Lymphoid Malignancies Think Tank Therapeutic Opportunities in Lymphomas

Transcription

1 Lymphoid Malignancies Think Tank Therapeutic Opportunities in Lymphomas Wyndham H. Wilson, MD, PhD Bethesda, Maryland

2 Distribution of Lymphoma Subtypes % of Total Cases Diffuse La rge B-ce ll Follicular Lymphoma Ma rgina l zone B-ce ll lymphoma, MALT 6.0% MCL DLBCL 30.6% Periphera l T-cell lymphomas CLL/SLL 6.7% 7.0% PTL 7.6% MZL FCC 22.1% Mantle Cell Lymphoma Mediastinal Large B-cell Lymphoma Ana pla s tic La rge Ce ll Lymphoma/T-null

3 Historical Outcome of Lymphoma Subtypes Aggressive B Cell Lymphomas Diffuse Large B-cell Lymphoma (DLBCL) Mantle cell lymphoma (MCL) Indolent B Cell Lymphomas Follicular center cell (FCC)

4 Aggressive Lymphoma (DLBCL) 100 Percent Cure 33% 20 P = 0.35 Fisher Intergroup Trial (PFS) Years After Randomization CHOP m-bacod ProMACE-CytaBOM MACOP-B Patients at Risk Relapses or Deaths 3-Year Estimate % 46% 46% 41%

5 Mantle Cell Lymphoma Median survival 3 years Fisher et al. Blood 85:1075; 1995

6 Indolent Lymphoma (FCC) Median Survival 10 years

7 Strategies in DLBCL Empiric Targeted Identify targets and reagents Clinically assess and validate Clinical trials Evaluate molecular mechanisms of treatment failure Build molecular prognostic models Assess tumor biology treatment regimens Rationally develop new-generation treatments

8 Rituximab: An Anti-CD20 MAb An Empiric Success Chimeric murine/human MAb Variable light- and heavychain regions from murine anti-cd20 antibody Linked to human IgGκ constant regions

9 LNH-98.5 Phase III CHOP v CHOP plus Rituximab Cyclophosphamide 750 mg/m² Doxorubicine 50 mg/m² Vincristine 1.4 mg/m² Prednisone 40 mg/m²/d x 5 d 3 weeks 8 cycles CHOP Rituximab 375 mg/m²

10 GELA study Median follow-up 5 y 1.0 Event-Free Survival 1.0 Survival R-CHOP CHOP % 0.4 R-CHOP CHOP p = p = Years Years

11 Diffuse Large B-Cell Lymphoma Molecular Prognostic Model of CHOP Failure

12 Proliferation Signature Percent Survival Low proliferation High proliferation Rosenwald et al NEJM 346:1937, 2002 Years

13 Ki-67 Analysis of Tumor Proliferation Survival Outcome With CHOP bolus Ki-67 < 80% Median survival 39 months Ki-67 > 80% Median survival 7 months Blood 83:1460, 1994

14 Hypothesis Drug schedule increases tumor drug sensitivity Doxorubicin 7 day 3 hr Schedule dependent drugs Doxorubicin Etoposide Vincristine SW6200

15 Hypothesis Drug schedule impacts drug sensitivity and mechanism Cell cycle apoptotic threshold Cell cycle Drug targets

16 Tumor Proliferation Survival Outcome CHOP v DA-EPOCH CHOP Bolus DA-EPOCH Infusional Survival Probability Low High P = High Low P = 0.11 Years on study Years on study High Proliferation (Ki67 > 80%) Low Proliferation (Ki67 < 80%)

17 DA-EPOCH-R Infusional Survival Outcomes PFS and OS: 83% Percent Untreated DLBCL (n=90) 20 Median Follow-up: 3 years Months on Study 72

18 Diffuse Large B-Cell Lymphoma Biology of CHOP Failure

19 Effect of GCB v ABC Subtypes on Outcome CHOP Bolus Treatment

20 GCB v ABC DLBCL BCL-2 impacts survival 25% v. 8 yrs (P < 0.001) CHOP-based (Blood 83:1460, 1994) BCL-2 Expression Associated with ABC ABC v GCB (p = 0.003)

21 Effect of Rituximab on BCL-2 BCL-2 Expression CD20+ CD20- BCL-2 Expression Clin Cancer Res 2001 Mar;7(3):709-23

22 Effect of Rituximab in BCL-2+ Tumors NCI EPOCH v EPOCH-R

23 Effect of Rituximab in BCL-2+ Tumors GELA CHOP v R-CHOP % survival CHOP OS, P=0.05 bcl2 (45) bcl2 + (92) Years % survival R-CHOP OS, P=0.71 bcl2 (54) bcl2 + (101) Years

24 GCB v ABC Survival Outcome EPOCH-R Infusional Survival (%) ABC: 69% GCB: 89% p 2 = Median Follow-up: 36 months Months on Study 72

25 CALGB Phase III Randomized Study of R-CHOP v. DA-EPOCH-R with Microarray ARM A: R-CHOP Treatment completed C1 C2 C3 C4 C5 C6 C7 C8 Randomization Tumor Biopsy Blood Samples Stage Stage Stage C1 C2 C3 C4 C5 C6 C7 C8 Repeat Blood Samples at Staging Proteomics/Pharmacogenomics ARM B: DA-EPOCH-R Treatment completed if no change C5 to C7 staging Treatment completed if change C5 to C7 staging Time Line (weeks)

26 Targeting NF- κb in the ABC Subtype

27 Bortezomib and NF-κB Bortezomib inhibits release of NF-κB dimers through inhibiting proteosome clearance of IκB Activation of the NF-kB Signaling Pathway

28 Phase I/II Study of Bortezomib + EPOCH Part A Bortezomib single agent Part B DA-EPOCH + Bortezomib days 1 and 4 Bortezomib Dose Escalated: Level I 0.5 mg/m 2 Level II 1.0 mg/m 2 Level III 1.5 mg/m 2 Level IV 1.7 mg/m 2

29 Phase I/II Study of Bortezomib + EPOCH Part A Bortezomib single agent Part B DA-EPOCH + Bortezomib days 1 and 4 Bortezomib Dose Escalated: Level I 0.5 mg/m 2 Level II 1.0 mg/m 2 Level III 1.5 mg/m 2 Level IV 1.7 mg/m 2 ORR 6% (1/16) 23% (6/26)

30 Strategies in Mantle Cell Lymphoma Chemotherapy sensitive but persistent MRD Characterized by cell-cycle dysregulation Proliferative Signal DNA DS Breaks Cyclin D1 / cdk4 p16 ATM 50%? Sequestration Rb E2F p14 ARF Methylated promoter mdm2 p53 More common in blastic p27 Cyclin E/cdk2 p21 BAX Deleted PROLIFERATION Deleted APOPTOSIS Courtesy O. O Connor

31 Tumor Proliferation

32 Tumor Proliferation Predicts Outcome

33 PFS Not Dependent on Proliferation Signature EPOCH-R Infusional

34 Immune Eradication of MRD Idiotype Vaccine Protocol Schema LN Bx EPOCH-R Begins EPOCH-R Ends Id/KLH + GM-CSF s.c. Weeks n = 26 EPOCH-R 6 cycles EPOCH-R Rituximab iv Day 1 Continuous infusion Etoposide, Doxorubicin, Vincristine Days 1-5 Cyclophosphamide iv Day 5 Prednisone po Days 1-5 Dose Adjustment Id-KLH+GM-CSF 0.5 mg autologous Id mg KLH µg/m 2 GM-CSF

35 PFS and OS With Idiotype Vaccine Progression-Free Survival Overall Survival OS 4 years Percent Percent Median follow-up 46 months Median PFS 22 months PFS 4 years 20 Median follow-up 46 months Years on Study Years on Study 3 4 5

36 Inhibition of Cell-Cycle Targets Proteosome inhibitor Known Proteosome Substrates CLASS Cyclins Tumor Suppressor Oncogenes Inhibitory Proteins Enzymes PROTEIN Cylins A, B, D E Cdk Inhibitors P53 (p21 and p27) C-fos/c-jun C-myc N-myc IkB P130 / bcl-2 Cdc25 phosphatase Tyrosine aminotransferase PROTEIN FUNCTION Cell cycle Cyclin regulation Transcription factor Transcription factor Transcription factor Transcription factor Inhibitor of NF-kB Inhibitor of E2F-1 CDK1/cyclin B phosphatase Tyrosine metabolism

37 Summary of Recent Data Mantle Cell Lymphoma Study N CR/CRu PR ORR O Connor et al (MSKCC) 26 3/2 (19%) 9 (38%) 54% (ASH 2004) Strauss et al (St. Barts) 18 1 (6%) 6 (33%) 39% (ASH 2004) Belch et al (NCIC) 28 1 (4%) 12 (43%) 46% (ASH 2004) Goy et al (MDACC) 29 6 (21%) 6 (21%) 41% (JCO 2005, ahead of print Dec 21, 2004)

38 Summary of Recent Data Indolent Lymphoma Study N CR/CRu PR ORR O Connor (MSKCC) (ASH 2004) Follicular 15 1/1 (13%) 7 (47%) 60% SLL (20%) 20% MZL (50%) 50% Strauss et al (St. Barts)* (ASH 2004) Follicular (18%) 18% Goy et al (MDACC) (JCO 2005, ahead of print Dec 21, 2004) Follicular NA* 0/1 - NA* SLL NA* 1/0 - NA*

39 Inhibition of mtor Growth Factor Cell Membrane PI3k Cell Growth PIP-3 AKT PTEN CCI-779/ RAD001 Regulate Translation of cell cycle regulatory proteins P P Courtesy of O Connor mtor P70 S6K1 4E-BP1

40 Phase II Study CCI-779 (Temsirolimus) Relapsed Mantle Cell Lymphoma Arm A: N = 34 Response: ORR: 38% CR 1 PR 12 PFS Median (range) 6.5 ( ) Arm B: N= 13 Toxicity (Grade 3): Thrombocytopenia: 63% Neutropenia: 23% Response: ORR: 54% CR 1 PR 6 Delayed cycles PFS too early 6/7 responses 2 months Toxicity (Grade 3): Thrombocytopenia: 23% Neutropenia: 23% Lower thrombocytopenia Witzig, T, Geyer S, Ghobrial I, et al. Proceed ASCO # 129, 2005

41 Inhibition of Histone Deacetylation

42 Phase I Study of Suberoylanilide Hydroxamic Acid (SAHA) Histone Deacetylase (HDAC) Inhibitor Inhibition of Histone H3 Deacetylation by SAHA in PBMC Kelly WK et al. Clin Cancer Res 9:3578, 2003

43 Cyclin-Dependent Kinase Inhibitor Flavopiridol Derived by synthesis from Dysoxylum binectariferum, plant indigenous to India CDK inhibitor: Directly binds to the ATP binding site at nanomolar concentrations (e.g. cyclin D1) Kaur G, et al., JNCI, 1992, 84: 1736, 92.

44 Flavopiridol in Mantle Cell Lymphoma No Prior Therapy Prior Therapy Total # Pts. (n=28) Duration Range Complete Remission Partial Remission Stable Disease POD Overall Response 2 / 11 [18%] 1 / 17 [6%] 24% - - Kouroukis et al., 2003

45 Immunomodulatory Drugs (IMiD) Inhibition of TNF-α Production in Monocytes Mediator of inflammation Pro-angiogenic Induces cellular proliferation T-cell Costimulatory Activity Increased activation/proliferation Increased cytokine production (IL-2, IL-12 and TNF-α) Shift toward Th1 (helper) phenotype Enhance NK and LAK activity

46 Survival Outcomes in Mantle Cell Lymphoma Thalidomide and Rituximab Overall Survival PFS; Median 20.4 months Prior Therapy PFS Thalidomide + Rituximab Kaufmann, H. et al. Blood 2004;104:

47 Lenalidomide (CC-5013, Revlimid ) New-Generation ImiD O N O H N O O N O H N O O Thalidomide NH 2 Lenalidomide Courtesy of O Connor Bartlett JB et al. Nat Rev Cancer. 2004;4:314 Stirling D. Semin Oncol. 2001;28:602

48 Protocol Construction Opportunity window For activity biomarkers Targeted Agent Obtain pre and post Bx after one cycle Maximize cytotoxicity and therapeutic index Neoadjuvant Eradicate RTC Targeted Agent Chemotherapy + Targeted agent Post-CT+ TA Randomize Observation

49 Protocol Construction Biomarkers Microarray Proteomics Bortezomib Obtain pre and post Bx after one cycle Endpoints EFS OS MRD Correlate bortezomib biomarkers with outcome MRD Detection Bortezomib X 18 months DA-EPOCH-R + Bortezomib Post-CT+ TA Randomize Observation

50 Acknowledgements Clinical Studies John Janik, Kieron Dunleavy Nicole Grant, Therese White Martin Gutierrez, Upendra Hegde Bruce Chabner, Michael Grossbard Metabolism Branch Louis Staudt Andreas Rosenwald Adrian Wiestner Pharmacology Studies (Pediatric Branch) Frank Balis, Diane Cole Elizabeth Lowe Laboratory of Pathology Stefania Pittaluga Elaine Jaffe Mark Raffeld, Mary-Alice Stetler-Stevenson