %

CHOP -14 vs CHOP-21 vs CHOEP-14 vs CHOEP-21 for Patients <60 with DLBCL: Event-Free Survival

Pfreundschuh et al. Blood 104: 626-633, 2004.

CHOP-14 CHOP-21

RICOVER-60 Study

Pfreundschuh M; Lancet Oncol 2008

Findings

• Only R-CHOP14 superior to CHOP14 in terms of EFS,

PFS and OS (3 yr OS 78.1% vs 67.7%)

• R-CHOP14 x 8 no better than R-CHOP14 x 6

Does 6 or 8 cycles of R-CHOP14 improve

• utcomes compared to

CHOP14 in patients aged 61-80?

6x CHOP14 8x CHOP14 6x R-CHOP14 8x R-CHOP14

Randomised Stage I-IV n=1222

R-CHOP-14 vs R-CHOP-21 for DLBCL (# 8506)

• 1080 Pts stratified by Age (> 60), PS (0-1), LDH
• Median age 61
• TX: R-CHOP21 x 8 vs R-CHOP14 x 6, plus 2 Rituximab

Features R-CHOP 21 (%) R-CHOP 14 (%) IPI 4-5 17 15 Stage III-IV 63 62 B SX 44 48 Bulky > 10 cm 51 48

Cunningham et al JCO 27: 435s, 2009 (abst 8506).

R-CHOP 21 vs R-CHOP-14 for DLBCL: Tolerability

All patients received G-CSF with R-CHOP 14 *P<0.01 Gr 3-4 Events R-CHOP 21 (%) R CHOP 14 (%) ANC 57* 31 PLT 5 9* Infection 22* 17 Cardiac 1 2 Nausea/Vomit 8 8 Mucositis 2 3 Resp: CR,CRu/OR 63/87 58/90

Cunningham et al. JCO 27: 435s, 2009 (abst 8506).

2 Year FFS and OS by Prognostic Factors

FFS OS % p % p Age: ≤60 >60 76 73 0.48 83 79 0.047 WHO: 0 1 2 80 73 56 <0.0001 87 79 63 <0.0001 Stage: I/II III IV 81 70 68 0.0017 85 81 75 0.012 IPI score: 0-1 2-3 4-5 85 72 60 <0.0001 90 80 64 <0.0001

GLSG Study for Pts < 60 with AA IPI 0-1 DLBCL Based on Risk Factors

All have Low Risk according to IPI, excluding Stage I, Non-Bulky Bulky is defined as > 5 cm mass IPI 0 with Non-Bulky Disease: R-CHOP 21 x 6 vs R-CHOP 21 X 4 IPI 1 or Bulky Disease: R-CHOP 21 x 6 vs R-CHOP 14 x 6 All receive 36 GyRT to bulky sites

Pfreundschuh et al. JCO 23: 567s, 2005 (abst 6529).

Aggressive Lymphomas

• 1. # 8506: R-CHOP-21 vs R-CHOP-14 for Untreated

DLBCL (Cunningham)

• 2. # 8508: ER-CHOP Phase II Trial of ER-CHOP for

Untreated DLBCL (Micallef)

• 3. # 8509: R-ICE vs R-DHAP followed by SCT for

Relapsed/Refractory DLBCL (Gisselbrecht)

Selected Anti-Lymphoma Antibodies in Clinical Trials

Antibody Company Target US Status Rituximab Genentech, Biogen-IDEC CD20 Approved Alemtuzumab Bayer Healthcare CD52 Approved Human(ized) anti-CD20 Various CD20 Phase 1-2 Lumaliximab Biogen-IDEC CD23 Phase 3 Bevacizumab Genentech VEGF Phase 3 Galiximab Biogen-IDEC CD80 Phase 2-3 Epratuzumab Immunomedics CD22 Phase 2 SGN-40 Seattle Genetics CD40 Phase 2-3 SGN-30, SGN-35 Seattle Genetics CD30 Phase 2

Phase II Trials: Epratuzumab Plus Rituximab in Recurrent NHL

Regimen – Epratuzumab 360 mg/m2 – Rituximab 375 mg/m2 – Weekly for 4 weeks Most AEs were grade 1/2, self limited, or infusion related Response Leonard, 2005 Strauss, 2005 FL DLBCL FL DLBCL N 15 6 34 15 ORR 10 (67%) 4 (67%) 21 (64%) 7 (47%) CR/CRu 9 (60%) 3 (50%) 8 (24%) 5 (33%) TTP 17.8 months NR NR DOR NR 16 months 6 months PFS 11 months 6 months

• Leonard. J Clin Oncol. 2005;23:5044; Strauss. J Clin Oncol. 2006;24:3880.

Phase II ER-CHOP for DLBCL: Patient Features (#8508)

• 107 pts, 29 (26%) ineligible (no follicular allowed)
• Therapy: E-360 mg/m2 d 1/cycle, R-CHOP d 1 x 6
• 78 eligible patients: Med age 61 (21-92); PS 0-1: 88%

Features Number % IPI: 0-1 17 22 2 22 28 3 29 37 4-5 10 13 R-IPI: 3-5 39 50 LDH: High 55 71

Micallef et al. JCO 27: 426s, 2009 (abst 8508).

Phase II ER-CHOP for DLBCL: Results at One Year by IPI Risk (%)

IPI Patients OR CR EFS PFS OS 0-2 39 95 74 82 88 92 3-5 39 95 72 77 77 85 ALL 78 95 73 80 82 88

Micallef et al. JCO 27: 436s, 2009 (abst 8508).

• ER-CHOP might be better than R-CHOP for

higher risk disease?

ER-CHOP for DLBCL: Comparisons to Results with R-CHOP

Group 1 YR EFS 2 YR EFS 1 YR OS 2 YR OS GELA 58 57 82 72 ECOG 72 64 80 71 Canada

• 85

77 Current 79 62 89 79

Micallef et al. JCO 27: 436s, 2009 (abst 8508).

• A randomized study is needed to demonstrate for

whom ER-CHOP might be better than R-CHOP

Aggressive Lymphomas

• 1. # 8506: R-CHOP-21 vs R-CHOP-14 for Untreated

DLBCL (Cunningham)

• 2. # 8508: ER-CHOP Phase II Trial of ER-CHOP for

Untreated DLBCL (Micallef)

• 3. # 8509: R-ICE vs R-DHAP followed by SCT for

Relapsed/Refractory DLBCL (Gisselbrecht)

100 80 60 40 20 15 45 30 90 75 60

P = 0.038

Transplantation Conventional treatment

Months after Randomization Percent Alive

Philip et al. N Engl J Med 1995;333:1540-1545

Auto SCT vs Chemotherapy Alone for Relapsed Chemotherapy-Sensitive Aggressive NHL (PARMA Trial)

R-ICE vs R-DHAP for Rel/Ref DLBCL Followed by ASCT: The CORAL Study

(COllaborative Trial in Relapsed Aggressive Lymphoma)

• AutoSCT is standard second-line therapy for

relapsed DLCL – Original study required CR to CHOP, no marrow disease, and pts <60 years

• Best induction therapy for relapsed DLBCL prior to

ASCT unknown – DHAP invented at MDACC in 1980’s – R-ICE from MSK popular for mobilization – No randomized comparisons of various combinations

• In era of rituximab , value of R in relapse is unclear
• CORAL trial: R-DHAP vs R-ICE, SCT, Maint R vs Obs

CORAL Trial of R-ICE vs R-DHAP (#8509)

CD20+ DLBCL

Relapsed/Refractory Age < 65

R-ICE x 3 R-DHAP x 3

R A N D O M I Z E R A N D O M I Z E

SD/PD → Off PR/CR A B S E C A T M R x 6 Obs N=396, 11 Countries Which salvage regimen is the best? Place of immunotherapy post transplantation? N=202 N=194

R-ICE vs R-DHAP for Rel/Ref DLBCL: Patients in the CORAL Trial (#8509)

• 90 (45%) SAEs with R-ICE, 120 (62%) with R-DHAP
• 206 underwent SCT

Category Feature Patients % LDH High 149 38 Prior Rituximab Yes 224 57 Relapse Stage III-IV 240 61 Relapse Status < 12 mo 166 42 > 12 mo 225 57 Relapse IPI 0-1 226 57 2-3 149 38

Gisselbrecht et al. JCO 27: 436s, 2009 (abst 8509).

R-ICE vs R-DHAP for Relapsed DLBCL: 3 Year Results (ITT Group, #8509)

• By MVA, all 3 features important: If no factors, ORR > 80%
• Longer F/U needed for R vs Obs (second randomization)

Feature OR P EFS P OS TX: R-DHAP 63 NSig 35 0.3 51 R-ICE 64 26 47 Rit: Yes 51 <.001 21 <.001 NRep No 83 47 Ref: Yes 46 <.001 20 <.001 NRep No 88 45 AA-IPI:0-1 52 <.001 18 <.001 NRep 2-3 71 40

Gisselbrecht et al. JCO 27: 436s, 2009 (abst 8509).

OVERALL SURVIVAL ACCORDING TO TREATMENT ARM (INDUCTION ITT) PROGRESSION-FREE SURVIVAL ACCORDING TO TREATMENT ARM (INDUCTION ITT)

Gisselbrecht et al. JCO 27: 436s, 2009 (abst 8509). 56% 56% 42% 45%

The CORAL Trial

PROGRESSION-FREE SURVIVAL ACCORDING TO PRIOR RITUXIMAB (INDUCTION ITT) PROGRESSION-FREE SURVIVAL ACCORDING TO FAILURE FROM DIAGNOSIS (INDUCTION ITT)

Gisselbrecht et al. JCO 27: 436s, 1009 (abst 8509). N=160 N=228 N=147 N=241 31% 64% 30% 62%

The CORAL Trial

The CORAL Trial: Failure-Free Survival by Prior Rituximab and Time to Relapse

Failure from Diagnosis > 12 mo Prior Rituximab may delay relapse, but at 3 years, results are the same Standard salvage regimen does not overcome poor prognosis of early relapse Failure from Diagnosis < 12 mo

N= 106

N= 54

N= 41

N= 187

Gisselbrecht JCO 27: 436s, 2009 (8509)

Follicular Lymphoma

• 1. # 2: Intensive Chemotherapy followed by Anti-

Idiotype Vaccine for Advanced Untreated Follicular Lymphoma (Schuster)

• 2. # 8550: Bortezomib, Bendamustine, and

Rituximab for Relapsed or Refractory Follicular Lymphoma (Matous)

Follicular Lymphoma

• 1. # 2: Intensive Chemotherapy followed by Anti-

Idiotype Vaccine for Advanced Untreated Follicular Lymphoma (Schuster)

• 2. # 8550: Bortezomib, Bendamustine, and

Rituximab for Relapsed or Refractory Follicular Lymphoma (Matous)

Id+KLH Protein

• The idiotype of the SmIg of

a B-cell lymphoma can be used as a tumor-specific immunogen that induces immunity against Id- bearing tumor cells

• Keyhole lympet

hemocyanin (KLH) carrier serves as an immune stimulant

• GM-CSF administered

concurrently at site of injection as an adjuvant

KLH

(with GM-CSF)

antigen binding site / idiotype

Idiotype Vaccine Phase III Trials

Favrille NCI/ Accentia Genitope Manufacturing Recombinant Hybridoma Recombinant Cytoreductive Treatment Rituximab PACE CVP Months to Vaccine 3 6-12 12 Patients Treated CR, PR, or SD CR CR or PR

• Vose. Hematol Oncol. 2006;24:47.

NCI=National Cancer Institute; PACE=prednisone, doxorubicin, cyclophosphamide, etoposide; SD=stable disease.

Phase III Trial: ID-KLH + GM-CSF in Previously Untreated Patients with FL

Levy et al. AACR, 2008.

Primary Analysis: PFS (N=287)

Red Blue Curve 0.297 23.3 19.1 Med PFS 95 192 N P Control MyVax Percent Free of Progression Months

Genitope trial

Idiotype Vaccine Phase III Trials

Favrille NCI/ Accentia Genitope (closed) Manufacturing Recombinant Hybridoma Recombinant Cytoreductive Treatment Rituximab PACE CVP Months to Vaccine 3 6-12 12 Patients Treated CR, PR, or SD CR CR or PR

• Vose. Hematol Oncol. 2006;24:47.

NCI=National Cancer Institute; PACE=prednisone, doxorubicin, cyclophosphamide, etoposide; SD=stable disease.

Mitumprotimut-T for Untreated FL: Time to Progression from Randomization

6 12 18 24 30 36 42 48 10 20 30 40 50 60 70 80 90 100 Placebo + GM-CSF: TTP 17.2 months (n = 138) Mitumprotimut-T + GM-CSF: TTP 11.9 months (n = 137) Time from Randomization, months Percent Not Progressed

HR = 1.196, P = .258 Freedman et al. Blood 112: 2008 (abst 236).

Mitumprotimut-T for Rel/Ref FL: Time to Progression from Randomization

Mitumprotimut-T + GM-CSF:TTP 6.0 months (n=37) 6 12 18 24 30 36 42 48 10 20 30 40 50 60 70 80 90 100 Time from Randomization, months Percent Not Progressed Placebo + GM-CSF: TTP 11.2 months (n = 37)

HR = 2.265, P = .004 Freedman et al. Blood 112: 2008 (abst 236).

Idiotype Vaccine Phase III Trials

Favrille (closed) NCI/ Accentia Genitope (closed) Manufacturing Recombinant Hybridoma Recombinant Cytoreductive Treatment Rituximab PACE CVP Months to Vaccine 3 6-12 12 Patients Treated CR, PR, or SD CR CR or PR

• Vose. Hematol Oncol. 2006;24:47.

NCI=National Cancer Institute; PACE=prednisone, doxorubicin, cyclophosphamide, etoposide; SD=stable disease.

Anti-ID Vaccine After Intensive Therapy for Follicular Lymphoma (# 2)

• Prospective, double-blinded, placebo-controlled
• Multicenter, Phase III Trial
• Required excision of 2 cm node prior to therapy to

make vaccine

• Therapy: PACE (prednisone, doxorubicin,

cyclophosphamide, etoposide) to CR/CRu for 6 - 12 months followed by vaccine

• Stratification by IPI risk group
• Enrollment: 2:1, vaccine vs control
• Primary endpoint: Disease-Free Survival

Schuster et al. JCO 27: 2s, 2009 (abst 2).

Day 1 Day 8 Day 29 Cyclophosphamide 650 mg/m2 per dose IV X X Next cycle begins Doxorubicin 25 mg/m2 per dose IV X X Etoposide 120 mg/m2 per dose IV X X Prednisone 40 mg/m2 orally once daily Days 1 to 14

Induction Chemotherapy (PACE)

Anti-ID Vaccine After PACE Therapy for Advanced FL (# 2)

• 234 patients enrolled, 176 (76%) achieved CR/CRu
• 117/176 (66%) maintained CR/CRu for at least 6

months, and then underwent therapy with vaccine

• Non-randomized patients: 55 had PD, 4 had failure

to make vaccine, 1 protocol violation Therapy Patients Med DFS (mo)* Vaccine 76 44.2 Control 41 30.6

Schuster et al. JCO 27: 2s, 2009 (abst 2).

*P = 0.045, but no difference in survival results

Disease Free Survival from Randomization for Id-KLH vs. Control Arms

log-rank p=0.045

Median Follow-up 56.6 mo (range 12.6 – 89.3) Median DFS Vaccine = 44.2 mo Control = 30.6 mo N = 117 Vaccine N = 76 Control N = 41 Events Id-KLH = 44 Control vaccine = 29 Cox PH Model HR = 0.62; [95% CI: 0.39,0.99] (p=0.047)

control vaccine arm Id-KLH (BiovaxID) arm

Overall Survival from Randomization for Id-KLH vs Control Arms (modITT)

Id-KLH arm control vaccine arm

Probability

Median OS not yet reached at median follow-up 56.6 months Overall Survival Id-KLH = 95.4% Control = 91.2% N = 117 Id-KLH N = 76 Control N = 41 Events Id-KLH = 3 Control = 2 Cox PH Model HR = 0.7 (p=0.7)

Idiotype Vaccine Phase III Trials

Favrille (closed) NCI/ Accentia Genitope (closed) Manufacturing Recombinant Hybridoma Recombinant Cytoreductive Treatment Rituximab PACE CVP Months to Vaccine 3 6-12 12 Patients Treated CR, PR, or SD CR CR or PR

• Vose. Hematol Oncol. 24:47, 2006.

NCI=National Cancer Institute; PACE=prednisone, doxorubicin, cyclophosphamide, etoposide; SD=stable disease.

Idiotype Vaccine Phase III Trials

Favrille (closed) NCI/ Accentia Genitope (closed) Manufacturing Recombinant Hybridoma Recombinant Cytoreductive Treatment Rituximab R-CHOP CVP Months to Vaccine 3 6-12 12 Patients Treated CR, PR, or SD CR CR or PR

• Vose. Hematol Oncol. 24:47, 2006.

NCI=National Cancer Institute; PACE=prednisone, doxorubicin, cyclophosphamide, etoposide; SD=stable disease.

Follicular Lymphoma

• 1. # 2: Intensive Chemotherapy followed by Anti-

Idiotype Vaccine for Advanced Untreated Follicular Lymphoma (Schuster)

• 2. # 8550: Bortezomib, Bendamustine, and

Rituximab for Relapsed or Refractory Follicular Lymphoma (Matous)

VBR (Bortezomib, Bendamustine, Rituximab) for Rel/Ref FL: VERTICAL

• Bortezomib plus rituximab is active in rel/ref FL

– OR: 55-57%, CR/CRu: 19-45%

• Bendamustine is active alone or with rituximab

– OR: 93%, CR/CRu: 54%

• Bortezomib potentiates activity of alkylators in in

vitro models, used in myeloma

• VBR in rel/ref FL with: Min neuropathy (< Gr 2);

< 4 prior tx’s; No Prior Bortezomib or bendamustine

• Blum. Blood 112:3053, 2008; DeVos. Blood 108:694, 2006; Robinson.

JCO 26: 4473, 2008; Mitsiades. Blood 101: 2377, 2003; Ma. Clin Cancer Res 9: 1126, 2003; Hrusovsky. Blood 106: 5112, 2005.

VBR for Relapsed/Refractory FL: VERTICAL Trial Design (#8550)

• Doses of Bortezomib escalated in 3 x 3 fashion
• Cycles repeated Q 35 days
• Patients given antiemetics, antidiarrheal meds,

acetaminophen, diphenhydramine, no GFs Drug Dose (mg/m2/dose) Schedule V (Bortezomib) 1.6 Days 1, 8, 15, 22 B (Bendamustine) 50, 70, or 90 Days 1 and 2 R (Rituximab) 375 Weekly x 4 cycle 1;

• nce/cycle, day 1,

cycle 2-5

Matous et al. JCO 27: 446s, 2009 (abst 8550).

VBR for Relapsed/Refractory FL: The VERTICAL Trial

• 16 patients (all had prior SCT!); Age 55 (44-80);

PS > 80 in 13 (81%) Features Patients % FLIPI : Low 6 38 Intermed 4 25 High 6 38 Prior Txs: 1 4 25 2-3 5 31 > 4 7 42 Ref to R 10 63

Matous et al. JCO 27: 446s, 2009 (abst 8550).

VBR for Rel/Ref FL in the VERTICAL Trial: Tolerability

Tolerability Gr 1-2 Gr 3 Gr 4 Heme: HGB 12 (65%) ANC 5 (31) 3 (19) 1 (6) PLT 7 (44) 1 (6) (6) Non-Heme: P Neuro 6 (38) 1 (6) Fatigue 8 (50) 8 (50)*

• Fever

8 (50) Rash 4 (25) Diarrhea 6 (38) 5 (3)*

• *Includes Gr 3, 4: AE’s resulting in stopping study: 4 (25%)
• No deaths on study.

Matous et al. JCO 27: 446s, 2009 (abst 8550).

VBR for Rel/Ref FL in the VERTICAL Trial: Results

• Study continues with Bendamustine dose of 90 mg/m2

Matous et al. JCO 27: 446s, 2009 (abst 8550).

Bendamustine Dose Patients CR (%) PR (%) 50 3 2 (67) 1 (33) 70 6 2 (33) 1 (17) 90 6 4 (67) 2 (33) Total 15 8 (53) 4 (27) Response in 15 patients

T-Cell and Hodgkin’s Lymphomas

• 1. # 8561: Pralatrexate for Relapsed and Refractory

T-Cell Lymphomas (O’Connor)

• 2. # 8500: SGN-35 Immunotoxin for Relapsed and

Refractory CD-30 Positive Lymphomas (Bartlett)

T-Cell and Hodgkin’s Lymphomas

• 1. # 8561: Pralatrexate for Relapsed and Refractory

T-Cell Lymphomas (O’Connor)

• 2. # 8500: SGN-35 Immunotoxin for Relapsed and

Refractory CD-30 Positive Lymphomas (Bartlett)

Single Agents for Relapsed or Refractory PTCL (Off Study)

Agent Total Pts PTCL in Study Resp Study Pentostatin 68 6 Single Gemcitabine 13 8 5 Single Gemcitabine 10 4 NS Single Alemtuzumab 14 14 5 Multi Pentostatin 42 8 NS Single Denileukin Dif 27 27 13 Single Bortezomib 12 2 1 Single Lenalidomide 16 16 4 Multi Nelarabine 19 8 1 Multi

Pralatrexate for Patients with Relapsed or Refractory PTCL: The PROPEL Trial

• PTCL: A difficult disease to treat

– 15% of NHLs in the US – No successful standard of care – 24% 5-yr PFS even with SCT

• Pralatrexate: an antifolate with high affinity for:

– 1-carbon reduced folate carrier (RFC-1) – Folylpolyglutamyl synthetase (FPGS) – Significant activity in Phase I-2 trial in relapsed NHL

• Confirmation needed: prior study not well

controlled from pathologic standpoint

Pralatrexate for Patients with Relapsed or Refractory PTCL: PROPEL Trial (#8561)

• Pralatrexate in Patients with Relapsed Or Refractory

PEripheral T-Cell Lymphoma – International Phase 2 Pivotal Trial – 109 patients enrolled – Primary endpoint: OR – Secondary: Duration Response, PFS, OS

• Therapy: 30 mg/m2 IV PUSH weekly for 6 weeks

– Vitamin B12 IM Q 8-10 wks, folic acid 1-1.25 mg po daily

• Prevent mucositis, significant myelosuppression

– Dose decreased to 20 mg/m2 for AEs – Cycles every 7 weeks

O’Connor et al. JCO 27: 449s, 2009 (abst 8561).

Pralatrexate for Patients with Relapsed or Refractory PTCL: The PROPEL Trial

• Pathology in 111 pts (%): PTCL- 53, Anaplastic-15,

AIBL-12, Transformed MF-11, Blastic NK- 7, Other-5

• Prior Therapies (%): CHOP-70, Platinum-41, Other-5

SCT-16, HCVAD-7, Denileukin-6, Invest Drugs-6

• Med PFS- 106 days (3.4 mo)
• Med Duration Resp - 9.4 mo
• Med OS - 14.7 mo

Group Total OR (%) CR (%) All Evaluable 109 29 (27) 11 (10) Refractory to last tx 68 14 (21) Refractory to all tx 26 5 (19)

O’Connor et al. JCO 27: 449s, 2009 (abst 8561).

Pralatrexate for Relapsed/Refractory PTCL: Tolerability (%)

• 23% discontinued due to AEs
• 72% had > one dose omitted
• 69% received 20 mg/m2 or more

Feature Grade 3 Grade 4 Overall Mucositis 18 4 71 Plts 15 19 41 Anemia 15 2 34 ANC 13 7 24 Fatigue 5 2 36 Nausea 4 41 Fever 1 1 32

T-Cell and Hodgkin’s Lymphomas

• 1. # 8561: Pralatrexate for Relapsed and Refractory

T-Cell Lymphomas (O’Connor)

• 2. # 8500: SGN-35 Immunotoxin for Relapsed and

Refractory CD-30 Positive Lymphomas (Bartlett)

Efficacy of Unconjugated Anti-CD30 Antibodies in CD30 Positive Lymphomas

Drug Patients Dose Outcomes Authors SGN-30 Chimeric Ab 24 pt (21 HL, 3 ALCL) Phase I 2 - 12 mg/kg weekly x 6 1 CR in cALCL, 6 SD (4 in HL) Bartlett Blood 111: 2008 SGN-30 79 pt (38 HL, 41 sALCL) Phase II 6 - 12 mg/kg weekly x 6 HL No Resp, sALCL 17% Resp, 2 CR, 5 PR, All were ALK neg Forero- Torres Br J Haematol, 2009 MDX-060 Fully Human Ab 72 pt (63 HL, 4 ALCL) Phase I/II 1 - 15 mg/kg weekly x 4 RR 8% (CRs in 2 HL, 2 ALCL) Ansell JCO 25: 19, 20007

SGN-35 Mechanism of Action

SGN-35 antibody-drug conjugate – CD30-targeted antibody (cAC10) conjugated to an auristatin (MMAE), an anti-tubulin agent Selectively induces apoptosis in HL and ALCL cells: – Binds to CD30 – Becomes internalized – Releases MMAE

• ADC traffics to

lysosome Enzymatic linker cleavage releases MMAE from ADC MMAE binds tubulin G2/M cell cycle arrest & apoptosis

• SGN-35

Binds CD30 Endocytosis ADC traffics to lysosome Enzymatic cleavage releases MMAE from ADC Binds tubulin G2/M cell Cycle arrest and apoptosis

SGN-35 Antibody- toxin conjugate

78 100 90 80 70 60 50 40 30 20 10 54 48 42 36 30 24 18 12 6 84 72 60 66 <1.2 mg/kg (n=10) >1.2 mg/kg (n=29) All Doses (n=45)

>1.2 mg/kg Median PFS = 6.3 mths <1.2 mg/kg Median PFS = 2.2 mths

Time (Weeks)

Patients Without Disease Progression (%)

• Median PFS for patients treated at >1.2 mg/kg is 6.3 months
• Median duration of response is at least 7.3 months (range, 0.6 – 17.3)

Phase I Trial of SGN-35 for Relapsed HL and ALCL: PFS and Dur Resp

• Younes. Pan-Pacific, Hawaii, 2009.

Weekly SGN-35 for CD-30 Positive HL and ALCL: Patient Characteristics (*8500)

† Median (range) Diagnosis Hodgkin lymphoma Systemic ALCL ALK-1 negative 29 (85%) 5 (15%) 4 (80%) Age 34 (13-82)† ECOG status 0/1 2 30 (88%) 4 (12%) Prior Treatment Regimens Number of chemo regimens ASCT 5 (1-13)† 21 (62%)

Bartlett et al. JCO 27: 434s, 2009 (abst 8500).

Adverse Events with Weekly SGN-35

SGN-35 was generally well tolerated in 34 treated patients Related Grade 3-4 AEs (no Gr 5 events occurred) Related AEs in ≥10% patients (includes Gr 3-4 events above) Bartlett et al. JCO 27: 434s, 2009 (abst 8500).

– Nausea 26% (9 patients) – Neutropenia 18% (6) – Fatigue 24% (8) – Dizziness 12% (4) – Peripheral neuropathy 18% (6) – Hyperglycemia 12% (4) – Paresthesia 12% (4) Grade 3 Grade 4 – Neutropenia (3) – Neutropenia (1) – Diarrhea (1) – Hyperglycemia (1) – Paresthesia (1) – Vomiting (1) – Leucopenia (1)

Maximum Reduction in Target Lesions

81% of patients achieved tumor reductions

Bartlett et al. JCO 27: 434s, 2009 (abst 8500).

Weekly SGN-35: Best Clinical Response in 27 Patients*

Dose mg/kg (N) CR PR SD PD 0.4 (4)   4+  0.6 (3)  1 1 1 0.8 (6) 4++  1 1 1.0 (6) 4++ 1 1  1.2 (5)  1 3 1 1.4 (3) 2  1  Total (27) 10 3 11 3

* Based on IWG Revised Response Criteria (Cheson, 2007)

*For eligible patients after 2 cycles, 7 not yet evaluable + systemic ALCL-1; ++ systemic ALCL-2;  1 pediatric patient (12-17 yrs) Bartlett et al. JCO 27: 434s, 2009 (abst 8500).

Therapy for Lymphomas: An Update from ASCO 2009

F B Hagemeister, MD Professor of Medicine Department of Lymphoma/Myeloma M D Anderson Cancer Center