1. SATTVA NEELAPU, MD
Houston, USA
• Associate Professor Department of Myeloma/Lymphoma,
at The University of Texas MD Anderson Cancer Center
• Dr. Neelapu is the Director of Laboratory and Translational
Research, Director, Lymphoma Tissue Bank at the
Department of Lymphoma/Myeloma, Division of Cancer
Medicine, The University of Texas MD Anderson Cancer
Center. He is also Member, Graduate Faculty, Immunology
Program, Graduate School of Biomedical Sciences, The
University of Texas Health Science Center, Houston, TX. Dr.
Neelapu has won several awards including Faculty Scholar
Award, UT MD Anderson Cancer Center; Emil Frei, III Award
for Excellence in Translational Research, Division of Cancer
Medicine, UT MD Anderson Cancer Center and LLS
Translational Research Program Award, Leukemia and
Lymphoma Society.
2. Novel Targeted Therapies in B-cell
Non-Hodgkin Lymphomas
Sattva S. Neelapu, M.D.
Department of Lymphoma and Myeloma
UT MD Anderson Cancer Center
Houston, TX, USA
6th International Hematologic Malignancies Conference
Jan 31-Feb 01, 2015
Beijing, China
3. • Btk inhibitors
• PI3K inhibitors
• Other agents – Exportin, Bcl2, and aurora kinase inhibitors
Outline
4. Bruton’s Tyrosine Kinase (BTK): Critical kinase for
lymphoma cell survival and proliferation
• BTK is an essential element of the B cell
antigen receptor (BCR) signaling pathway.
• Inhibitors of BTK block BCR signaling and
induce apoptosis
• Ibrutinib is a highly potent oral BTK inhibitor
• Ibrutinib binds to cysteine-481 in BTK
5. Ibrutinib Monotherapy in Rel/Ref FL: Preliminary
Results of a Phase 2 Consortium (P2C) Trial
Bartlett et al, ASH, 2014
• Treatment: Continuous dosing at 560 mg po daily on 28-day cycles
until progression or toxicity
• Primary endpoint: ORR (CR+PR)
• Results: Single agent ibrutinib had modest antitumor activity in
relapsed or refractory FL with an ORR of 28%
– Suggestion that rituximab sensitive patients may derive more
benefit (42% vs 6%)
• Ibrutinib may need to be used in combination with other agents for
optimal benefit in FL
6. Ibrutinib + Rituximab in relapsed Mantle Cell
Lymphoma: Preliminary Results from a Phase II Trial
Wang et al, ASH, 2014
Background
• Single-agent oral ibrutinib in relapsed mantle cell lymphoma (MCL)
ORR 68%; CR 21%; DOR 17.5 months; PFS 13.9 months (Wang et al, NEJM, 2013)
Preclinical Data
• In patient-derived xenograft
(PDX) model, ibrutinib +
rituximab was superior to
either agent alone
MCL PDX Model
7. Ibrutinib + Rituximab in relapsed Mantle Cell
Lymphoma: Preliminary Results from a Phase II Trial
Wang et al, ASH, 2014
• Treatment
– Continuous dosing at 560 mg po daily on 28-day cycles until PD or toxicity
– Rituximab weekly x 4; then monthly x 6; and then q 2 mo x 8 (up to 2 years)
• Primary endpoint: ORR (CR+PR)
• Secondary endpoints: DOR, PFS, and OS
Key Eligibility:
• Relapsed or refractory MCL
• No upper limit on number of prior therapies
• No prior BTK inhibitor therapy
• Adequate organ function
8. Baseline Characteristics (N = 50)
Wang et al, ASH, 2014
Median Age (Range) 67 (45-86)
Male (%) 38 (76%)
ECOG PS (0 or 1) 50 (100%)
Median Prior Therapies (Range) 3 (1 - 9)
> 3 27 (54 %)
Previous Therapy
Hyper-CVAD 32 (64%)
Lenalidomide 10 (20%)
Bortezomib 18 (36%)
Simplified MIPI
Low Risk 22 (44%)
Intermediate Risk 22 (44%)
High Risk 6 (12%)
Tumor Features
Bulky Mass 3 (6%)
At least one node > 5 cm 17 (34%)
Refractory disease 35 (70%)
Advanced disease 15 (30%)
9. Best Clinical Response
Wang et al, ASH, 2014
50%
100%
88%
42%
44%
48%
8%
56%
40%
0
10
20
30
40
50
60
70
80
90
100
Ki67 ≥ 50% Ki67 < 50% Total
%
ORR
PR
CR
N
=
50
5 34 15 19 50 24 2012 1
** Ki67 N/A for 4 patients **
p = 0.0001
p = 0.006
10. Progression Free Survival
Time (Months)
Probability
0 3 6 9 12 15
0.0
0.2
0.4
0.6
0.8
1.0
PFS and OS with ibrutinib + rituximab in relapsed MCL
Wang et al, ASH, 2014
Median F/U 11 months
PFS OS
Months
Probability
Overall Survival
Time (Months)
Probability
0 3 6 9 12 15
0.0
0.2
0.4
0.6
0.8
1.0
Months
Probability
11. Conclusions: Ibrutinib + Rituximab in rel/ref MCL
Wang et al, ASH, 2014
5 deaths
PD 3
Pneumonia 1
Gastric hemorrhage 1
• The combination was well tolerated.
• It is highly efficacious in rel/ref MCL (ORR of 88%, N=50)
• Patients with Ki67 <50% benefited the most (ORR of
100%; N = 34)
• Compartmental shift was not observed with this
combination
• Other combinations with ibrutinib are being explored
12. 2nd generation Btk inhibitors
• Highly selective oral Btk inhibitors with IC50 in the sub-
nanomolar range - ONO-4059; ACP-196
Best response with ONO-4059 in rel/ref NHL
Rule et al, ASH, 2013
13. Targeting PI3K in B-cell NHL
• PI3K inhibition impacts multiple critical pathways in B-cell malignancies
Expression Ubiquitous Ubiquitous Leukocytes Leukocytes
a b g Class I PI3K
Isoform
14. Idelalisib: Inhibitor of PI3K Delta
Select Phase I Results in NHL
Slide Courtesy Nathan Fowler
Agents Histology N ORR PFS
(mo)
Ref
Idelalisib Indolent 64 48% 7.8 Benson ASCO 2013
Idelalisib + Rit Indolent 32 77% 2 yr
60%
Fowler ASH 2012
Idelalisib + Benda Indolent 33 88% 2 yr
62%
Fower ASH 2012
Idelalisib Mantle 40 40% 3.7 Spurgeon ASCO
2013
Idelalisib + R +
Benda
Mantle 4 100% NR Wagner ASCO 2013
Idelalisib +
Everolimus
Mantle 18 39% 4.3 Wagner ASCO 2013
Idelalisib +
Bortezomib
Mantle 11 46% 5.2 Wagner ASCO 2013
15. Phase 1 Study of Duvelisib (IPI-145), a PI3K-δ,γ
Inhibitor, in Relapsed/Refractory iNHL
Flinn et al, ASH, 2014
Treatment
– Duvelisib administered orally BID in 28-day cycles to 36 iNHL
patients
• 15 mg (n=1), 25 mg (n=18), 50 mg (n=1), 75 mg (MTD; n=16)
– 25 mg BID selected for Phase 2/3 development
Key Endpoints
– Safety
– Pharmacodynamics
– ORR
Key Eligibility:
• Relapsed or refractory indolent NHL
16. Baseline Characteristics
Flinn et al, ASH, 2014
Characteristics
25 mg BID *
n=19
All Doses
N=36
Disease Subtype FL=14, SLL=4, WM=1
FL= 24, SLL=5,
WM=4,
MZ= 2, NOS=1
Age (years), median (range) 63 (37, 76) 64 (37, 78)
Male, n (%) 14 (74) 21 (58)
ECOG Score 0 / 1 / 2 / missing, n 9 / 9 / 0 / 1 14 / 20 / 1 / 1
Prior Systemic Therapies, median (range) 3 (1, 7) 3 (1, 8)
≥ 3 Prior Systemic Therapies, n (%) 11 (58) 22 (61)
< 6 Months from Previous Therapy, n (%) 7 (37) 12 (33)
≥ 3 FLIPI Factors at Screening, n (%) 6/14 (43) 10/24 (42)
Stage IV, n (%) 7/19 (37) 15/35 (43)
17. Best Clinical Response with Duvelisib
Flinn et al, ASH, 2014
Population
Pts Best Response, n (%)
Median
Time to
Response,
Months
(Range)
n CR PR MR SD PD ORR
25 mg BID 18 6 (33) 6 (33) 1 (6) 4 (22) 1 (6) 13 (72) 1.8 (1.7, 5.5)
All Doses 34 7 (21) 13 (38) 1 (3) 11 (32) 2 (6) 21 (62) 1.8 (1.5, 5.5)
• 69% (9/13) ORR in FL patients, including 38% (5/13) CR
• Median time to CR = 3.4 months (range 1.8-8.5)
18. PFS and OS with Duvelisib in Rel/Ref iNHL
Flinn et al, ASH, 2014
PFS OS
• Median PFS not reached
– 69% progression-free at 2 yrs
(25 mg BID)
• Median OS not reached
– 89% survival at 2 yrs
(25 mg BID)
20. Conclusions: Duvelisib in Rel/Ref iNHL
Flinn et al, ASH, 2014
5 deaths
PD 3
Pneumonia 1
Gastric hemorrhage 1
• Majority of AEs Grade 1 or 2, reversible, and clinically manageable
• Encouraging ORR, PFS, and OS in R/R iNHL patients
• Rapid response (median 1.8 months)
• Phase 2/3 studies with 25 mg BID are ongoing in patients with
iNHL (DYNAMOTM and DYNAMO+R)
21. Phase 1 Ublituximab + TGR‐1202 in CLL & B-NHL
Lunning et al, ASH, 2014
5 deaths
PD 3
Pneumonia 1
Gastric hemorrhage 1
Ublituximab (UTX) – a novel chimeric CD20 mAb glycoengineered to
enhance affinity to FcγRIIIa receptors, thereby demonstrating greater
ADCC than rituximab – 43% ORR in R/R NHL and CLL
TGR-1202 – a next generation once daily, oral PI3Kδ inhibitor which
notably lacks the hepatotoxicity associated with other PI3Kδ inhibitors
Treatment
• UTX on days 1, 8, 15 of cycles 1 and 2 and then maintenance
• TGR-1202 started with 800 mg orally once daily and then escalated
Key Eligibility
• Relapsed/refractory CLL or NHL
• Patients failing prior PI3K and Btk inhibitors are eligible
22. Phase 1 Ublituximab + TGR‐1202 in CLL & B-NHL
Lunning et al, ASH, 2014
5 deaths
PD 3
Pneumonia 1
Gastric hemorrhage 1
• N = 21; 8 CLL/SLL, 7 DLBCL, 5 FL, and 1 Richter’s
• Median number of prior therapies = 3 (range 1-9)
Adverse Event Percentage
Infusion reaction 48%
Neutropenia 38%
Diarrhea 29%
Nausea 29%
Hepatotoxicity None
Histology (n) ORR
CLL/SLL (5) 80%
DLBCL (5) 40%
FL (4) SD
Richter’s (1) SD
Total (15) 40%
Safety Efficacy
All PRs
23. • Exportin 1 (XPO1/Crm1) is
the major nuclear export
protein with >200 protein
and a few RNA cargos
• XPO1 is overexpressed in
many hematological (DLBCL
and MCL) and solid tumors
and correlates with poor
prognosis or resistance to
chemotherapy
• Selinexor is a novel, oral,
small molecule selective
inhibitor of XPO1
o Reduces expression of the proto-oncogene proteins c-myc, Bcl-2, Bcl-6, Mdm2, BTK,
Cyclin D and survivin
o Blocks NF-κB activation, which is required for ABC DLBCL cell survival
o Reactivates p53, for which mutation is associated with poor prognosis
Targeting exportin 1 using selinexor in NHL
24. Selinexor Phase 1 Study Design
Objectives (modified 3+3 design)
– Primary: Safety, tolerability and Recommended Phase 2 Dose (RP2D) of
KPT-330;
– Secondary: Pharmacokinetics (PK), pharmacodynamics (PD), anti-tumor
response; confirmation of RP2D of selinexor
Selinexor oral dosing
– 10 doses/cycle (2-3 doses/week) or 8 doses/cycle (twice weekly) or 4
doses/cycle (once weekly)
– Doses 3 mg/m2 – 80 mg/m2
– Dose expansion for DLBCL
Major eligibility criteria:
– Patients (ECOG ≤1) with relapsed/refractory hematologic tumors with no
available standard treatments
– No active CNS disease
– Documented progression at study entry
– ANC >1000/µL, Platelets >30,000/µL
Kuruvilla et al, ASH, 2014
26. Rel/Ref DLBCL 040-050: PET Confirmed Complete
Response
Baseline Cycle 14
51 year old female – DLBCL
March 2006 – R-CHOP
Jan 2010 –GDP and Auto SCT –
Maintenance Rituximab
April 2011 – Radiation
Jan 2012 – Steroids
Feb 2012 – Panabinostat
Jul 2013 – Steroids
Selinexor Treatment
October 7, 2013, initiates Selinexor 35
mg/m2
MRI: 74% reduction in cycles 1 & 2
PET CT negative Cycle 12, : CR
Kuruvilla et al, ASH, 2014
27. Selinexor Phase 1 Study: Drug Related AEs
0 10 20 30 40 50 60
Leukopenia
Neutropenia
Anemia
Thrombocytopenia
Hyponatremia
Blurred vision
Dehydration
Sensory neuropathy
Proteinuria
Syncope
Dyspepsia
Confusion
Muscle weakness
Constipation
Dizziness
Weight loss
Dysgeusia
Diarrhea
Vomiting
Anorexia
Fatigue
Nausea
AE incidence (% of pts)
Grade 1
Grade 2
Grade 3
Grade 4
N=67
AEs for ³ 5% of pts
Kuruvilla et al, ASH, 2014
28. Conclusions: Selinexor Phase 1
Selinexor (KPT-330) is safe in patients with heavily pretreated NHL
Main toxicities: anorexia, nausea, fatigue, thrombocytopenia
Phase 2/3 Recommended Dose is 60 mg/m2 BIW
Single-agent anti-tumor activity across all NHL types with durable cancer
control >9 months; median DOR ~ 7 months
Marked activity across GCB, non-GCB, and Double-Hit DLBCL
Further evaluation of selinexor is ongoing in two separate Phase 2 Studies
in DLBCL and Richter’s transformation
Kuruvilla et al, ASH, 2014
29. Other novel targeted therapies in B-NHL
Harb et al, ASH 2014 # 1716
Sven de Vos et al, ASH 2014 # 1722
Sharman et al, ASH 2014 # 4419
Maddocks et al, ASH 2014 # 3082
Collins et al, ASH 2014 # 4481
Agent(s) Target Phase Histology N ORR AEs
PNT2258 BCL-2 II B-NHL 9 56% Low toxicity
ABT-199 + BR BCL-2 I B-NHL 26 62% GI
Cytopenias
FL 15 73%
DLBCL 8 38%
Entospletinib
(GS-9973)
SYK II FL 29 55% Hepatic
GI
Alisertib+/-
Rituximab
Aurora A
kinase
II B-NHL
(DLBCL)
11 9% Cytopenias
Barasertib Aurora B
kinase
II DLBCL 15 20% Cytopenias
