First Clinical Trial Day: Update on AML and CML trials. Barbara De Moerloose Brussels, June 20 th 2014

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1 First Clinical Trial Day: Update on AML and CML trials Barbara De Moerloose Brussels, June 20 th 2014

2 Update on CML trials I-CML-Ped Study StopImaPed Study Nilotinib Phase 2 Study Guidelines for the management of CML in children and adolescents (by I-BFM CML committee) de la Fuente J, et al. Br J Haematol 2014, in press

3 Update on CML trials I-CML-Ped Study StopImaPed Study Nilotinib Phase 2 Study Guidelines for the management of CML in children and adolescents (by I-BFM CML committee) de la Fuente J, et al. Br J Haematol 2014, in press

4 I-CML-Ped study International registry of CML treatment and outcome in children and adolescents Aim = to register newly diagnosed CML cases (since 2000) < 18y, whatever the disease phase, whatever treatment Clinical Investigation Center (Poitiers) Support by grant from Novartis Status in Belgium: Participation of all BSPHO sites Resubmission to ethical boards planned

5 I-CML-Ped study February 2014: 283 pts (161 boys, 122 girls) Median age 11,6 y [10 mo 17 y] Chronic/accelerated/blastic phase: 92/7/1% Clinical and biological data at diagnosis, preliminary results regarding response and outcome ASH meeting 2012 WBC count higher than adults Sokal score: 51% high risk Symptoms: asthenia 34%, fever 23%, weight loss 22%, splenomegaly more frequent than in adults

6 Update on CML trials I-CML-Ped Study StopImaPed Study Nilotinib Phase 2 Study Guidelines for the management of CML in children and adolescents (by I-BFM CML committee) de la Fuente J, et al. Br J Haematol 2014, in press

7 StopImaPed study An international collaborative study to discontinue Imatinib/Glivec in pediatric CML patients with sustained complete molecular response I-BFM CML committee & DCOG Open in The Netherlands Will be opened in 2014 in France and Germany Belgium: in preparation

8 StopImaPed study

9 StopImaPed study Monitoring PCR t(9;22) Every month (1st year after stop) Every 2 nd month (2 nd year after stop) Every 3 rd month (3 rd year after stop) RIZIV/INAMI reimbursement of PCR t(9;22) = max. 4x/y (art 33 bis: 117,32 euro) Cost for daily Glivec 300 mg = 58,11 euro 28 days of Glivec = 1.627,08 euro

10 Update on CML trials I-CML-Ped Study StopImaPed Study Nilotinib Phase 2 Study Guidelines for the management of CML in children and adolescents (by I-BFM CML committee) de la Fuente J, et al. Br J Haematol 2014, in press

11 ITCC trials in CML Dasatinib 226 study (phase II, BMS) Imatinib-resistant CML: closed Relapsed/refractory Ph+ ALL: closed Newly diagnosed CML: open (not in Belgium) Nilotinib phase I (Novartis): PK-study in pediatric Ph+ leukemias <10y: open (not in Belgium) >10y: closed Nilotinib phase II (Novartis)

12 ITCC trials in CML Nilotinib phase II (Novartis) = Protocol no. CAMN107A2203 to evaluate efficacy and safety of oral nilotinib (Tasigna ) in pediatric patients with newly diagnosed Ph+ CML in chronic phase or with Ph+ CML in chronic or accelerated phase resistant or intolerant to either imatinib or dasatinib 1-18y (dose <10y to be confirmed?) 230 mg/m² po, twice daily, max 400 mg/d for up to 24 cycles (1 cycle = 28d) Open in UZGent

13 Update on AML trials DB AML-01 NOPHO-DBH AML 2012 Pediatric relapsed AML 2010/01 (APL, ML-DS) New compounds: Volasertib Dacogen Vidaza

14 Update on AML trials DB AML-01 NOPHO-DBH AML 2012 Pediatric relapsed AML 2010/01 (APL, ML-DS) New compounds: Volasertib Dacogen Vidaza

15 DB-AML 01 AIET BM D15 AM after recovery FLA-Dx immediately And t(8;21), but not immediately CR Blasts 5% HA 2 E + HA 3 + HA 2 E Total cumulative dosages: Anthracyclins: 330 mg/m 2 (conv 5) Ara-C: 43.3 gr/m 2 Etoposide: 1200 mg/m 2 Blasts >5%; off protocol: eligible for relapse study

16 DB-AML 01

17 DB-AML 01 Recruitment: Netherlands: 03/02/ /12/2013 Belgium: 01/05/ /03/2014 Protocol patients: Netherlands: 72 patients Belgium: 42 patients Database cleaning Belgium (17/03/14) Netherlands (10-11/06/14) No final analysis yet } 114

18 DB-AML Belgian patients 7 patients with t(8;21) Sites involved: HUDERF: 4 UCL: 10 UZ Brussel: 1 UZ Gent: 19 1(MPAL) = 18 UZ Leuven: 11-2 (MPAL, 2 nd AML) = 9

19 DB-AML 01 No SUSARs 24 SAE reports (part 1): 5 before/at start of AIET 2 congenital leukemia, fatal 3 pulmonary leucostasis; respiratory failure 7 during or after AIET 1 sudden death (unexplained) 1 painful erythema (hand-foot) 5 sepsis/infection (1 fatal due to pulm bleeding)

20 DB-AML SAE reports (part 2): 8 after FLA-Dx 7 infectious (aspergillus, strep, staph, unknown) incl 1 pseudomonas typhlitis, fatal 1 neurologic: ataxia and muscle weakness lower limbs 4 unspecified timing 1 bleeding after BAL 1 somnolence after anesthesia 2 infection

21 DB AML-01: Interim analysis November 2013

22 NOPHO AML 2004

23 NOPHO AML 2004

24 NOPHO AML 2004 Flow cytometric MRD detection after induction

25 NOPHO AML 2004: t(8;21) EFS t(8;21) - t(8;21) +

26 NOPHO AML 2004: t(8;21) EFS in t(8;21)

27 Update on AML trials DB AML-01 NOPHO-DBH AML 2012 Pediatric relapsed AML 2010/01 (APL, ML-DS) New compounds: Volasertib Dacogen Vidaza

28 NOPHO DBH-AML 2012 a collaborative research study NOPHO Hong Kong BSPHO DCOG

29 NOPHO-DBH AML 2012 Approved by FAGG 23/12/2013 Ethical Board 11/04/ participating sites HUDERF UCL UZ Brussel UZ Gent UZ Leuven

30 NOPHO-DBH AML 2012 Inclusion criteria: Primary AML, age <19y, informed consent Exclusion criteria: Secondary AML, MDS, JMML, APL Down syndrome, Fanconi anemia Known intolerance to protocol chemo Major organ failure Pregancy, lactating female

31 NOPHO-DBH AML2012 Overview MEC R1 BM d22* R2 ADxE BM** CR Inv(16) and SR HA 3 E FLA HAM HA3E FLA DxEC FLADx No CR SCT for HR Daunoxome vs mitoxantrone HD AraC vs LD AraC Salvage therapy CR, EFS, OS Toxicity MRD (flow) 31

32 1st induction standard arm: MEC Cytarabine 200 mg/m 2 12h ci iv Day 6-12 MEC Mitoxantrone 5 mg/m 2 iv Day 6-10 Inf 1 hour Etoposide 150 mg/m 2 iv Day 1-5 Inf 2 hours Mtx it* Mtx it age-adjusted <1y 6 mg 1-<2y 8 mg 2-<3y 10 mg 3y 12 mg Day Children < 1y or < 10kg Cytarabine 6.7 mg/kg Etoposide 5 mg/kg Mitoxantrone 0.17 mg/kg 32

33 1st induction experimental arm: DxEC Cytarabine 200 mg/m 2 12h ci iv Day 6-12 Daunoxome 60 mg/m 2 iv Day 6, 8 and 10 Inf 1 hours Etoposide 150 mg/m 2 iv Day 1-5 Inf 2 hours Mtx it* Mtx it age-adjusted <1y 6 mg 1-<2y 8 mg 2-<3y 10 mg 3y 12 mg DxEC Day Children < 1y or < 10kg Cytarabine 6.7 mg/kg Etoposide 5 mg/kg Daunoxome 2 mg/kg 33

34 Treatment flow course 1 Randomize MEC/DxEC Randomise FLADx study Give course 2 direct Treatment response day 22 Yes 5% MRD flow day 22 Informative? Yes < 5% No Randomise FLADx study Give course 2 after regeneration Weekly bone marrow controls Yes 5% BM morphology result day 22 Yes < 5% Register BM results on day 22 in all patients Register also BM results from last sample before course 2 in those who wait

35 2nd induction standard arm: ADxE Cytarabine 100 mg/m 2 ci Day 1,2 Cytarabine 100 mg/m 2 iv Day 3-8, 30 min inf, every 12h Daunoxome 60 mg/m 2 iv Day 2,4,6 1 hour inf Etoposide 150 mg/m 2 iv Day 6,7,8 2 hour Mtx it Mtx it age-adjusted <1y 6 mg 1-<2y 8 mg 2-<3y 10 mg 3y 12 mg ADxE Day Children < 1y or < 10kg Cytarabine 3.3 mg/kg Etoposide 5 mg/kg Daunoxome 2 mg/kg 35

36 2nd induction experimental arm: FLADx Fludarabine 30 mg/m 2 iv (30min) Day 1-5 Cytarabine 2000 mg/m 2 inf (3h) Day 1-5 4h after fludarabine FLADx Daunoxome 60 mg/m 2 iv inf (1h) Day 2,4,6 immediately after fludarabine Mtx it Mtx it age-adjusted <1y 6 mg 1-<2y 8 mg 2-<3y 10 mg 3y 12 mg Day Children < 1y or < 10kg Cytarabine 67 mg/kg Fludarabine 1 mg/kg Daunoxome 2 mg/kg 36

37 Treatment flow course 2 Course 2 direct Course 2 after regeneration Response day 22 Informative flow? Yes < 5% No Wait for regeneration Weekly bone marrow controls Last BM before regeneration used for risk group strat BM blasts 5% No Yes 5% Yes Resistant disease Salvage therapy BM evaluation immediately prior to consolidation (HAM) Yes 5% Register last BM results in all patients and BM results from day22 when applicable Informative flow? Yes < 5% Consolidation If 0.1% HR Yes 5% Beware that patients with Inv(16) that are SR Should receive HA3E as first consolidation Therefore MRD after course 2 must be known before starting consolidation No BM blasts 5% No Consolidation SR if not FLT3-ITD

38 Riskgrouping AML2012 High risk Poor response after 1 st course ( 15% leukemic cells) and < 5% after course 2 0.1% leukemic cells after the 2 nd block FLT3-ITD without NPM1 mutation Resistant disease 5 % leukemic cells after course 2 Standardrisk All others

39 AML2012 Overview MEC R1 BM d22* R2 ADxE BM** CR Inv(16) and SR HA 3 E FLA HAM HA3E FLA DxEC FLADx No CR SCT for HR Salvage therapy *Response evaluation on day 22 after first course with flow 5% leukemic cells start second course directly. Repeat BM weekly until regeneration **Response evaluation after second course with flow 5% leukemic cells remission failure HR 15% leukemic cells after course % leukemic cells after course 2 FLT3-ITD without NPM1 mutation

40 Anthracycline cumulative dose Grupp Dauno Mitox Ida AMSA Equivalents NewEq AIEOP BFM 2004 SR BFM 2004 HR BFM LAME MRC CCG St Jude NOPHO NOPHO2012 A NOPHO2012 B AML AML05 Japan AML05 LR Conversion factor COG Daunorubicin/DaunoXome 0.83 Mitoxantrone 4 Idarubicin 5 Amsacrine 0

41 NOPHO AML 2012

42 NOPHO AML 2012

43 NOPHO AML 2012

44 NOPHO AML 2012

45 NOPHO AML 2012

46 Update on AML trials DB AML-01 NOPHO-DBH AML 2012 Pediatric relapsed AML 2010/01 (APL, ML-DS) New compounds: Volasertib Dacogen Vidaza

47 Pediatric Relapsed AML 2010/01

48 Pediatric Relapsed AML 2010/01 Status in Belgium: Approved by FAGG on 15/10/2013 Approved by ethical board on 14/10/2013 Participating sites: HUDERF, CHC Espérance, UCL, UZ Brussel, UZ Leuven & UZ Gent Not open yet (Labels of Mylotarg vials are lacking (Pfizer)) Marvin database Initiation in the near future?

49 Update on AML trials DB AML-01 NOPHO-DBH AML 2012 Pediatric relapsed AML 2010/01 (APL, ML-DS) New compounds: Volasertib Dacogen Vidaza

50 Volasertib trial ( ) Inhibitor of PLK1 (polo-like kinase 1): Associates with mitotic spindle poles in early mitosis Trigger for G2/M transition Proto-oncogene Phase I, Boehringer-Ingelheim 2-18y Relapsed/refractory leukemia and solid tumors (extracranial) Open in UZGent

51 Volasertib trial ( )

52 Volasertib trial ( )

53 Update on AML trials DB AML-01 NOPHO-DBH AML 2012 Pediatric relapsed AML 2010/01 (APL, ML-DS) New compounds: Volasertib Dacogen Vidaza

54 Hypomethylating agents 1)Azacytidine (Vidaza ) 2)5-aza-2 -deoxycytidine Decitabine (Dacogen )

55 Dacogen trial (Janssen) 27 sites selected; 2 patients recruited so far (UK, DK); TIV UZGent planned

56 Dacogen trial Days 1-5 decitabine Days 8-12 cytarabine = sequential therapy New cycles starting at least 28 days apart Phase 1: Decitabine 20 mg/m 2 /dose IV (1 hour) Cytarabine ( 2.000) ( 1.500) mg/m 2 /dose IV (4 hours) Phase 2: Decitabine 20 mg/m 2 /dose (1 hour) Cytarabine maximum tolerated dose from phase 1 (4 hours) Up to 4 cycles of sequential therapy continuation phase (decitabine but no cytarabine) ITCC-044 Dacogen followed by cytarabine for refractory or relapsed AML 56

57

58 Vidaza trial: Celgene proposal

59 Vidaza trial (Celgene) CBF + NPM 1 + Flt3 ITD + MLL Molecular relapsed AML ( 1 log), after CR1 (PB follow up after frontline treatment) Phase 1 (safety run-in): 100 mg/m2 IV on days 1-7 of the 28 day cycle in 6 patients Phase 2: 68 pts, watch & wait versus up 3 cycles of Vidaza MRD level before HSCT < 10-3 No sites selected yet

60 Update on AML trials DB AML-01 NOPHO-DBH AML 2012 Pediatric relapsed AML 2010/01 (APL, ML-DS) New compounds: Volasertib Dacogen Vidaza