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- 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 Therapiesin 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 inRel/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 + Rituximabin 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 + Rituximabin 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 Wanget 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 Btkinhibitors • 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 inB-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 ofPI3K 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 Studyof 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 etal, 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 Responsewith 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 OSwith 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)
- 19. Adverse Events in>20% of patients with Duvelisib Flinn et al, ASH, 2014 5 deaths PD 3 Pneumonia 1 Gastric hemorrhage 1 Adverse Event 25 mg BID (n=19) All Doses (N=36) Any Grade Gr 3 Gr 4 Any Grade Gr 3 Gr 4 ALT or AST increased 9 (47) 6 (32) 1 (5) 19 (53) 10 (28) 3 (8) Rash (combined) 7 (37) 1 (5) 0 19 (53) 4 (11) 0 Diarrhea 6 (32) 3 (16) 0 18 (50) 8 (22) 0 Pyrexia 6 (32) 0 0 16 (44) 1 (3) 0 Cough 8 (42) 0 0 14 (39) 0 0 Nausea 7 (37) 1 (5) 0 14 (39) 2 (6) 0 Fatigue 6 (32) 0 0 14 (39) 0 0 Neutropenia 4 (21) 2 (11) 2 (11) 11 (31) 5 (14) 5 (14) Pneumonia (combined) 4 (21) 2 (11) 1 (5) 10 (28) 5 (14) 2 (6)* Decreased appetite 3 (16) 0 0 8 (22) 0 0 Dyspnea 2 (11) 0 0 8 (22) 0 0
- 20. Conclusions: Duvelisib inRel/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 1Study 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
- 25. -100 -80 -60 -40 -20 0 20 40 60 80 130 140 Tumorvol.(max%changefrombaseline) Aggressive Lymphoma Follicular Lymphoma MantleCell Lymphoma Richter'sTransformation T-cell Lymphoma -100 -80 -60 -40 -20 0 20 40 60 80 130 140 Tumorvol.(max%changefrombaseline) Aggressive Lymphoma Follicular Lymphoma Mantle Cell Lymphoma Richter'sTransformation T-cell Lymphoma Selinexor Phase 1: Maximal % Change in Lymph Nodes from Baseline Progressive Disease Partial Response Denotes patients with PET/CT confirmed Complete Response N=40 Kuruvilla et al, ASH, 2014 ORR – 37% CR – 10%
- 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 1Study: 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 Phase1 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 targetedtherapies 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
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