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Biological Characterization
MDS phenotype Environment Adhesion Genetic Loss of Heterozygosity Molecular Gain of Function Epigenetic Gene Silencing Immunologic Effectors Angiogenic Molecules TREATING PATHOGENESIS
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EPIGENETICS Alteration of the heritable state of gene expression causing disruption of gene function (loss of function), in cancer Gene silencing mediated by: DNA methylation (DNA Methyltransferase) Histone de-acetylation (Histone deacetylase) RNA interference (post-transcriptional) MicroRNA Epigenetic events reversible Potentially targets for cancer therapy (gene reactivation)
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CALGB 9221 A Randomized Phase III Controlled Trial of Subcutaneous Azacitidine in Myelodysplastic Syndromes No Continue until Endpoint + * Minimum duration of supportive care = 4 months unless transform to AML; death or plts š 20 x 109/L at week 8 or later QOL – Quality of Life Assessment M = Bone Marrow Aza C – Azacitidine S.C. M 57 29 113 1) Supportive Care* QOL + RA RARS RAEB RAEB-T CMML S t r a i f y R n d o m z e 2) Aza C75mg/m2/d x 7 days q28 x 4 Exit Criteria Yes Aza C (dose as per arm #2) A E Response Continue Rx No Response - Off Study Day Silverman L, et al. J Clin Oncol : Kornblith AB, et al. J Clin Oncol :
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Analysis of Response SC AZA Crossover No. Evaluated 92 99 49
PR 0 (0%) 15 (16%) ** 2 ( 4%) Improved 5 (5%) 38 (37%) ** 16 (36%) Total 5 (5%) 60 (60%) ** 23 (47%) P - value * < 0.01 **<0.001 Silverman L, et al. J Clin Oncol :
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Time to AML Transformation
P=.001 Remaining Event-Free Probability of 0.0 0.2 0.4 0.6 0.8 1.0 6 12 18 24 30 36 42 48 54 Azacitidine Supportive Care Months + p=0.007 Silverman L, et al. J Clin Oncol :
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Probability of Survival
Silverman L, et al. J Clin Oncol : 0.0 0.2 0.4 0.6 0.8 1.0 Probability of Survival Months Induction Azacitidine Crossed before 6 months Did not cross before 6 months 10 20 30 40 50 5 15 25 35 45 12 24 42 54 6 18 36 48 Azacitidine Supportive Care p=0.1 p=0.03
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Survival: FAB Classification
Silverman L, et al. J Clin Oncol : 10 20 30 40 50 0.0 0.2 0.4 0.6 0.8 1.0 Probability of Survival Months Aza/Low Supp Care/Low Aza/High Supp Care/High
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Confirmatory Trial Design
Patient Randomized Azacitidine 75 mg/m2 x 7 days Every 28 days Standard of care Options 1) Best Supportive Care 2) Low Dose 3) Standard Chemotherapy vs Standard of care Low Dose Ara-C Primary endpoint: Time to leukemic transformation or death Chris Mitchell Make consistent with other two schematics
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Cytotoxicity vs Hypomethylation
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Low Dose DAC 135mg/m2, c.i./72 h 15 mg/m2, tid/Dx3, i.v.
15 mg/m2, tid/Dx3, s.c. Kantarjian, Blood 2006
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Median response duration 36 weeks
Cumulative analysis of 177 MDS patients treated with low-dose decitabine within 4 Phase II studies in Europe and the USA Toxic death 7% Progressive disease 18% Stable disease 20% Improvement 14% Partial response 10% Not evaluable RESPONSE RATE 49% Median response duration 36 weeks Median survival 15 months 2 years survival 31% (Wijermans, Lübbert et al., Ann. Hemat. 2005)
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Report of Phase III Trial of Decitabine in advanced MDS
170 pts, DAC 15 mg/m2, tid/Dx3 Q 6 wks, 10 cycles IPSS No. DAC SC P Int HR All pts Median time to AML or death (months)
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Time to AML P=0.16
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Time to AML P=0.028
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Combination Therapy for MDS/AML
AZACITIDINE + PHENYLBUTYRATE AZACITIDINE + SAHA (Vorinostat) AZACITIDINE + MS-275 AZACITIDINE + Gemtuzumab Ozogamicin DECITABINE + VALPROIC ACID
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CANDIDATE DRUGS FOR EPIGENETIC THERAPY
DNMT inhibitors Vidaza, Dacogen, zebularine, DNMT antisense and siRNA HDAC inhibitors
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HDAC inhibitors Short-chain fatty acids (SCFA) Butyrate derivatives,
Valproic acid Hydroxamic acids Trichostatin A , SAHA, Pyroxamide, LAQ824, ITF2375 Epoxyketone-containing cyclic tetrapeptides Trapoxins Non-epoxyketone-containing cyclic tetrapeptides FK228, Apicidin Benzamides MS-275, CI-994 MGCD0103
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Pharmion Corp. MethylGene Taiho HDAC programme
MGCD 0103 Profile: HDAC1,2,3 and 11 inhibitor Oral Lacks cardiac toxicity (Herg channel negative) characteristic of the class. Appears synergistic with Vidaza
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MG-0103 Clinical Studies in Cancer
001 002 003 004 Ph I solid Ph I – MDS, leukemia 3-week cycle # Patients 12 28 23 3 005 Ph I/II – azacitidine combo MDS 006 Ph I/II – gemcitabine combo pancreatic 007 Ph II – AML 008 Ph II – Lymphoma Status Closed 56 mg/m2 70 mg/m2 53 mg/m2 90 mg total At sites Underway
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MG-0103 Clinical Studies in Cancer
When the highly promising Vidaza, ATRA, Valproate studies in HR MDS/AML and Phase II MGCD0103 studies are completed 0103 will progressively replace valproate
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HDAC class3 Sirtuins Treatment of BCL6-expressing Burkitt lymphoma cells with cambinol (Sirt1 inhibitor) induced apoptosis, accompanied by hyperacetylation of BCL6 and p53. Acetylation inactivates BCL6 and activates p53 and other checkpoint pathways* *Heltweq, Cancer Res, 2006
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