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Is there anything new for relapsed AML? Steven M. Kornblau, M.D. Department of Leukemia Department of Stem Cell Transplantation and Cellular Therapy.

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Presentation on theme: "Is there anything new for relapsed AML? Steven M. Kornblau, M.D. Department of Leukemia Department of Stem Cell Transplantation and Cellular Therapy."— Presentation transcript:

1 Is there anything new for relapsed AML? Steven M. Kornblau, M.D. Department of Leukemia Department of Stem Cell Transplantation and Cellular Therapy

2 The Status Quo Most patients achieve remission – 80% < age 60, no AHD – 50% >60 or prior AHD Most relapse – Cure rate 20-25% overall therefore 2/3 rd relapse Cure after relapse without SCT very unlikely – Exceptions: APL & those inadequately treated Conventional chemotherapy hasn’t advanced in a long, long time. Strategy – Get to SCT, Directly, or chemo to temporize – No donor. Palliate, chemo or symptomatic care.

3 Allogeneic SCT Curative in – ~35% subsequent CR – 25% refractory relapse (IBMTR data) When to perform – ASAP- but most can’t wait & will need something – In CR2 But most won’t achieve a second CR Toxicity and infections can close window of opportunity

4 CR1 duration< 1 year or 1 o ref 1-2 years>2 years # prior salvage attempts>1>1000 N CR Rate<1%14%47%73% Model for Predicting 2 nd Remission Attainment CR1 duration< 1 year or 1 o ref1-2 years>2 years Prior Salvage Therapy?YesNoYesNo Prior Salvage ResponseNo CRCRNo CRCR # of Prior Salvage> 1111 Cytogenetics/AHDFavUnfavFav CR/N 1/ 901/ 105/6216/872/115/914/3010/15 CR rate1%10% 20% 40% 66% Therapy choicePhase IPhase IICombination Chemo Estey & Kornblau Blood 1996;88 :756 Estey & Kornblau unpublished 1998 As an aside, perhaps Phase I and II studies should be sure to include patients form each category, or report what category they had

5 Models for Predicting Survival After Relapse GOELAMS CR1 Duration EPI > 12 Mo < 12 Mo 0 1 > 18 Mo 7-18 Mo < 6 Mo Cytogenetics Not High High Risk 0 1 Inv16 T(8;21) Other FLT3 ITD Neg Positive 0 1 < >45 Age Prior SCT? 2 Points% CR21 Yr OS5 Yr OS 0-685%70%46% 7-960%49%18% %16% 4% Points2 Yr OS 2 Yr EFS 058%45% 137%31% 2-312% Breems JCO 2005;23(9): CR1 Duration Cytogenetics Chevallier Leukemia 2011;25(6);939-44

6 FLT3-ITD: Poor prognosis at relapse too Overall Survival After Relapse 1 Overall Survival After CR#2 Ravandi LeukRes 2010:34; FLT3 -WTFLT3-ITD N6934 CR (p= 0.09)41%24% Med Surv (p= 0.001)37 weeks13 weeks Diploid Cytogenteics Not Tx with anti FLT3 agent CR#2 Remission Duration

7 Combination Chemotherapy Using Approved Agents

8 Current Common Chemotherapy Combinations: MEC Days 1-2-3: Mitoxantrone 12mg/m 2 /d & Ara-C 500 mg/m 2 /d Days : Etoposide 200 mg/m 2 /d & Ara-C 500 mg/m 2 N=133 Age (22 >60) Cytogenetics ? but 7 M4Eos and 13 APL Median 1 st CR 11 mo CR Overall 60% – 1 st salvage for CR1>6mo =76% for CR1 <6mo =46% – >1 st CR 45% – Primary refractory 41% Overall survival, not receiving SCT = 7 mo Archimbaud JCO 1995:13;11-18

9 Results of Randomized Trials In Patients With Relapsed or Refractory AML: Nothing Stands Out as Better StudyTreatmentN 2 nd CR Rate, % Median 2 nd CR Duration, Months ED, % Median OS, Months Kern W, et al. 1 HDAraC + Mit vs IDAC + Mit vs vs vs 175 vs NA Martiat P, et al. 2 HDAraC + Amsa vs HDAraC + Mit 5253 vs 6011 vs 1215 vs 88 vs 11 Larson R, et al. 3 HDAraC vs HDAraC + Amsa 3614 vs 53NA25 vs 252 vs 6 Vogler W, et al. 4 HDAraC vs HDAraC + Eto vs 4512 vs 25NA5 vs 5 Ohno R, et al. 5 MAE vs MAE + G-CSF 5842 vs 5414 vs 128 vs 0NA 9 Abbreviations: CR = complete remission; OS = overall survival; HDAraC = high-dose cytarabine; Mit = mitoxantrone; IDAC = intermediate-dose AraC; NA = not available; Amsa = amsacrine; Eto = etoposide; MAE = Mit + AraC + Eto; G-CSF = granulocyte-colony stimulating factor; EMA = Eto + Mito + AraC; GM-CSF = granulocyte, macrophage–colony stimulating factor; ADE = AraC + daunorubicin + Eto; CSA = cyclosporine; seq ADE = sequential ADE; MEC = Mit + Eto + AraC. 1 Kern W, et al. Leukemia. 2000;14: 226–231; 2 Martiat P, et al. Eur J Haematol. 1990;45:164–167; 3 Larson RA, et al. Br J Haematol. 1992;82:337–346; 4 Vogler WR, Leukemia. 1994;8:1847–1853; 5 Ohno R, et al. Blood. 1994;83:2086–2092. Slide Courtesy of Stefan Faderl

10 Current Common Chemotherapy Combinations: FLAG Fludarabine 30m g/m 2 /d, Ara-C 2 g/m 2 /d 1-5, G-CSF 300 day 1-6 Jackson Br J Haem 2001:112; 127 Group1 N=21Group 2 N=44 Since stopping TX>6 Mo< 6 mo or 1 o Ref Age median48 (18-69)47 (21-74) Cytogenetics F/I/U %19 /24 /10 48%?2 / 61 / 18 19%? CR81%30% Median Survival16 mo3 ml

11 Combinations of Purine Nucleotide Analogs With ARA-C in Patients With Relapsed/Refractory AML StudyN Salvage Regimen Overall CR Rate, % OS and TimeED, % Wierzbowska A, et al CLAG-M5814% at 4 yrs8 Steinmetz HT, et al. 2 36FLAG-IDA5215% at 1 yrs14 Jackson G, et al. 3 83FLAG8150% at 2 yrs18 de la Rubia J, et al. 4 32FLAG-IDA5340% at 1 yrs9 Clavio M, et al. 5 59FLAG/FLANG59NA10 Carella A, et al. 6 41FLAG5620% at 2 yrs7 Wrzesień-Kuśet A et al. 7 58CLAG5042% at 1 yrs17 Pastore D, et al. 8 46FLAG-IDA52NA7 Hänel M, et al. 9 29Mit-FLAG5934% at 1 yrs14 Huhmann I, et al FLAG5058% at 1 yrs5 Camera A, et al FLAD525.8 months12 1 Wierzbowska A, et al. Eur J Haematol. 2008;80:115–126; 2 Steinmetz HT, et al. Ann Hematol. 1999;78: 418–425; 3 Jackson G, et al. Br J Haematol. 2001;112:127–137; 4 de la Rubia J, et al. Leuk Res. 2002;26:725–730; 5 Clavio M, et al. Haematologica. 1996;81:513–520; 6 Carella AM, et al. Leuk Lymphoma. 2001;40:295–303; 7 Wrzesień-Kuśet A, et al. Eur J Haematol. 2003;71:155–162; 8 Pastore D, et al. Ann Hematol. 2003;82:231–235; 9 Hänel M, et al. Onkologie. 2001; 24:356–360; 10 Huhmann IM, et al. Ann Hematol. 1996;73:265–271; 11 Camera A, et al. Ann Hematol. 2009;88:151–158. Slide Courtesy of Stefan Faderl

12 Fludarabine + Ara-C Effective After Mitoxantrone + Etoposide Failure N = 18 Fav = 1, Int = 15 Unfav = 1 (Flt3 ?) Prior CR with 3+7 alone (n=11) or with ME (n=7) Standard HDAC consolidation (most 4 cycles) Treated with – Mitoxantrone 10mg/m 2 & – Etoposide 100mg/m 2 x 5 days CR in 7 (39%) Median survival 4.5 mo, 2 still alive ~ 1 yr McLaughlin Int J Hema 2012:96;

13 Single Agents -Approved Clofarabine Hypomethylating agents Immunomodulatory- Lenalidomide Histone deacetylase inhibitors – Vorinostat Gemtuzumab ozogamicin

14 Hypomethylating agents Decitabine ASH 2009 ASCO 2011 ASH 2010Ganetsky The Ann of Pharmacotherapy 2012;46: page? Azacitidine ? Disappointing

15 10 of 37 Allo SCT relapses from – BU-Cy/Flu Cy +TBI in 4 – 4 sib 2 haplo sib, 4 MUD AML = 4 MDS = 6 Age Time from SCT to relapse: months Relapse = loss of donor chimerism + morphology/cytogenetics Azacitidine 75mg/m2/d x 5 d (n=9) 40mg (n=1) Best BM response = CR in 6, 3 progressed, 1 revert to MDS – 2 CR got DLI, 1 developed cGVHD – 4 CR lost all host chimerism 2 with MRD – 1 relapsed Median survival = 422 Days Median FU of CR = 624 Days 5 of 27 relapses not TX with aza from same period are alive. Hypomethylating agents after HSCT Bolanos-Meade Biol Blood Marrow Transplant 2011;17(5)

16 Clofarabine – Single Agent & Combo Purine analog Inhibits DNA synthesis Phase 1 40 mg/m 2 iv daily x 5 q4 wk. Kantarjian Blood 2003 – Salvage N = 31 CR = 42% StudyNRegimenCR%ORR% Faderl ASH Phase 1/2 CLO 40 mg/m 2 /dx5 + IDAC 1 g/m²/dx Agura ASCO (10 untr) Phase 2 CLO 40 mg/m 2 /d x5 + IDAC 1 g/m²/dx Powell ASH Phase 2 CLO 40 mg/m 2 /dx5 + HDAC 2 g/m 2 /dx Becker ASH Phase 1 CLO mg/m 2 /dx5 + HDAC 2 g/m 2 /dx5 with G-CSF priming (GCLAC) 4961 Faderl EHA Phase 2 (R) CLO 22.5 mg/m 2 /dx5 + IDA 10 mg/m 2 /dx3 CLO 40 mg/m 2 /dx5 + IDAC 1 g/m 2 /dx5 CLO 22.5 mg/m 2 /dx5 + IDA 6x3 + AC 0.75x Table courtesy of Stefan Faderl

17 Clofarabine – Combinations Day Ara-C 1000 mg/m2 over 2hr 4 hrs after Clof Clofarabine 40 mg/m2 over 1 hr Placebo over 1 hr Ara-CClof+ara-CPAra-C + Clofarabine + G-CSF N Age67 (55-82)67 (55-86) Cyto F/I/P %6/53/394/40/496% 54% 40% 30 D Mortality5%16%<0.01 Disease Status1 o RefRel1 o RefRel1 o RefRel % N = 18N =32 CR %>6 mo 60%, < 6 mo 26% ORR23 46 * 49 * <0.0161% Median Survival (Mo) mo Faderl JCO 2012:28; Day Ara-C 2g/m2 4 hrs after Clof Clof mg/m2 GCSF 5μ /kg Becker Br J Haem 2011:155;182-9 or

18 Clofarabine in the Elderly & Infirm Newly DX AML UWCM-001 >70, >60 & poor PS (WHO >2) or with cardiac comorbidity BIOV-121 >64 & unsuitable for intensive Dose: 30mg/m 2 /d over 1 hour days 1-5 Conclusion: Its better than LDAC Burnett JCO 2010: NAge median CRCRi UWCM %5% BIOV %24% Total %16% Fate of CR/CRi Relapse =27 Toxicity =10 Unknown = 5 Median Survival CR= 47 wks CRi = 30 All =19 wks

19 Lenalinomide AML N= 31 ALL = 4, Median age 63 (22-80) – Primary refractory 8 – Relapsed & Refractory to last therapy = 23 – Post SCT n= 8 7 Allo, 1 Auto Unfavorable cytogenetics = 17 Median # prior therapies = 2 (1-4) – First therapy for this relapse n=12 Response – MTD = 50 mg per day – DLT: fatigue – AML CR = 5 (16%) at mg/d Duration mo all with WBC <3500 Cyto complex, -7, tri13 Post Allo, 4 as initial tx, 2 got GVHD and achieved CR. – ALL CR = 0 Blum JCO 2010:28;

20 Can you spice up an old recipe by adding a new ingredient?

21 Adding Imatinib to MEC MTD = 400 mg, N = 39, MTD Primary refractory 32, MTD CR1 duration – <12 mo = 10, MTD – 12-24mo 12, MTD Cytogenetics Fav:1 Int: 27 UnFav;21 ? = 4 Response at MTD : 1 o Ref 43% Relapse 7/7 – Fav & Int 8/9Unfav 33% Response correlated with inhibition of AKT but not ERK phosphorylation Day Imatinib 200/300/400 Mitoxantrone 10 mg/m2 Etoposide 100 mg/m Brandwein Leukemia 2011:25;

22 Pravastatin + IA AML Blast make or eat a lot of cholesterol  resistance Blocking this with a statin reverses chemoresistance in vitro N=37 1 o Ref=7 Relapse #1=11, Rel #2=4 Age Median 55 Cyto Fav = 3% Int = 27% Unfav =70% Day Idarubicin 12 mg/m2/d Pravastatin Ara-C 1.5g/m2/d CI 6547 Doses: 40 …1680 mg/day MTD =1280 DLT= too many pills! New 11/15 73% CytogeneticsExpObsRatio Intermediate Unfavorable482.0 Salvage 9/22 41% StatusExpObsRatio R R All relapsed/Prim ref SWOG Phase III trial stopped early in Nov 2012 for POSITIVE result Kornblau JCO 2007:109;

23 DAC + Gemtuzumab + Ozogamicin Chowdhur y Am J Hema 2009:84; Day Gemtuzumab Ozo 3 mg/m2 Decitabine20 mg/m N = 12 A retrospective study? Age All relapsed with a median 3 prior Tx (1-6) Prior SCT Allo = 6, Auto = 1 CR in 5 (42%) all  SCT, 2 2, 15 mo – Ages , – Cyto : Diploid, Diploid, Tri8, Diploid, T9:11 – # PriorSalvage – CR1 duration? Mild Grade 1 & 2 tansaminitis Survival 4 still alive, median FU 1 yr.

24 Chemo + Gemtuzumab + Ozogamicin Middeldorf Am J Hema 2010:85; N = 23 with CD33+ CR1 duration? Drs choice of chemo, then if CD33+ Drs choice whether to give it a “GO”. CR after chemo & before GO ? GO singleGO  ChemoChemo  GO N3516 Age76 (70-82)62 (43-74)65 (43-76) 1 o Ref /R1 /R>12/1/01 /2 / 29 /5 /2 GO9 mg/m 2 D 1, 209 mg/m 2 D 19 mg/m 2 x1 D5-17 CR001381% Inc 8/9 1 o Ref

25 Vorinostat + IA Does adding Histone deacetylase inhibitor add? – Vorinostat 600 mg t.i.d. Days – Ida 12mg/m 2 /d x 3 Days – ara-C 1.5 g/m 2 /d x 3 or 4 Days (7) N= 75 newly diagnosed median age 52 (19-65) Cytogenetics – 29 diploid – FLT3-ITD =11 Mortality 4% CR = 76% (n=56) including 100% in FLT3 53% in Relapse in 27 OS median all patients =82 weeks FLT3-ITD 91 weeks Toxicity “ no excess” w.r.t. standard IA, Skin 38% Garcia-Manero JCO 2012;30:

26 Single Agents - Experimental Tosedostat mTOR inhibitors Vosaroxin Hypoxia Specific Aptamers Sapacitabine FLT3-inhibitors – Midostaurin – Lestaurtinib – Quizartinib (AC220) – Sorafenib

27 Tosedostat Aminopeptidase inhibitor Synergizes with Bortezomib MTD 120 mg 130 mg D x 28 D DLT – Thrombocytopenia & ALT elevation 51 AML, 41 at MTD, all >60yrs, 7 CR, 7 PR CR duration short days NH3-AA1-AAn….AAy-AAz-COOH NH3-AA1-AAn….AAy-COOH + AAz Proteosome Amino Acid depravation Inc Small peptides UPR ? Apoptosis Lowenberg JCO 2010;28:

28 PI3K/AKT/mTOR Pathway Promotes growth and proliferation Constitutively activated in the majority of AML but not in normal CD34+ cells Important for the survival of AML cells, particularly after genotoxic stress May be required by leukemic stem cells for survival mTOR inhibition causes cell cycle arrest of AML cells and increases the pro- apoptotic effect of chemotherapy HGF, Cytokines PI3K/AKT mTOR 4E-BP1P70S6K Translation Cell cycle progression Proliferation & Survival RAPALOGS FLT3 mTOR inhibition Slide courtesy of Stefan Faderl

29 Trials with AKT/mTOR inhibitors StudyNRegimenResponse Recher Blood (AML) Phase 1 (Sirolimus) S: 6 mg/d1, 2 mg/d2-28 PR 4/9 Perl Clin Cancer Res (AML) Phase 1 (MEC+Sirolimus) * S: MTD 12 mg/d1, 4 mg/d2-7 CR (n=4) =15% +PR (N=2) ORR= 22% Yee ASH (AML/ALL) Phase 2 (Temsirolimus) T: 25 mg weekly Modest activity (PB) Yee Clin Cancer Res various Phase 1/2 (Everolimus) E: 5-10 mg daily Modest activity (PB) Ravandi ASH (AML/MDS) Phase 1 (Triciribine) T: MTD 55 mg/m2 d 1,8,15 Modest activity (PB) Table courtesy of Stefan Faderl * Evidence of synergy with MEC not observed

30 Vosaroxin nee Voreloxin nee SNS-595 Quinolone derivative, intercalates DNA and poisons Topo II Not a P-gp substrate, active in anthra-resistant settings Non cardiotoxic N=67; median age 65y (21-81) 84% AML (78% refract) – Weekly D N= mg/m 2 /wk iv bolus (max 4 cycles) – Twice Weekly D 1, 4, 8, 11 N= mg/m 2 iv bolus (max 4 cycles) DLT: stomatitis (grade 3-4) MTD: Weekly 72 mg/m 2 ; Twice Weekly 40 mg/m 2 Complete remission CR or CRp – Weekly N=4 1) 1° Relapse, 3 refractory Duration mo – Twice Weekly 1 CR refractory suartion 19.2 mo Phase II trial «VALOR» of ara-C +/- V in untreated elderly AML Lancet Leukemia 2011:25;

31 Targeting Tumor Hypoxia: Hypoxia-Selective Cytotoxins Normal marrow is hypoxic 6%, Leukemic Marrow is 1% Agents are converted to toxic moieties only under hypoxia PR104 doses: 1100 (MTD in solid tumors), 1600, 2200, 3000 mg/m 2 Highly refractory population BM Blasts cleared in many CRp =4 CRi=2 Relapse 2  SCT 2, 2 pending Brown Nat Rev Ca 2004;4; Information Courtesy Marina Konopleva Patterson., Clin Can Res 2007

32 Sapacitabine (CS-682) PHASE 1 N=47; median age 65y; 42 R/R AML mg BID x 7d q3-4 wks (N=35) mg BID d1-3, d8-10 q3-4 wks (N=12) DLT: GI MTD 375 mg BID x 7 days; 425 mg BID d1-3, d8-10 ORR: 13/47 (28%): 4 CRs, 2 CRp, 7 CRi – 30-d mortality (4%) Kantarjian et al, JCO 2010 Orally bioavailable (fatty-acid modified) cyanocytosine analog with a unique mechanism of action Converts in vivo to CNDAC, incorporates into DNA, causes SS- DNA breaks, G2 arrest and apoptosis PHASE 2 N= 51 Untreated Median age 77y, 35% ≥80y Median 3 cycles ORR: A 45% (CR 10%); B 25% (CR/CRp 10%); C 35% (CR/CRp 25%) 30-d mortality 8/60 (13%) 400 Mg BID D q 3-4 wk selected for further testing Kantarjian et al, ASH 2009

33 FLT3-ITD Many available inhibitors Specificity of target varies greatly LestaurtinibMidostaurin Quizartinib

34 FLT3 inhibitors As single agents very few CRs – Better at reducing PB than BM blasts Will addition to Chemotherapy improve results ? ALL FLT3 mutChemoChemo + L N112 Age54 (21-79)59 (20-81) CR12%17% CRp9% CR1 <611%19% CR1 >629%32% Survival160D CR1 <6mo MEC + Lestaurtinib 80mg CR1 >6 mo HiDAC + Lestaurtinib 80mg Response correlates with target level inhibition Only 58% got inhibited at D 15 Levis Blood 2011:117; FLT3 MutFLT3 WT Dose N Age>6439%53%77%72% CR0000 PR0100 Heme improvement 50%41%43%26% Midostaurin 50 or 100 mg twice daily Fischer JCO 2010:28;

35 AC : Phase II in AML salvage Cohort>60, CR1 < 1 yr or 1 o Ref>18 Rel/Ref to 2 nd line or HSCT Mutation StatusITD+FLT3-WTITD+FLT3-WT N Age 70 (54-85)69 (60-78)50 (19-77)55 (30-73) CR composite54%32%44% (4% CR)34% (3% CR) PR18%9%24%13% Median CRc duration 12.7 wks22.1 wks11.35 Median Survival Cortes ASH 2012 Abstract # 48 Dose: Females 90 mg Males 135 mg continuously QTc 25 % Grade % 26% Gr % Levis ASH 2012 Abstract # 673

36 Alphabet Soup Trials for Relapsed AML at MDACC Agent MOA PhaseCombo?Group LintuzumabAntiCD33 Ab1+ LD araC> 60yrs OmacetaxineProtein Syn, histoneDAC1+ LD araC> 60yrs Pf Hedgehog1B+ LD araC or DAC> 60yrs SGI-110Super DAC1> 60yrs TosedostatAminopeptidase inhibitorI/IIaraC or AzaPost hypomethylating VosaroxinAnthracyclineIIIAra-C +/- VRelapse1 Plerixifor +G-CSFCXCR4 inhibitorI /II+MECRelapse1 BP L-GRB2 ASISalvage ABT348Aurora KinaseI+ ara-CSalvage AMG 900 Aurora KinaseISalvage KB004Anti EphrinA3ISalvage BKM120PI3K inhibitorISalvage LurbinectedinDs-DNA breaksISalvage CWP232291WNT inhibitorISalvage PRI-724B-Catenin inhibitorI /IISalvage AZD1208PIM Kinase inhibitor1A/!BSalvage DFP-10917Purine analog-SapacitabineI /II MK-8242HDM2 inhibitorI+ ChemoSalvage

37 Conclusions Thus far nothing is better than old fashioned combo chemo – Clofarabine single agent has utility Many fascinating ideas : – Hypoxia, cholesterol blockade, Imatinib – Results of follow up studies required Lots of new agents FLT3 – Many drugs, unimpressive results There is great chaos under (the relapsed AML ) heaven – the situation is excellent (for new ideas and new agents) - Mao Zedong

38

39 Overall Survival Using European Prognostic Index & GOELAMS Breems JCO 2005;23(9): Giles Br J Haem 2006 ;134(1):58-61 They are superimposable GOELAMS

40 Results of Randomized Trials In Patients With Relapsed or Refractory AML StudyTreatmentN 2 nd CR Rate, % Median 2 nd CR Duration, Mo ED, % Median OS, Mo Karanes C, et al. 1 HDAraC vs HDAraC + Mit vs 449 vs 510 vs 168 vs 6 Thomas X, et al. 2 EMA vs EMA + GM-CSF 7281 vs 894 vs 58 vs 59 vs 10 Liu Yin J, et al. 3 ADE +/-CSA vs Seq ADE +/- CSA vs 38NA16 vs 24NA List A, et al. 4 MEC vs MEC + PSC vs 39NA15 vs 18NA Greenberg P, et al. 5 MAE vs MAE + G-CSF vs 179 vs 1010 vs 165 vs 4 Feldmen E, et al. 6 MEC vs MEC + lintuzumab vs 29NA 8 vs 6 Giles FJ, et al. 7 HDAraC vs HDAraC + laromustine vs vs 2752 vs vs Karanes C,et al. Leuk Res.1999;23:787–794; 2 Thomas X,, et al. Leukemia. 1999;13:1214–1220; 3 Liu Yin JA,, et al. Br J Haematol. 2001;113:713–726; 4 List AF, et al. Blood. 2001;98:3212–3220; 5 Greenberg PL, et al. J Clin Oncol. 2004;22:1078–1086; 6Feldman EJ, et al. J Clin Oncol. 2005;23:4110–4116; 7Giles FJ, et al. Blood (ASH Annual Meeting Abstracts). 2006;108:Abstract Slide Courtesy of Stefan Faderl

41 Current Common Chemotherapy Combinations: Clofarabine +AraC N = 30, 18 Relapsed 13 with >1 prior salvage CR1 duration? Age 60 70% Cytogenetics Fav:1 Int: 13 Unfav 14 ? = 2 Many comorbidities – CV history 43% – Karnofsky PS 80 or less in 53% Early death rate = 28% in relapsed/refractory CR=47% Relapsed 5 (27%) 60% first 23% >1 Fav & Int Cyto 5/7 =70%, Unfav 2/9 = 22% Agura The Oncologist 2011;16: Day Clofarabine 40 mg/m2 over 1 hr Ara-C 1000 mg/m2 over 2hr 4 hrs after Clof

42 AC : Phase II in AML salvage Cohort123 Features>60 ITD+ R1 >18 ITD+ R2 or Post SCT >18 ITD- R1 R2 Planned N Analyzed2537 CR00 CRp or CRi9 (41%)15 (48%) PR7 (32%)6 (19% ) Median SurvivalNot Reached24 wks Dose 200 mg If QTc 135 males 90 females Opened 11/ Sites Planned Interim Analysis N=62 2/22/2011 QTc 34% Females > Males

43 AC220 = Quizartinib: Phase 1 in AML salvage N=76; median age 60y; 24% FLT3/ITD+ Dosing (oral solution) – mg once daily x 14d, q4wks (ID regimen) – 200 and 300 mg/d x 28d (CD regimen) MTD 200 mg CD – DLT at 300 mg CD (QTc prolongation) ORR 30%: CR+CRp+CRi 13%, PR 17% – Most cycle; median DOR 14 wks Higher ORR in FLT3/ITD+ (56% vs 20%) Phase 2 study in FLT3/ITD+ AML (advanced) ongoing Phase 1 combo trials planned Cortes et al, ASH 2009

44 Nucleolin targeting Aptamer AS HDAC Aptamers are “chemical antibodies” bind with specificity. AS1411 binds Nucleolin on cell surface  apoptosis Phase II trial N =71 Relapsed/refractory up to 3 prior TX – HDAC 1.5g/m2 q 12 hr x 8 doses Days 4-7 Alone N=23 – With AS mg CI Days 1-7 N= 22 – or with AS141140mg/kg.d CI Days 1-7 N=26 Stuart ASCO Proceedings 2009 #7019 HDACHDAC +10HDAC+40 Evaluable14219 Early Death211 “Response”0/133/19 4/7 Why no update in 3 years?


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