This document provides information about Dr. Jason Westin, an assistant professor at MD Anderson Cancer Center whose research focuses on improving therapy and outcomes for patients with lymphoma. His specific research interests include diffuse large B-cell lymphoma, developing systems to identify optimal therapeutic combinations for individual patients, drug synergy and antagonism, scale free networks in cancer therapy, and developing sensitive disease monitoring methods. The document also summarizes several of Dr. Westin's presentations on novel targeted therapies in T-cell lymphoma from 2014, including studies on drugs such as brentuximab, mogamulizumab, lenalidomide, alisertib, selinexor, romidepsin, panobinostat, and inhibitors of the

1. JASON WESTIN, MD
HOUSTON, USA
Assistant Professor at the University of Texas MD
Anderson Cancer Center
Dr Westin’s research focus is on improving therapy
and outcomes for patients with lymphoma. His
specific research interests include: Diffuse Large B-
cell Lymphoma; Development of systems to identify
novel, optimal therapeutic combinations for individual
patients; Drug synergy, additivity, and antagonism;
Scale free networks and their role in cancer therapy;
Development of highly sensitive disease monitoring
methods. Dr. Westin also chairs the Lymphoma Grand
Rounds and is the co-director of the Lymphoma
planning clinic at MD Anderson Cancer Center.

2. NOVEL TARGETED
THERAPIES IN
T CELL LYMPHOMA:
BEST OF 2014
JASON WESTIN, MD
MD ANDERSON CANCER CENTER
JWESTIN@MDANDERSON.ORG
TWITTER: @LYMPHOMA_DOC

3. In 2014, MDACC saw >1500 new patients with lymphoma
T-cell: 93 (48 treated, 45 untreated)

4. NHL BREAKDOWN IN US
Armitage JO, Weisenburger DD. J Clin Oncol. 1998;16:2780-2795.
DLBCL, 31%
FL, 22%
MALTL, 8%
PTCL, 7%
SLL/CLL, 7%
MCL, 6%
PMLBCL, 2%
ALCL, 2%
BL, 2%
MZL, nodal, 2%
T-ALL, 2%
Other, 9%

5. NHL BREAKDOWN IN CHINA
Yang et al, Diagnostic Pathology 2011

6. MOST COMMON PTCL SUBTYPES
PTCL-NOS and AITL are the most common
subtypes
Armitage J, et al. J Clin Oncol. 2008

7. cc

8. POOR OUTCOME OF
T-CELL LYMPHOMA
Armitage J, et al. J Clin Oncol. 2008

9. POOR OUTCOME AFTER 1ST
RELAPSE/PROGRESSION
Mak, V et al: J Clin Oncol 31 (16), 2013: 1970-6
Reprinted with permission. © 2013 American Society of Clinical
Oncology. All rights reserved.

10. FOR MAJORITY OF PTCL…
•Frontline treatment not well defined
• The most commonly used chemotherapy is CHOP
• Role of intensive regimens questioned (MDACC Escalon Cancer 2003)
• Role of doxorubicin questioned (International PTCL project, JCO 2007)
• Role of etoposide undetermined (DSHNHL, Schmitz et al. Blood 2010)
• Upfront transplant controversial (d’Amore JCO2012 and Reimer JCO2009)
•No effective salvage therapy
• Even stem cell transplant is with marginal benefit
• Mechanism oriented targeted therapy is needed

11. RECENTLY FDA APPROVED DRUGS
FOR RECURRENT/REFRACTORY PTCL
Agent Dose/schedule N ORR (%) CR (%) DOR, Mos PFS
Pralatrexate 30 mg/m2
weekly X 6
111 29 11 10.1 3.5 mo
Romidepsin 14 mg/m2
Weekly X 3
Q 28 days
131 25 14 17 4 mo
Belinostat 1000 mg/m² IV
on days 1-5
Q21 day cycle
129 26 10% 8.3
Brentuximab
Vedotin (ALCL)
1.8 mg/kg
Q 21 days
58 86 57 12.6 13.3 mo
ALCL: 12% of all PTCL
3% of adult NHL
Courtesy of Yasuhiro Oki

12. MUTATIONS VERY FREQUENTLY
OBSERVED IN PTCL
Mutated
Gene
AITL PTCL-NOS EATL
TET2 47-83% 38-49% 20%
IDH2 30-45% 0%
DNMT3A 26% 27%
RHOA 67-68% 0-18%
1. Sakata-Yanagimoto et al. Nat Genetics 2013
2. Palomero et al. Nat Genetics 2013
3. Cairns et al. Blood 2012
4. Lemonnier et al. Blood 2012

13. FREQUENT COEXISTENCE OF
MUTATION
Sakata-Yanagimoto et al. Nat Genetics 2013
Palomero et al. Nat Genetics 2013

14. TARGETED THERAPY

15. BRENTUXIMAB
• Anti-CD30 monoclonal antibody drug conjugate (MMAE)
• CD30 expression is variable, although this may not
correlate with response
• Phase II trial in Mycosis Fungoides / Sezary Syndrome
• 2 skin biopsies, maximum % of CD30 reported
• 32 patients enrolled (30 evaluable)
• Median age 62 (20-87)
• ORR 70% (21/30)
Kim et al, ASH 2014 Abstract #804

16. BRENTUXIMAB
• CD30 level vs response
• <5%: ORR: 17%
• >5%: ORR: 83%
• Multispectral imaging found +CD30 in 19/20 classified as
CD30 null with immunohistochemistry
• Infiltrating macrophages expressed CD30 - ? Target
Kim et al, ASH 2014 Abstract #804

17. • Multispectral imaging found +CD30 in 19/20 classified as
CD30 null with immunohistochemistry
• Infiltrating macrophages expressed CD30 - ? Target
BRENTUXIMAB
Kim et al, ASH 2014 Abstract #804

18. BRENTUXIMAB
Fanale et al, JCO 2014
• Phase I trial of Brentuximab and chemotherapy in PTCL
• 2 cycles of BV, followed by CHOP or CHP+B for 6 cycles
• 13 and 26 patients accrued (BV -> CHOP arm closed due to
PD on CHOP treatment portion)
• Median age: 57y (21-82)
• Median prior therapies: 0 (frontline)
• Sequential ORR: 85% (11/13, CR 62%, 2 progressed)
• Combination ORR: 100% (26/26, CR 88%, 0 progressed)

19. MOGAMULIZUMAB
(KW-0761)
• Defucosylated, humanized, anti-CCR4 monoclonal antibody
• CCR4: C-C Chemokine Receptor Type 4
• G protein-coupled receptor for CCL2, CCL4, CCL5, CCL17, and
CCL22
• Present on Th2, Treg (CD4+ CD25+ FoxP3+), & ~40% of CTCL/PTCL
• Phase I/II trial in relapsed CTCL (MF or SS)
• N=41 (MF=22, SS=19)
• Median age: 66y (35-85), Median prior therapies: 3 (1-17)
• No DLT, MTD not reached, no grade 4
• ORR 37% (SS: 47% vs MF 29%)
• Response may correlate with CCR4 expression
• Phase III trial of Moga vs vorinostat in rel MF/SS ongoing
Duvic et al, Blood 2015

20. MOGAMULIZUMAB
(KW-0761)
• Phase II trial in relapsed CCR4+ PTCL or CTCL
• N=38 (65 screened, 50 with CCR4+)
• PTCL: 29 (AITL: 12, ALCL Alk- :1)
• CTCL: 8 (MF=7)
• Median age: 64y (33-80), Median prior therapies: 2 (1-6)
• ORR 35% (PTCL: 34%, CTCL: 38%)
• Response vs CCR4 expression
• 1+ ORR 33% n=6
• 2+ ORR 50% n=6
• 3+ ORR 32% n=25
• Grade 3 lymphocytopenia in 73%
• Profound and durable depletion of Treg
Ogura et al, JCO 2014

21. LENALIDOMIDE
• Immunomodulatory agent (IMiD), targets cereblon, Ikaros,
Aiolos, and IRF4
• Used primarily in Myeloma, MDS (5q-), and B cell lymphoma
• Phase II trial in relapsed T-cell lymphoma
• N= 41
• Median age: 65y (36-91), Median prior therapies: 1 (0-5)
• ORR 26% (10/39), CR 7% (3/39)
• Rash 38%, may correlate with
response
Toumishey et al, Cancer 2014

22. LENALIDOMIDE
• Phase I/II trial of Lenalidomide + Vorinostat and Dexamethasone
• Vorinostat is HDAC approved for CTCL
• N=8
• ORR: 25% (1 CR, 1 PR, 2 SD, 4 PD)
• Median OS: 6.7m
• Stopped early due to poor response and low accrual
Hopfinger et al, Ann Hematology 2014

23. ALISERTIB
• Oral selective Aurora A kinase inhibitor
• Aurora kinase is expressed in all actively dividing cells
• Phase II trial in aggressive lymphomas of 50mg twice daily
• 48 patient enrolled, mainly with B-cell
• Median age: 67.5 (32-85)
• Median prior therapies: 3 (1-9)
• 8 patients with aggressive T cell lymphoma
• ORR: 50% (4/8)
Friedberg et al, JCO 2014

24. SELINEXOR (KPT-330)
• Selective inhibitor of
nuclear export (XPO1)
• Forces retention of tumor
suppressor proteins and
reduces proto-oncogene
• Phase I trial:
5 T cell lymphoma
• 1 CR
• 2 SD
• 2 withdrew
Kuruvilla et al, ASH 2014 abst # 396

25. ROMIDEPSIN
• Novel class I histone deactylase inhibitor
• FDA approved for relapsed CTCL and PTCL
• Pivotal trial updated for long term survival outcomes
• N:131 patients with relapsed PTCL
• ORR 25% (CR 15%) – unchanged from initial report
• Among CR: 84% had not
progressed at median f/u
of 26 mo
Coiffier et al, J Hematology Oncology 2014

26. PANOBINOSTAT
Goh, et al, ASH 2014 Abstract # 503
• Oral HDAC inhibitor
• Phase I trials in hematologic malignancies showed responses
• MTD of 20mg 3x weekly
• Phase II trial combined with bortezomib in PTCL or NK cell
• 25 lymphoma pts enrolled (23 evaluable):
• AITL n=8, PTCL n=11, ALCL ALK+ n=1, ALK- n=2, NKT n=2,
SPTCL n=1
• Median age: 59y (35-79)
• ORR: 43% (10/23) CR: 22 (5/23)
• 5 patients underwent alloSCT after response
• Adverse Events:
• ≥ Grade 3
• 68% thrombocytopenia
• 36% neutropenia
• 28% diarrhea

27. PI3K/Akt/mTOR PATHWAY
OVERVIEW
Phosphatidylinositol-3-kinases
(PI3K) have 3 classes
• Class II and III are ubiquitous
and non-oncogenic
• Class I:
• Class IA and B are
lymphoma therapy targets
PI3K
Class
Isofor
m
Tissue distribution Mouse -/-
Major phenotype
Function
I A p110α Leukocytes
+Ubiquitous
Embryonic lethal Proliferation,
Differentiation,
Survival,
Migration,
Chemotaxis,
Phagocytosis
Metabolism
p110β Leukocytes
+Ubiquitous
Embryonic lethal
p110δ Leukocytes
thymus, breast
Impaired B cell development
I B p110γ Leukocytes,
thymus, heart,
endothelium
Impaired inflammation
(+ p110δ -/-: Severe T cell and
NK cell defect)
Cell migration,
Chemotaxis.
Inflammation
Westin, Status of PI3K/Akt/mTOR Pathway Inhibitors in Lymphoma, Clin Lymph Myel Leuk, 2014

28. CLINICAL RESULTS OF PI3K/AKT/MTOR PATHWAY-SPECIFIC
INHIBITORS AS SINGLE AGENTS IN UNSELECTED PATIENTS WITH
RELAPSED LYMPHOMA
Target % Response Rate in Different Histologies
DLBCL FL MCL SLL/CLL T-Cell HL
SF1126(65) PI3K-class1 0% 0%
Buparlisib(66) PI3K-class1 * * *
SAR245408(67,69,70) PI3K-class1 25% 50% 50% 0%
BAY 80-6946(68,71) PI3K-class1 11% 40% 83% 67% 50%
Idelalisib(72-74) PI3K-δ 0% 45% 40% 64% 15%
IPI-145(75-77) PI3K-γδ 0% 67% 74% 33%
Rigosertib(78) PI3K-αβ 0% 0% 0%
Everolimus(79-81) mTORC1 30% 38% 32% 18% 42%
Temsirolimus(82-83) mTORC1 28% 54% 38% 11%
Apitolisib PI3K/mTOR * * * * *
GDC-0084 PI3K/mTOR      
BEZ235 PI3K/mTOR      
GDC-0332 PI3K-αγδ      
Pictilisib PI3K-αδ * * * * *
BYL719 PI3K-α
(WT/Mutant)
     
MK2206 AKT * * * * * *
* Trials ongoing without data  No ongoing trials in lymphoma (as of 2014)
Westin, Status of PI3K/Akt/mTOR Pathway Inhibitors in Lymphoma, Clin Lymph Myel Leuk, 2014

29. PI3K INHBITORS

30. DUVELISIB (IPI-145)
• Oral PI3K-δ,γ inhibitor
• Phase I trials in hematologic malignancies showed T cell
responses
• MTD of 75mg twice daily
• Disease-specific cohort at MTD for T cell lymphoma:
• 33 patients, 31 evaluable (17 CTCL, 16 PTCL)
• Median age: 64y (34-86)
• Median prior therapies: 4 (1-11)
• ORR: 42%
• PTCL: ORR 47% (7/15, 2 CR, 5 PR)
• CTCL: ORR 38% (6/16, 0 CR, 6 PR)
• Median OS 36.4 weeks
Horwitz, et al, ASH 2014 Abstract # 803

31. DUVELISIB (IPI-145)
• Correlative studies:
• By day 8, detection of cytokine alterations suggesting changes in
pharmacodynamic target modulation
• No correlation with response yet
• Cycle 1 Day 22 FDG PET/CT scan:
• Reduction in radiolabeled glucose uptake (SUV) in 6/11 patients
• Adverse Events:
• 26 of 33 patients had ≥ grade 3
• 36% increased liver function tests
• 21% rash
• 15% neutropenia
• 30% discontinued therapy due to toxicity
Horwitz, et al, ASH 2014 Abstract # 803

32. AKT INHIBITORS

33. MK2206
Oki et al, ASH 2014 Abstract #3093
• Oral, non-ATP competitive allosteric inhibitor of AKT 1, 2, and 3
• Phase II trials in hematologic malignancies
• MTD 200mg orally once/week (could increase to 300mg)
• 59 patients on Phase II trial – mainly B cell and cHL
• T cell lymphoma:
• 2 patients, 2 evaluable (2 AITL)
• Median age: 68y
• Median prior therapies: 4 (1-10)
• ORR ranged from 14%, with 29% showing tumor reduction
• AITL: ORR 0% (1 with tumor reduction <PR)
• Adverse Events:
• 15% rash
• 5% hyperglycemia
• 2% neutropenia

34. NOVEL TARGETED
THERAPIES IN
T CELL LYMPHOMA:
BEST OF 2014
JASON WESTIN, MD
MD ANDERSON CANCER CENTER
JWESTIN@MDANDERSON.ORG
TWITTER: @LYMPHOMA_DOC

35. QUESTIONS?
JASON WESTIN, MD
MD ANDERSON CANCER CENTER
JWESTIN@MDANDERSON.ORG
TWITTER: @LYMPHOMA_DOC