Therapeutic targets and unmet medical needs in children with acute myeloid leukaemiaTodd M. Cooper, Seattle Children's Hospital

Therapeutic Targets in Pediatric AML: Outline

• Pediatric AML: Historical Perspective• Survival Plateau• Clinical Trial Designs at relapse: Historical Challenges• Incidence of AML in children

• Biology of Childhood AML: Should we treat children as adults?

• Reviewing Targets in Childhood AML

• Opportunities for alignment on pediatric drug development for Phase I/II studies in childhood AML

Our Challenge: Improving Survival for Childhood AML

3

recent plateauin EFS

High-riskStandard risk

Relapse Non-response

De Novo Survival: COG

Relapse Survival: i-BFMRasche et al., Leukemia 2018

De Novo Survival: -BFM

Clinical Trials for Childhood AML in First Relapse

Author group (yrs) n= CR2, % pOS % (yrs)Stahnke BFM (1987-1996) 134 51 21 (5 yrs)Sander BFM (1997-2001) 63 59 23 (5 yrs)Rubnitz St. Jude (1987-2002) 60 69 23 (5 yrs)Webb MRC (1988-1995) 125 69 24 (3 yrs)Wells CCG (1997-2001) 101 77 24 (2 yrs)Gorman TACL (1995-2004) 91 56 29 (5 yrs)Aladjidi LAME (1988-1998) 106 71 33 (5 yrs)Abrahamsson NOPHO (1988-2003) 146 77 34 (5 yrs)Nakayama JPLSG (>2000) 71 50 37 (5 yrs)Kaspers I-BFM-SG (2001-2009) 394 64 38 (4 yrs)Karlsson NOPHO (1993-2012) 208 70 39 (5 yrs)Cooper COG (2016-2018) 38 68 50 (2 yrs)

Courtesy: G. Kaspers

Clinical Trial Development Challenges: Patient Numbers Affect Designs

• Clinical Trial Designs heavily influenced by available patients for study

• Historically, about 50% of children enroll on relapse trials for AML

• De Novo AML: ~900 children enrolled on international trials yearly

• 1st Relapse AML: ~300 annually, about half expected to enroll

• 2nd Relapse AML: ~100-150 annually, about half expected to enroll

• Targeted agents: e.g. FLT3/ITD• ~ 90-115 de novo• ~ 40 in first relapse

Genomic Era Confirms Pediatric AML is Biologically Distinct

Tarlock, Meshinchi, ASH 2016Boulori et al, Nature Medicine 2018

Impact of Gene Fusions on Clinical Outcome

NUP98-KDM5ANUP98-NSD1NUP98-PHF23NUP98-BRWD3NUP98-HMGB3NUP98-HOXA9NUP98-TOP2BNUP98-HOXD13NUP98-PHF23

Bolouri, Nature Medicine 2018

Tim-3

Gal-9

PD-L1PD-1

T cell

IFN-γ

Leukemia Stem Cell

CD123

LSC

Bcl-2

CD44

CD93CD70

Cycling

β-catenin IDO1

CD47

SIRP-α

Macrophage

Phagocytosis

Hyaluronicacid

IL-3

CLL-1 CD33

CAR T cellsADCs, BiTEs

Therapeutic antibodies

CAR T cellsADCs, BiTEs/DARTs

Checkpoint blockade

Therapeutic antibodiesTherapeutic antibodies

venetoclax

Therapeuticantibodies

Therapeuticantibodies

Nucleus

FLT3CAR T cells

BiTEs

Pediatric AML: Relevant Targets

adapted from Tasian, Börnhauser, and Rutella Biomedicines 2018

The most impactful cell lineage target to date: CD33

• Gemtuzumab ozogamicin (GO) in COG AML trials demonstrated minimal increased risk of VOD/SOS and improved DFS in subgroups of patients

• Bright CD33 expression and CC genotype associated with improved DFS

• Despite years of study, no approval for de novo AML in children

• CD33 ADC developed to improve upon this experience abandoned due to toxicities in older patients.

CD33bright

CD33bright

CD33bright

OS

DFS

Landscape of FLT3 inhibitors for pediatric AML

• FDA approval for several in adults• Midostaurin approved for adults• Quizartinib break through designation, fast track for adults• Gilteritinib fast track for adults, approved in adults

• Pediatrics:• De novo (~150/yr)– Gilteritinib in COG Phase III study; Quizartinib – St. Jude

study; Midostaurin – 34 European sites in 14 countries• Relapse: (~40/yr) Quizartinib in international Phase I/II; Gilteritinib in

international Phase I/II; Midostaurin study completed.• Nov 2019: Accelerate Paris: Specific recommendation for

development of FLT3 inhibitors in children

CD123 Directed AgentsProduct Company/Instituti

onPhas

eTrial Status Results

(ORR)Notes

MonoclonalAb

Talacotuzumab Xencor/J&J 3 NCT01632

852 Completed 20%Discontinu

ed (efficacy)

Antibody DrugConjugate

SGN-CD123A Seattle Genetics 1 NCT02848

248 Terminated

IMGN632 ImmunoGen 1 NCT03386513 Recruiting 33%

Protein DrugConjugate

SL-401 StemlineTherapeutics 1/2 NCT02270

463 Recruiting 3 deaths (BPDCN)

Bispecific Antibody

Flotetuzumab MacroGenics 1 NCT02152

956 Recruiting 26%

JNJ-63709178 Genmab/J&J 1 NCT02715

011 Recruiting Hold (x2) /lifted

XmAb14045 Xencor/Novartis 1 NCT02730

312 Hold 23% Hold/2 deaths

CART UCART123

Cellectis(MD Anderson) 1 NCT03190

278 RecruitingHold/lifted

1 death (BPDCN)

MB-102 Mustang Bio (City of Hope) 1 NCT02159

495 Recruiting

CAR123 UPenn 1 NCT03766126 Recruiting

• Expressed in B-ALL, AML, BPDCN, and hairy cell leukemia

• Differentially overexpressed in 93% of AML patients• High CD123 expression

associated with lower CR and OS

• Also present on quiescent leukemic stem cells

• Nov 2019: Accelerate Paris: Addressed CD123 development in children

Prioritization of New Agents in Childhood AMLAgent Target PIP?

IMGN632(Immunogen)

Anti-CD123 ADC Planned

AnetumabRavtansine(Bayer)

Anti-Mesothelin ADC

No

Trametinib(Novartis)

Mek inhibitor Not in AML

Uproleselan E-selectin inhibitor Planned

SNDX-5613(Syndax)

Menin Planned

Flotetuzumab(Macrogenics)

CD123 DART Yes

Venetoclax BCL2 Yes (needs amendment)

CPX-351 Liposomal dauno/araC

Yes

Agent Target PIP?

Ivosidenib(Agios)

IDH1 Yes

Enasidenib(Celgene)

IDH2 Yes

Cusatuzumab(Janssen)

CD70 Planned3/20

AMG-330, AMG-673(Amgen)

CD33 BiTE PlannedQ22020

AMG-427(Amgen)

FLT3 BiTE

TC-210(TCR2)

Mesothelin TCR

Magrolimab(Forty Seven)

CD47 blocking antibody

MGB453(Novartis)

TIM3

IMGN853(Immunogen)

FOLR1-ADC

Opportunities: Clinical Trial Development in Pediatric AML

• Patient numbers limited, lack of good historical controls making efficacy assessments challenging.

• Often competing agents of same class in rare populations. Ex. FLT3 inhibitors

• Align on mechanism for prioritization and development for pediatric specific new agents.

• Early alignment on pediatric new agent prioritization, endpoints, clinical trial designs and development

• LLS Master Trial in development for pediatric acute leukemia: Early international collaboration between academia, industry, regulatory bodies

• Unique opportunity for international alignment

Thank You!