2 Workshop Nazionale SIES Ematologia Traslazionale Nuovi Farmaci e Strategie Terapeutiche nelle LMA

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1 2 Workshop Nazionale SIES Ematologia Traslazionale Nuovi Farmaci e Strategie Terapeutiche nelle LMA Adriano Venditti Ematologia Universita Tor Vergata, Roma

2 Current Treatment Results in AML AGE, y CR% ED% DFS%(3-5 yr) OS%(3-5 yr) < >

3 AML: main areas of focus Stem cell transplantation Pool of potential patients has expanded New therapeutic strategies Optimal use of old drugs New formulation of old drugs New agents Targeted-therapy LSC therapy

4 Optimal use of old drugs Daunorubicin dose intensification STUDY FHCRC 1 DAUNO DOSE 70 mg/m 2 CR% Dauno mg/m 2 never 80 compared ALFA 2 to 80 mg/m higher 2 dose 76 CALGB mg/m Appelbaum, Ann Int Med, Castaigne Blood, Kolitz Blood, 1998

5 ECOG Protocol E1900: Dose Intensification in Induction and GO pre AuSCT Cytarabine DNR 45 mg/m 2 x 3 High-risk AlloSCT CR AuSCT Cytarabine DNR 90 mg/m2 x 3 HiDAC x 2 HPSC after 2 course Mylotarg 6 mg/m 2

6 Optimal use of old drugs Daunorubicin dose intensification A randomized trial of anthracycline dose intensification during induction of younger patients with AML: results of ECOG study E1900 SDD HDD P CR% ID% 48 5 n.s. OS (months) Fernandez et al, ASCO 2009, abstract no. 7003

7 New formulation of old drugs CP-4055cytarabine 5 -elaidic acid ester Lipid Vector Elaidic acid ARA-c

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9 CP-4055 (ELACYT) in hematologic malignancies Phase I dose-finding study 66 pts (57 AML, 1 MDS, 1 BAL, 3 ALL, 2 CML- BP, 2 CMML) Starting dose 200 mg/m 2, D 1-5, q3w schedule 2000 mg/m2 reccommended MTD determined at 2500 mg/m 2 All DLT reversible dose for phase II Nausea, diarrhea, fever, thrombocytopenia, elevation of LFTs Responses seen at doses mg/m 2 1 CR, 1 CRp, 2 PR 10 pts with stable disease 1 pt referred to SCT

10 A PHASE II STUDY WITH CP-4055 AS SECOND SALVAGE THERAPY IN PATIENTS WITH AML 40 pts with refractory/relapsed and 2 previous CHT regimens 2000 mg/m 2, D 1-5, q3w schedule Grade 3/4 adverse events Myelosuppression, nausea, diarrhea, fever, fatigue Responses seen in 6 cases (15%) 4 CR, 2 CRp, Median OS 88 days (8-88) EHA, Berlin 2009

11 New Agents AML-14A Clofarabine in combination with a standard remission induction regimen (AraC and Idarubicin) in patients years old with untreated intermediate and poor risk AML or high risk MDS EORTC/GIMEMA

12 New Agents AML-14A Phase 1-2 Untreated AML (HR-MDS) Age 18-60y All cytogenetic groups (except favorable with WBC < 100K) Clofarabine + Ida/Ara-c Clo (iv push) Clo (1 hr inf) Primary E-P MTD (phase I) Efficacy (phase II)

13 NEW Agents AML-1107 Phase 2, open-label, multicenter study Target: patients age >60 with AML in 1st relapse or refractory to 1 induction attempt Objective: to determine the efficacy and toxicity of the combination Clofarabine+Temsirolimus (1 or 2 courses) Primary EP: rate of response (CR+CRi) Status: ongoing Enrolment: 54 patients (first stage 19)

14 New Agents CloTor regimen Induction (1 or 2 courses) Torisel 25 mg (flat dose) iv over 30 min, on day 1, 8, 15 Clofarabine 20 mg/m 2, iv over 1-hr, on days 1 to 5 Maintenance (monthly courses x 12) Torisel 25 mg (flat dose) iv over 30 min, on day 1, 8 Primary E-P: rate of CR/CRi Secondary E-P: DFS, OS, toxicity

15 New Agents Amonafide (Xanafide) "Non-Classical" Topo-2 inhibitor Unique mechanism of action Inhibits Topo-2 binding to DNA ATP-independent Not cross-resistant with classical Topo-2 inhib. Not a substrate for Pgp mediated efflux

16 AMONAFIDE: A TOPO II INHIBITOR WITH NOVEL PHARMACOLOGICAL PROPERTIES AND UNIQUE ACTIVITY FOR THE TREATMENT OF SEC. AML (Capizzi et al, #890) Combination of amonafide (600mg/m2/day1-5 and Ara-C, 200 mg/m2/day 1-7 c.i.) 88 saml patients Median age 63 yrs (range 23-87); Prior MDS: 45.5%; t-aml: 54.5%; Unfavorable cytogenetics: 47%.

17 Amonafide: Results Median CR duration : 10 mos. CCR at 12 mos: 44% Death within 28 days: 20% Marrow recovery: 1 mo. 6% moderate diarrhea and skin rash

18 Phase 3 trial in saml Secondary AML: Previously untreated Prior MDS (documented) Prior exposure to leukemogen Stratified: Age < 60, 60 Type of saml Prior therapy for MDS Cytogenetics Amonafide (d1-5) + ara-c (CI d1-7) vs Daunorubicin (d1-3) + ara-c (CI d1-7) Post-remission therapy: - BMT if eligible - Otherwise 3 courses ara-c < 60, HiDAC > 60, ara-c 1 gm/m 2 Primary Endpoint: Confirmed CR rate (CR + CRi) Secondary Endpoints: Duration CR and Overall Survival, Safety, PK Cytology, cytogenetics and P-gp status are centrally performed or reviewed 18

19 New Agents A randomized phase II study of sapacitabine, an oral nucleoside analogue, in elderly patients with AML, previously untreated or infirst relapse or previously treated MDs (Garcia- Manero et al, #7021, ASCO 2009) Sapacitabine induces single-strand DNA breaks and G2 cell-cycle arrest 60 AML ( 70 yrs) and 13 MDS ( 60 yrs) 3 dosing regimens 200 mg bid x 7 days, every 4 weeks 300 mg bid x 7 days, every 4 weeks 400 mg bid x 3 days per week, every 4 weeks ORR is 31% ( 13% CR/CRp, 5% PR, 13% HI)

20 Targeted Therapy MRC AML 15 Trial Course 1 Course 2 Course 3 Course 4 Course 5 ADE ± GO R I S K ADE MACE ± GO MidAc Stop therapy R DA 3+10 ± GO FLAG-Ida ± GO A S S E S S M E N T DA 3+8 FLAG-Ida Ara-C 1.5g/m2 ± GO AraC 3g/m2 ± GO Ara-C 1.5g/m2 Ara-C 3g/m2 R AraC 1.0g/m 2 Burnett AK et al. ASH Abs13

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23 AML-19 AML-19 GO monotherapy versus best supportive care for previously untreated AML in older patients not considered fit for intensive chemotherapy EORTC and GIMEMA

24 AML-19 Sequential phase 2-3 Target: patients not considered fit for intensive chemotherapy Age >75 years OR Age years with a WHO PS >2, OR unwilling to receive intensive chemotherapy Phase 2: completed Phase 3: ongoing

25 Phase 2 outline Control Arm BSC ± palliative HU Rand Condensed GO 6 mg/m 2, d 1 GO 3 mg/m 2, d 8 Fractionated GO 3 mg/m 2 d 1, 3, 5 Day 36 CR/CRp/PR/SD CR/CRp/PR/SD Day 50 Continuation GO 2 mg/m 2 q4 wks x 8

26 Phase 3 outline (target accrual 184 pts; primary EP: OS) Rand Control Arm BSC ± palliative HU Best GO Arm GO 6 mg/m 2 d 1 GO 3 mg/m 2 d 8 Day 36 CR/CRp/PR/NC Day 50 Continuation GO 2 mg/m 2 q4 wks x 8

27 HOVON-SAKK AML-43 Protocol AML/RAEB-t CYCLE 1 CYCLE 2 Post-Remission ARA-c 200 mg/m 2 x 7 DNR 45 mg/m 2 x 3 ARA-c 1 gr/m 2 x 12 No therapy R R ARA-c 200 mg/m2 x 7 DNR 90 mg/m2 x 3 ARA-c 1 gr/m 2 x 12 Mylotarg 6 mg/m 2 q 4 wks x 3

28 SWOG Trial ARA-c + DNR + Mylotarg 6 mg/m 2 d 4 No therapy High High High R Dose ARA-c Dose ARA-c Dose ARA-c ARA-c + DNR Mylotarg x 3

29 ECOG Protocol E1900: Dose Intensification in Induction and GO pre AuSCT Cytarabine DNR 45 mg/m 2 x 3 High-risk AlloSCT CR AuSCT Cytarabine DNR 90 mg/m2 x 3 HiDAC x 2 HPSC after 2 course Mylotarg 6 mg/m 2

30 Targeted Therapy Direct inhibitors of FLT3 Compound Chemical class FLT3 IC 50 Other targets Clinical stage AG1295 Quinoxaline 1000nM PDGFR, KIT Lab only AG1296 Quinoxaline 1000nM PDGFR, KIT Lab only AGL2033 Quinoxaline 700nM PDGFR, KIT Lab only SU5416 (Sexamanib) 3-substituted indolinone 100nM KIT, VEGFR Phase 2 SU substituted indolinone 10nM KIT, FMS Lab only SU11248 (Sunitinib) 3-substituted indolinone 50nM KIT, PDGFR, VEGFR Phase 1 PKC412 (Midostaurin) Staurosporine 10nM PDGFR, KIT Phase 3 CEP701 (Lestaurtinib) Indolocarbazole 3nM TrkA Phase 3 MLN-518 (Tandutinib) Piperazinyl quinazoline 30nM KIT, PDGFR Phase 2 CHIR-258 Benzimidazole quinoline 1nM KIT, FMS, VEGFR, FGFR Phase 1 BAY (Sorafenib) Bi-aryl urea <50nM B-RAF, PDGFR, VEGFR Lab only ABT-869 Urea derivative 4nM KIT, KDR, PDGFR Phase 1 Ki23819 Quinoline-urea 10nM n/a Lab only KW-2449 n/a 6nM KIT, Aurora kinase Phase 1

31 FLT3 inhibitors: monotherapy trials in AML (summary) PKC412 1, CEP701 2 Single agent, oral administration in advanced AML Generally well tolerated Sustained inhibition of FLT3 phosphorylation Clinical activity seen with all of them 30-50% of patients Clearance of circulating blasts Reduction of marrow blasts less common (a few CRs) Transient responses (weeks to months) Synergism with many cytotoxics when used simultaneously or sequentially 1 Stone et al, Blood 2005; 2 Smith et al, Blood 2004

32 FLT3 inhibitors: combo trials in AML (summary) 1 PKC412 (DA 3+7) newly diagnosed patients (age <60y) regardless of FLT3 status CR rate: 69% FLT3wt, 92% FLT3mut (100% sequential schedule) Toxicity: manageable at 50 mg/bid 2 CEP701 (MEC or HiDAC) Relapsed FLT3mut patients CR rate 58% Good correlation of CRs if FLT3 inhibited >85% and blasts sensitive in vitro 1Stone et al, ASH 2006; 2Levis et al, ASH 2005

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34 Targeted Therapy Direct inhibitors of FLT3 Compound Chemical class FLT3 IC 50 Other targets Clinical stage AG1295 Quinoxaline 1000nM PDGFR, KIT Lab only AG1296 Quinoxaline 1000nM PDGFR, KIT Lab only AGL2033 Quinoxaline 700nM PDGFR, KIT Lab only SU5416 (Sexamanib) 3-substituted indolinone 100nM KIT, VEGFR Phase 2 SU substituted indolinone 10nM KIT, FMS Lab only SU11248 (Sunitinib) 3-substituted indolinone 50nM KIT, PDGFR, VEGFR Phase 1 PKC412 (Midostaurin) Staurosporine 10nM PDGFR, KIT Phase 3 CEP701 (Lestaurtinib) Indolocarbazole 3nM TrkA Phase 3 MLN-518 (Tandutinib) Piperazinyl quinazoline 30nM KIT, PDGFR Phase 2 CHIR-258 Benzimidazole quinoline 1nM KIT, FMS, VEGFR, FGFR Phase 1 BAY (Sorafenib) Bi-aryl urea <50nM B-RAF, PDGFR, VEGFR Phase 1-2 ABT-869 Urea derivative 4nM KIT, KDR, PDGFR Phase 1 Ki23819 Quinoline-urea 10nM n/a Lab only KW-2449 n/a 6nM KIT, Aurora kinase Phase 1

35 Conclusive remarks Standard chemotherapy may have reached its potential A wide range of novel agents is available for phase III clinical trials ( multitargeted therapy ) New strategies should consider combination therapies LSC targeted therapy