Table 1 Therapies targeting apoptosis currently in clinical development

From: Targeting apoptosis in acute myeloid leukaemia

Compound

Drug class/targets

Study in AML

Design

Status

N (AML)

CR/PR

Refs

MDM2 inhibitors

Idasanutlin

MDM2-p53

Phase 1b

Combination with cytarabine

Completed

76

22/75 (29%) CRc

Reis et al

  

Phase 3

Combination with cytarabine

Ongoing

  

NCT02545283

  

Phase 1b/2

Combination with venetoclax

Ongoing

  

NCT02670044

MK-8242

MDM2-p53

Phase 1b

Single agent and combination with cytarabine

Terminated

 

1/24 (4%) CRi, 1/24 (4%) PR

Ravandi et al (2016)

HDM201

MDM2-p53

Phase 1a

Single agent

Ongoing

  

NCT02143635

CGM097

MDM2-p53

No

     
 

SAR405838

MDM2-p53

No

    

BCL2 inhibitors

Obatoclax

pan-BCL2

Phase 1/2

Single agent

Completed

19

0/19, 3 patients had minor marrow response

Schimmer et al (2014)

Navitoclax

BCL2, BCLXL

No

     

Venetoclax

BCL2

Phase 1a

Single agent

Completed

32

6/32 (19%) CR/CRi 6/32 (19%) PR. But short lasting

Konopleva et al (2016)

  

Phase 1b

Combination with azacytidine

Ongoing

29

13/29 (45%) CR, 11 (38%) Cri, 2 (7%) PR (early report)

Pollyea et al (2016)

  

Phase 3

Combination with azacytidine

Ongoing

  

NCT02993523

  

Phase 1b

Combination with low dose cytarabine

Ongoing

   
  

Phase 3

Combination with low dose cytarabine

Ongoing

  

NCT03069352

  

Phase 1b/2

Combination with idasanutlin

Ongoing

  

NCT02670044

  

Combination with cobimetinib (MEK inhibitor)

On-going

  

NCT02670044

 

S055746

BCL2

Phase 1a

Single agent

Ongoing

  

NCT02920541

S64315/MIK665

MCL1

  

Ongoing

  

NCT02979366 NCT02992483

XIAP/IAP inhibitors

AEG35156

XIAP antisense

Phase 1b

Combination with idarubicin and cytarabine

Completed

56

16 CR (29%), 15/32 patients (47%) in the expansion phase

Schimmer et al (2009)

  

Phase 2

Combination with idarubicin and cytarabine

Terminated

50

11/27 with AEG35156 and chemotherapy vs 9/13 with std chemotherapy

Schimmer et al (2011)

LY2181308

Survivin antisense

phase 1b

Combination with idarubicin and cytarabine

Completed

24

4/16 CR among patients treated with LY2181308 combined with chemotherapy

Erba et al (2013)

Debio1143

SMAC mimetic

Phase 1b

Combination with daunorubicin and cytarabine

Completed

29

11/29 CR, 3/29 CRp, 1/29PR

DiPersio et al (2015)

Biniparant

SMAC mimetic

Phase 1a

Single agent

Completed

20

no CR/PR

 
  

Phase 2

Combination with azacytidine

Terminated

NR

ORR 32% for azacytidine alone, 29% for Azacytidine+birinapant. More myelosuppression and fatal AEs in the birinapant arm

Donnellan et al (2016)

  1. Abbreviations: AE=adverse event; AML=acute myeloid leukaemia; BCL2=B-cell lymphoma 2; CR=complete response; IAP=inhibitor of apoptosis proteins; MDM2=mouse double minute 2; PR=partial response; SMAC=second mitochondrial-derived activator of caspases; XIAP= X-linked inhibitor of apoptosis.
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