Nuovi farmaci nelle sindromi mielodisplastiche

Maria Teresa Voso

Istituto di Ematologia

Padova,  30  Maggio  2014  

Leukemia-free survival

Heterogeneity of MDS IPSS-R

(n=  380  pa5ents)  

GROM

J  Clin  Oncol  2013  

Overall  survival    

Azaci6dine  in  Lower-­‐Risk  MDS  

Silvermann et al, JCO 2002

Lyons et al, JCO 2009

% o

f TI

Oral Azacitidine

  Absorb approximately 11% of given oral dose   Cleared from plasma by 8 hrs   Hydrolysis: cytidine deaminase

  Oral AZA 300 mg x 21 d provides 56% cumulative exposure of SC AZA 7 days

Garcia-Manero et al. JCO 2011

Combination Treatment  

HDACi

Hypomethylating treatment + HDACi

HDAC Inhibitors  

L. Silverman et al. ASH 2013

  Patients with IPSS int-1, -2 and high-risk disease were eligible. Secondary MDS were eligible, AML were excluded.

AZA + Vorinostat (Merck Sharp & Dohme) (NYCC 6898: Phase II)  

AZA SC mg/m2

Vorinostat

PO BD mg

CR

PR HI Stable

Overall

9 n=13

55 1-7

200 3-16 6 2 1 2 69%

10 n=13

75 1-7

300 3-9 1 3 2 5 77%

11 n=14

55 1-7

300 3-9 5 1 5 3 78%

Median duration of response

(mo)

Median Survival (mo)

9 (n=13) 11.4 (4.7-23.9)

18.3 (8.1-27.7)

10 (n=13) 23 (14.1-NR)

37.4 (29.5-NR)

11 (n=14) 24.8 (3.9-29) 16.4 (8.6-NR)

 Grade 3 fatigue occurred during cycle 1, 2 or 3 in cohort 1 (8%), cohort 2 (16%) and cohort 3 (8%). GI toxicity grade 3 (vomiting, diarrhea, dehydration) occurred in 8% of patients in each of the cohorts. There was no suggestion of cumulative toxicity for either fatigue or GI adverse events.   Analysis for the MDS clone at best response demonstrated the persistence of the clone in 45% of patients as marked by cytogenetic or FISH abnormalities, suggesting a modulating rather than cytotoxic effect of the combination on the clone.   Overall RR superior and time to response more rapid than AZA alone   AZA 75 mg/sqm/d + Vorinostat 600 mg is one of the arms in SWOG S1117, currently enrolling patients

L. Silverman et al. ASH 2013

Garcia-Manero et al. ASH 2013

  Mocetinostat (MGCD0103) is an orally available, spectrum-selective, non-hydroxamate HDACinhibitor targeting HDACs 1, 2, 3 and 11.   66 AML and intermediate and high-risk MDS were enrolled in this phase I/II trial.   The objectives were to determine the MTD of mocetinostat when combined with AZA (75 mg/m2 SC; days 1-7 every 28 days) and to estimate the ORR of this combination.   Mocetinostat was administered 3x/wk starting on Day 5 of treatment with AZA.

Mocetinostat Dosing, n (%)

90 mg 18 (82) 110 mg 3 (14) 135 mg 1 (4)

Mocetinostat (Mirati Ther) + Azacitidine  

Subset analysis: 22 pts 5-20% BM-Blasts Median number of cycles on study: 4.5 (range <1-13). This

included 18 patients initiated at 90 mg mocetinostat (median 4, range <1-13), 3 patients initiated at 110 mg mocetinostat (median 6.5 , range <1-8) and 1 patient initiated at 135 mg mocetinostat (1 cycle).

CR/CRi + PR rate was 13/22 (59%) + 1 HI The CR/CRi + PR rate appeared similar regardless of line of

therapy and the percentage of blasts at baseline (5-9% vs. 10-20%)

CONCLUSIONS   The combination of mocetinostat and AZA is active in patients with MDS,

including patients who were previously treated.   Patients with 5-20% bone marrow blasts at screening obtained 59% CR/CRi+PR

and 33% transfusion independency.

Garcia-Manero et al. ASH 2013

R. Mawad et al. ASH 2013

Tosedostat + Cytarabine or Decitabine  

Tosedostat  (Cell  Therapeu0cs  Inc)  is  a  novel,  orally  administered  aminopep0dase  inhibitor  that  deprives  tumor  cells  of  the  amino  acid  building  blocks  they  need  for  tumor  cell  survival.    

R. Mawad et al. ASH 2013

TST  at  120  mg  in  combina0on  with  ARA-­‐C  or  DAC  resulted  in  54%  CR/CRi  rate  In  26  older  pts  with  untreated  AML  or  HR-­‐MDS  Although  similar  efficacy  was  seen  with  cytarabine  or  decitabine,  grade  3-­‐4  Febrile  neutropenia  and  infec0ons  were  more  common  with  cytarabine    

SGI-110, a Novel Subcutaneous Hypomethylating Agent Dinucleotide of Decitabine and Deoxyguanosine  

GJ Roboz et al., ASH 2013

  Small volume, pharmaceutically stable subcutaneous (SQ) injection which allows longer half-life and more extended DAC exposure than DAC intravenous infusion.   Randomized Phase 1-2 first-in-human PK/PD-guided, dose-escalation study in patients with relapsed or refractory intermediate or high-risk MDS or AML.   93 patients (74 AML, 19 MDS), median age 70 years (29–86 yrs), 68% male, 87% ECOG PS of 0-1.   Prior regimens: 3 (range, 1–9) and 68% of patients had prior HMT (59% AML, and 100% MDS).   Patients received a median of 2 courses of SGI-110 (range, 1-20).

Pa6ents   Regimen  

44   Daily  x  5  

34   Weekly  x  3  

15   2  x  Weekly  x  3  

LINE-1 demethylation  

  Most potent average LINE-1 demethylation: Dailyx5 regimen   Most prolonged LINE-1 demethylation: Twice Weeklyx3   Least potent demethylation: Weeklyx3 regimen.   No additional demethylation at the 90 mg/m2 dose compared to 60 mg/m2 in all 3 regimens.

GJ Roboz et al., ASH 2013

  Complete remissions were observed in 5 AML patients (2CRs, 1CRp, and 2CRi). Clinical responses (2 mCR and 3 HI-E, 1 HI-N, 1 HI-P) in 6 MDS patients, all of whom had been previously treated with HMA.   All AML responses and both mCR in MDS patients achieved ≥10% LINE-1 demethylation.

Regimen   AE  in  >  10%  of  pa6ents  

Daily  x  5   injection site pain, thrombocytopenia, neutropenia, anemia, fatigue  

Weeklyx3   injection site pain and diarrhea  Twice Weeklyx3  

injection site pain, injection site reaction, fatigue, dizziness, febrile neutropenia, neutropenia, anemia, and thrombocytopenia  

Conclusions: SQ SGI-110 is a potent HMA using all 3 regimens evaluated. All 3 regimens were well tolerated. Clinical responses were observed in heavily pretreated patients, including those with prior HMA exposure.

GJ Roboz et al., ASH 2013

T Cluzeau et al., ASH 2013

  Acadesine (ACA), also known as AICAR or Aica-Riboside is a nucleoside analogue that has been shown to trigger autophagy in AZA resistant cells.

 In vitro effect on the AZA-resistent cell line SKM1-R: 1µM AZA: slight decrease of cell metabolism and moderate increase of PI staining

ACA: robust increase of cell death in AZA-res. cells with maximal effect at 2mM. Induction of cell death by ACA was independent of apoptosis but relied on autophagy induction, as shown by the conversion of LC3-I to LC3-II and an increase of cathepsin B activity, that are respectively early and late markers of autophagy.

Acadesine  

 Ex vivo effect: primary bone marrow cells from AZA-resistant MDS or AML patients (n=12).

 Bonferroni’s Multiple Comparison Test performed in 6 AZA-resistant MDS patients showed significant reduction of cell metabolism between ACA and untreated cells (66% and 78% at 1 and 2 mM of ACA) and between ACA and AZA-treated cells (60% and 72% at 1 and 2mM of ACA,). Identical results were found in 6 AML AZA-resistant AML patients with a significant reduction of cell metabolism between ACA and untreated cells (63% and 81% at 1 and 2mM of ACA) and ACA and AZA-treated cells (56% and 75% at 1 and 2 mM of ACA).

 Induction of cell death by autophagy seems to be the main mechanism by which ACA circumvents AZA resistance in MDS and AML cells. These encouraging results prompted us to initiate a multicenter phase I/II clinical trial with the French MDS Group (GFM) to assess the safety and efficacy of ACA in MDS and AML patients with 20 to 30% of marrow blasts not responding or relapsing after AZA treatment (clinicalTrials.gov identifier: NCT01813838)

Birinapant

Birinapant/TL32711: A bivalent Smac mimetic that

unblocks apoptosis Smac (Second mitochondria-derived activator of caspases)

Targets and antagonizes the Inhibitor of Apoptosis Proteins (cIAP1, cIAP2, ML-IAP, XIAP)

Suppresses NF-kB activation and signaling

Standard  of  Care  Agents  

5-­‐aza  

(n  =  7)   (n  =  4)  

Birinapant  has  single-­‐agent  and  combina0on  ac0vity  with  azaci0dine  in  pa0ent-­‐derived  AML  cells  and  purified  AML  “stem”  cells    

Birinapant  (TL))+  5-­‐AC  ,  48  h  

CI = 0.35 ± 0.02 CI = 0.31 ± 0.02

CI:    “combina0on  index”  where  <1  implies  synergy  AZA:    azaci0dine  

Studies  conducted  in  the  laboratory  of    Michael  Andreeff  (MD  Anderson  Cancer  Center)  

Flow  cytometric  analysis  performed  in  triplicate  Results  expressed  as  mean  ±  standard  error  of  the  mean  

TL  AZA  TL  +  AZA  

TL  AZA  TL  +  AZA  

AZA,   AZA,  

+    AZA,  48  h  

Birinapant  shows  ac0vity  in  pa0ent-­‐derived  AML  samples  with  sparing  of  normal  progenitor  cells  

1932 718 878 990 2093 19560

102030405060708090

100110120

10nM100nM

Patient Sample #

% C

ontr

ol

De  novo  pa0ents  –  990,  2093,  1956  Relapsed  –  1932,  718  Unknown  –  878  

BM43 CD340

102030405060708090

100110120

10nM100nM

Patient Sample #

% C

on

tro

l

Primary  AML  Tumor  Samples   Normal  Bone  Marrow  Samples  

Studies  conducted  in  the  laboratory  of    Mar0n  Carroll  (University  of  Pennsylvania)    

Growth  Inhibi6on  in  14-­‐day  colony  assays  for  pa6ent-­‐derived  AML  and  normal  BM  samples  

birinapant   birinapant  

AML/MDS: Phase 1 Dose Escalation Study

•  Mostly  elderly  relapsed/refractory  pa6ents  (n  =  20),  majority  evolved  from  MDS  •  Birinapant  generally  well-­‐tolerated  in  these  heavily  pre-­‐treated  pa6ents  –  No  hematological  toxici0es  

•  MTD  as  single  agent  –  17mg/m2  bid  3  weeks  out  of  4  •  Birinapant  suppressed  cIAP1  and  inhibited  NF-­‐κB  in  leukemic  blasts  •  Evidence  of  hematological  ac6vity:  –  Decrease  in  circula0ng  AML  blasts  –  Repeated  blast  cell  response  with  repeated  dosing  –  Decrease  from  60%  to  10%  in  BM  blasts  in  one  subject  

•  Pharmacodynamic  data  re:  NF-­‐κB    •   Pa0ents  with  very  low/absent  basal  NF-­‐κB  ac0vity  did  not  show  any  decrease  in  

circula0ng  blast  •  Pa0ents  with  ac0va0on  of  NF-­‐kB  at  baseline    

–  4/7  showed  reduc0on  in  circula0ng  blasts    

ON  01910.Na  (rigoser0b)  -­‐  mul0kinase  inhibitor  

ON  01910.Na  

Mul0kinase  inhibitor  

Polo-­‐like  kinase  1  modulator  

PI3Kab/Akt/ERK  pathway  inhibitor  

Induces  Bim,  inhibits  Mcl-­‐1  ac0va0on  

Reduces  cyclin  D1  levels  

Barr  F  et  al  Nature  Reviews  Molecular  Cell  Biology  2004;  5:  429-­‐441  

Cell-­‐cycle  func0ons  and  localiza0ons  of  Plk1  

  Inhibitor of two important cellular signaling pathways, PI3K and PLK ( Polo-like kinase), both of which are frequently over-active in cancer cells.   PI3K (phosfo-inositide 3 kinase) signaling promotes the growth and survival of cells under stressful conditions, such as under low oxygen levels that are often found in tumors. If the PI3K pathway is over-active, apoptosis of cancer cells is diminished, leading to excessive cellular growth.   By inhibiting the PI3K pathway, rigosertib promotes tumor cell apoptosis. Rigosertib also influences signals along the PI3K pathway, such as those leading to the production of cyclin D1.

RIGOSERTIB

  39 patients with MDS who failed after HMT were enrolled in four phase 1-2 clinical trials of IV rigosertib. Thirty five (88%) had higher risk disease according to the Revised International Prognostic Scoring System.   Median overall survival for this group of 39 patients was 35 weeks. Of 30 evaluable patients with follow-up bone marrow biopsies, 12 (40%) achieved complete (n = 5) or partial (n = 7) bone marrow blast responses. In addition, 15 patients achieved stabilization of bone marrow blasts.

Silvermann et al, Hematol Oncology 2014

VATALANIB

The median age was 70.5 years; 51 % had low risk (International Prognostic Scoring System {IPSS} Low/Intermediate-1) and 32 % had high risk (IPSS Intermediate-2/High) MDS. Hematological improvement was achieved in 7/142 (5 %) patients; all 7 were among the 47 patients able to remain on vatalanib for at least 3 months (hematological improvement achieved in 15 % of these 47 patients). For patients with low risk and high risk MDS, respectively, median progression-free survivals were 15 and 6 months, median times to transformation to AML were 28 and 6 months, and median overall survivals were 36 and 10 months.

A  phase  II  study  of  the  oral  VEGF  receptor  tyrosine  kinase  inhibitor  vatalanib  (PTK787/  ZK222584)  in  myelodysplas6c  syndrome:  Cancer  and  Leukemia  Group  B  study  10105  (Alliance).  

Gupta et al, Invest New Drugs 2013