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LBH589 e altri inibitori delle istone-deacetilasi nel Mieloma Multiplo

LBH589 e altri inibitori delle istone-deacetilasi nel Mieloma Multiplo. Claudia Polloni Clinica di Ematologia Azienda Ospedaliero-Universitaria Ospedali Riuniti Ancona. Introduction to Deacetylases (DACs).

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LBH589 e altri inibitori delle istone-deacetilasi nel Mieloma Multiplo

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  1. LBH589 e altri inibitori delle istone-deacetilasi nel Mieloma Multiplo Claudia PolloniClinica di EmatologiaAzienda Ospedaliero-UniversitariaOspedali Riuniti Ancona

  2. Introduction to Deacetylases (DACs) • Deacetylases (DACs) are enzymes that remove the acetyl groups from target proteins, leading to regulation of gene transcription and other cellular processes • Histones are one of the target proteins, which is why the class is sometimes referred to as histone deacetylases (HDACs) • DACs also target non-histone proteins, which include transcription factors, -tubulin, and HSP90

  3. There are 4 Classes of DACs (I and II), Which Act on Different Target Proteins There are 2 main classes of DACs Class I DACs act on HISTONES and TRANSCRIPTION FACTORS located in the nucleus Class II DACs act on NON-HISTONE proteins located in the cytoplasm (e.g. HDAC6) HDAC1 HDAC2 HDAC3 HDAC6 HDAC8 HDAC4 HDAC5 HDAC7 HDAC7 HDAC9 HDAC10

  4. Pan-DAC Inhibitors Target Both Classes of DACs, Modulating Histone and Non-Histone Proteins There are 2 main types of DAC inhibitors Pan-DACinhibitors target both Class I and Class II DACs – interfering with both histone and non-histone proteins Specific DAC inhibitors may target Class I DACs only HDAC1 HDAC2 HDAC3 HDAC6 HDAC8 HDAC4 HDAC5 HDAC7 HDAC9 HDAC10

  5. Isoenzyme-selectivity of pan-HDACi:

  6. Genetic Variations and Epigenetic Changes Can Both Contribute to Oncogenesis EPIGENETIC Chromatin Enzyme modification errors Replication errors Mutations/translocations Open/closed chromatin DNA sequencenot altered DNA sequence altered Altered mRNA/proteins Altered DNA/mRNA/proteins Can be caused by: • Abnormal modifications to histone proteins • Abnormal DNA methylation Transformedcells Oncogenesis GENETIC DNA

  7. Altered Expression of DACs is Found in Several Malignancies DAC expression can increase cell-cycle progression and prevent cell death, which leads to increased cell proliferation DAC expression can correlate with estrogen and progesterone receptor expression DACs can be upregulated in malignant prostate cancer, with the highest levels found in HRPC DAC expression can be associated with tumor aggressiveness MULTIPLE MYELOMA BREAST CANCER PROSTATE CANCER GASTRIC CANCER

  8. Pan-DAC Inhibition May Have Potential in Several Cancers 50% of Cancers Hematologic & Solid Tumors DAC Inhibitor Histone p53 DACs HSP90 -tubulin HIF-1a CML, Breast, Prostate, NSCLC Breast, Multiple Myeloma RCC, Melanoma

  9. Epigenetic Changes Can Drive Cancer • Epigenetic changes, such as histone modifications and DNA methylation, play key roles in chromatin structure and gene activity • Altered patterns of epigenetic modifications are common in many human diseases, including cancer • Silencing of tumor suppressor genes by abnormal histone modifications is a key feature of cancer cells • DAC inhibitors were developed when they were found to reactivate genes that had been epigenetically silenced

  10. –Ac Ac– Ac– Ac– Acetylation of Histones by HAT Allows Gene Expression Acetylation by histone acetyltransferases (HATs) allows transcription and gene expression HAT Transcription factors HISTONE ACETYLATION Deacetylated Histone Closed chromatin Transcription factors cannot access DNA Acetylated Histone Open chromatin Transcription factors can access DNA Ac: acetyl group

  11. –Ac Ac– Ac– Ac– Deacetylation of Histones by HDAC Can Prevent Gene Expression Acetylation by histoneacetyltransferases (HATs) allows transcription and gene expression HAT Transcription factors HISTONE ACETYLATION HISTONE DEACETYLATION Deacetylated Histone Closed chromatin Transcription factors cannot access DNA Acetylated Histone Open chromatin Transcription factors can access DNA HDAC Deacetylation by histonedeacetylases (HDACs) can prevent transcription and gene expression Ac: acetyl group HDAC depicts a class I deacetylase

  12. –Ac Ac– In Tumor Cells, Imbalanced HAT and HDAC Activity Can Result in Deregulated Gene Expression Decreased HAT Activity IncreasedHDAC Activity HAT HDAC HDAC TF HDAC Decreased Tumor Suppressor Gene Activity (p21, p27) TumorCell Ac: acetyl group TF: transcription factors HDAC depicts a class I deacetylase Unchecked CellGrowth and Survival

  13. HDAC HDAC HDAC –Ac Ac– Ac– Ac– HDAC Inhibition Restores Gene Expression in Tumor Cells DAC Inhibition Increases Acetylation of Histones HAT DAC Inhibitor TF Increased Tumor Suppressor Gene Activity (p21, p27) Normalized Cell Ac: acetyl group TF: transcription factors HDAC depicts a class I deacetylase Cell-Cycle Arrest and Differentiation

  14. DACs are Implicated in Cancer by Modulating Histone and Non-Histone Proteins Involved in Oncogenesis DAC DAC DAC DAC DAC Proteins modulated by DACs Histone p53 HSP90 HIF-1 -tubulin Histone proteins are implicated in epigenetic modifications that could cause cancer Non-histone proteins are implicated in multiple oncogenic pathways

  15. Downstream effects Microtubule depolymerization/ aggresome formation Tumor suppressor gene activity Loss of tumor suppressor function Oncoproteins VEGF Tumor effects Cell-cycle arrest Cell proliferation and survival Cell motility and Invasion Angiogenesis Apoptosis Pan-DAC Inhibition Interferes with the Multiple Hallmarks of Cancer DAC Inhibitor DAC DAC DAC DAC DAC Proteins modulated by DACs Histone HIF-1 -tubulin HSP90 p53 DAC depicts individual deacetylases, e.g. HDAC1, HDAC4, HDAC6

  16. HSP90 HSP90 DAC Inhibitor Growth and survival proteins Growth and survival proteins HDAC6 HDAC6 Acetylated HSP90 – binding to growth and survival proteins prevented Deacetylated HSP90 – binds growth and survival proteins Proteins protected from degradation Proteins degraded Overexpression of growth and survival proteins Overexpression of growth and survival proteins Proliferation and survival Proliferation and survival DAC Inhibition can Control Myeloma Cell Proliferation and Survival Through HSP90 DAC Activity through HSP90 DAC inhibition through HSP90

  17. DAC Inhibitor Deacetylated α-tubulin Acetylated α-tubulin HDAC6 HDAC6 No aggresome formation Aggresome formation Accumulation of cytotoxic misfolded proteins Misfolded proteins recruited to aggresomes Protein degradation Protein degradation Cell survival Apoptosis DAC Inhibition can Induce Apoptosis in Myeloma Cells Through the Aggresome Pathway DAC inhibition through aggresomes DAC Activity through aggresomes

  18. Misfolded proteins Acytelated α-tubulin DAC Inhibitor Proteasome Inhibitor (Bortezomib) HDAC6 Proteasome No aggresome formation Accumulation of misfolded proteins Protein degradation Protein degradation Apoptosis DAC Inhibition can Synergize with Proteasome Inhibition to Induce Increased Apoptosis in Myeloma Cells Multiple Myeloma cell

  19. DAC Inhibition Can Lead To Decreased Angiogenesis in Tumor Cells Through HIF-1 DAC Inhibition HIF-1a DAC Inhibitor HDAC4 HDAC6 Deacetylated HIF-1α • Stabilized Acetylated HIF-1α • Destabilized • Degraded VEGF VEGF Angiogenesis Angiogenesis Implicatedin RCC, melanoma and other solid tumors DAC Activity HIF-1a HDAC4 HDAC6

  20. DAC Inhibition can Induce Apoptosis in Myeloma Cells

  21. Studi in corso: Tab 3 Hematology review

  22. LBH-MPT STUDIO DI FASE II, MULTICENTRICO, IN APERTO DI LBH589 ORALE IN ASSOCIAZIONE CONMELPHALAN, PREDNISONE E TALIDOMIDE (LBH-MPT)IN PAZIENTI CON MIELOMA MULTIPLO AVANZATO O REFRATTARIO

  23. Rationale LBH589-MPT • Activty of LBH589 in solid tumors and hematologic malignancies • Combination treatments standard for MM (MPT) • Each drug has different mechanisms of action • Safety will be closely evaluated

  24. Safety of iv LBH-589 QTcF prol: 27% Nausea: 40% Diarrhea: 33% Vomiting: 33% Hypokalemia: 27% Anorexia: 13% Thrombocytopenia: 13%

  25. ARM ARM 1 (32 pts) 15 mg MWF (3 pts) 20 mg MWF (19 pts) 30 mg MWF(10 pts) ARM 3 (22 pts) 30 mg MWF eow(20 pts) 45 mg MWF eow(2 pts)$ ARM 5 (8 pts) 30 mg MT (3 pts) 45 mg MT ( 5 PTS) No grade 3 0 0 1 (diarrhea) 0 1 (diarrhea) 0 1 (fatigue) 1 (QTcF prol) 1 (PLTpenia)* No grade 4 0 0 1 (PLTpenia)* 1 (PLTpenia)* 1 (PLTpenia)* 0 0 Prot CLBH589B2101: safety of oral LBH589 * Transient and reverseble; $ 1 pt grade 2 anemia and 1 pt grade 2 fatigue

  26. ARM (dose) 20 mg 30 mg FA 2 2 AFlutter 1 0 Prot CLBH589B2101: cardiac toxicity 1046 post dose ECG: median prolongation <10 msec T-wave flattening in 25 patients CK in 2 patients (not clinically relevant) QTc prol. 1 1 1 ARM (dose) 30 mg 20 mg 30 mg msec 100 58 (QTc:503) 77 notes 4 days later, sepsis BBD

  27. G 1- 4 G 1- 4 TREATMENT 6 cicli da 28 giorni 1 3 5 8 10 12 15 17 19 LBH 589 per os Livello 0: 15 mg, Livello -1: 10 mg, Livello +1: 20 mg Melphalan 0,18 mg/kg Prednisone 1,5 mg/kg Talidomide 50 mg continuativamente

  28. Mantenimento:(pazienti con risposta ≥ malattia stabile) cicli da 28 giorni fino a progressione o tossicità intollerabile 1 3 5 8 10 12 15 17 19 LBH 589 per os alla dose utilizzata per LB-MPT Prednisone 25 mg nei giorni 1, 3, 5 di ogni settimana fino a progressione

  29. LBH-MPT: type of study and population • Phase I-II, multicenter, non-comparative, non-randomized, open-label • Adult patients with relapsed MM with any sign of PD during melphalan or thalidomide and who have not received melphalan or thalidomide in the last six months suitable for treatment or re-treatment with melphalan and thalidomide

  30. Endpoints Primary • The safety profile will be assessed by showing: • Any grade 3 non-hematologic toxicity • Grade 4 neutropenia ≥ a week, or any grade 4 hematologic toxicity except neutropenia The efficacy will be assessed by showing a significant PR rate Secondary - Determine the progression-free survival (PFS) - Determine the overall survival (OS) - Determine whether responses are associated with a prolongation of PFS, in comparison with that of non-responding patients. - Quality of Life assessment (QoL) - Assessment of common chromosomal abnormalities in multiplemyeloma by FISH

  31. STUDY DESIGN(Briant and Day method) 19 pts livello +1 STOP RP ≤ 4 Tox g 3-4 ≤ 3 23pts 19 pts livello -1 RP ≥ 5 Tox g 3-4 >10 19 pts Livello 0 STOP 23 pts livello 0 RP ≥ 5 Tox g 3-4 ≤10 STOP RP ≤ 4 Tox g 3-4 ≥ 4

  32. Wolf et. Al, ASH 2008

  33. Siegel, San Miguel et al, ASH 2009

  34. Phase Ib study: Panobinostat combined with bortezomib ± dexamethasone in relapsed MM (B2207) Study design International, open-label, phase Ib, dose-escalation study Treatment 21-day cycles: Escalating doses of oral panobinostat (cohorts 1–3: 10 mg, 20 mg, 20 mg) TIW Escalating doses of bortezomib (cohorts 1–3: 1.0 mg/m2, 1.0 mg/m2, 1.3 mg/m2) given on days 1, 4, 8, 11 Optional dexamethasone (20 mg on day of and day after bortezomib) in cycle 2 onwards (i.e. after the DLT observation period) Patient characteristics (n=22) Median 3 previous lines of therapy (range 1–6), 11pts had previously received bortezomib Disease status at baseline: 10 relapsed and refractory, 11 relapsed, 1 unknown Median age 61 years (range 46–78), 19 had previously undergone SCT Sezer O et al. IMW 2009, Abstract 337 (data updated in oral presentation)

  35. Safety of panobinostat combined with bortezomib ± dexamethasone in relapsed MM (B2207) MTD for panobinostat not reached at 20 mg TIW Accrual ongoing for cohort 4 (panobinostat 30 mg, bortezomib 1.3 mg/m2) Assessment of DLTs (cycle 1): Cohort 1 (panobinostat 10 mg, bortezomib 1.0 mg/m2): no DLTs Cohort 2 (panobinostat 20 mg, bortezomib 1.0 mg/m2): 1 DLT (grade 4 febrile neutropenia) Cohort 3 (panobinostat 20 mg, bortezomib 1.3 mg/m2: no DLTs After 1035 post-baseline ECGs: No dose-related increase in QTcF time No QTcF >500 ms or increase in QTcF from baseline >60ms Sezer O et al. IMW 2009, Abstract 337 - data update at ASH09

  36. Preliminary efficacy of panobinostat combined with bortezomib ± dexamethasone in relapsed MM (B2207) 11 responses to date: 3 CRs, 1 VGPR and 7 PRs, across cohorts 1–3 5 of these responders were refractory (a, b) to their last bortezomib-based therapy b a b b a a: Non-responder to prior bortezomib (i.e. best response SD (IMWG 2006) b: Disease progression on prior bortezomib-based therapy Number of patients All responders Cohort 1 panobinostat 10 mg bortezomib 1.0 mg/m2 Cohort 2 panobinostat 20 mg bortezomib 1.0 mg/m2 Cohort 3 panobinostat 20 mg bortezomib 1.3 mg/m2 Three of 22 treated patients were not evaluable for efficacy as they discontinued treatment in cycle 1 Sezer O et al. IMW 2009, Abstract 337 - data update at ASH09

  37. Phase Ib study: Panobinostat combined with lenalidomide and dexamethasone in relapsed MM (B2206) Study design Multicentre, international open-label phase Ib dose-escalation study Patients Adults with active MM (IMWG criteria) whose disease has relapsed after at least 1 previous line of therapy primary refractory MM, grade >2 peripheral neuropathy, or cardiac diseases/factors associated with QT prolongation were excluded Treatment Patients were treated on 28-day cycles until PD or unacceptable toxicity Escalating doses of oral panobinostat (cohorts 1–3: 5, 10, 20 mg) TIW Lenalidomide 25 mg given orally on days 1–21 Dexamethasone 40 mg given orally on days 1–4, 9–12 and 17–20 for cycles 1–4, and on days 1–4 for cycle 5 onwards Spencer A et al. ASCO 2009 Abstract #8542 (data updated in the poster)

  38. Safety of panobinostat combined with lenalidomide + dexamethasone in relapsed MM (B2206) Safety MTD for panobinostat not reached at 20 mg TIW Study is now recruiting patients at the 25 mg dose level Assessment of DLTs (cycle 1): Cohort 1 (5 mg panobinostat): 7/8 evaluable, no DLT Cohort 2: (10 mg panobinostat): 6/8 evaluable, 1 DLT (grade 1 QTcF prolongation) Cohort 3: (20 mg panobinostat): 6/11 evaluable, 1 DLT (grade 4 neutropenia lasting for >5 days) Most frequent grade 3/4 AEs: neutropenia (5/23 pts), thrombocytopenia (5/23 pts), fatigue (4/23 pts), hyponatraemia (3/23 pts) High-dose dexamethasone may be responsible for many AEs After 1375 post-baseline ECGs: no QTcF >500 ms, no QTcF change >60 ms from baseline Spencer A et al. ASCO 2009 Abstract #8542 (data updated in the poster)

  39. Responses with panobinostat combined with lenalidomide + dexamethasone in relapsed MM (B2206) 20 patients evaluable for efficacy (cohorts 1–3 combined) 12/20 responded: 1 sCR, 1 CR, 5 VGPR, 4 PR, 1 MR 1 responder was refractory to their last bortezomib-based regimen 4 responders were refractory to their last thalidomide-based regimen Number of patients NE, not evaluable; sCR, stringent CR Spencer A et al. ASCO 2009 Abstract #8542 (data updated in the poster)

  40. Weber et al, ASH 2008

  41. Siegel et al,

  42. Harrison et al, ASH 2008

  43. Pivotal Phase III Study: D2308 A multicentre, randomized, double-blind, placebo-controlled phase III study of panobinostat in combination with bortezomib and dexamethasone in patients with relapsed multiple myeloma

  44. D2308 study design Bortezomib 1.3 mg/m2QW, 2 weeks on, 1 week off (x2)+ dexamethasone on same days as and 1 day after each bortezomib dose Bortezomib 1.3 mg/m2BIW, 2 weeks on, 1 week off+ dexamethasone on same days as and 1 day after each bortezomib dose n = 672 Relapsed or Relapsed & Refractory MMa (≥1 up to 3 lines of prior therapy) Panobinostat 20 mg TIW2 weeks on, 1 week off Panobinostat 20 mg TIW2 weeks on, 1 week off (x 2) Follow-up after therapy: 1 year for PD, up to 4 years for OS Treatment phase 2 4 cycles of 42 days each (weeks 25–48) Treatment phase 1 8 cycles of 21 days each(weeks 1–24) R Bortezomib 1.3 mg/m2BIW, 2 weeks on, 1 week off+ dexamethasone on same days as and 1 day after each bortezomib dose Bortezomib 1.3 mg/m2QW, 2 weeks on, 1 week off (x2)+ dexamethasone on same days as and 1 day after each bortezomib dose + Placebo TIW2 weeks on, 1 week off + Placebo, TIW 2 weeks on, 1 week off (x2) Treatment with panobinostat or placebo in combination with bortezomib +dexamethasone (phase 1, 24 weeks) Patients with ‘no change‘ of disease status or response continue into treatment phase 2 (a further 24 weeks). Continuation of combination therapy up to a total of 48 wks, or until PD, withdrawal of consent, or unacceptable toxicity. Screening 3 weeks aNot refractory to bortezomib

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