AML in 2017: the molecular therapeutic era finally arrives William - - PowerPoint PPT Presentation

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AML in 2017: the molecular therapeutic era finally arrives

William Blum, MD

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William Blum, MD

Beat AML A new trial sponsored by LLS

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Case discussion

• 73 yo male with thrombocytopenia, WBC 2K,

ECOG PS 2, no objective organ dysfunction

• History of Hodgkin Lymphoma
• Autologous PBSCT 5 years prior
• Presented with thrombocytopenia and was found

to have MDS, BMT planned

• Progressed to AML within 4 months
• TP53 mutation detected…

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?

• This patient needs standard induction chemotherapy, to achieve CR

quickly and receive curative alloHCT as soon as possible.

• This patient is going to do horribly with standard chemotherapy, BMT is

a pipe dream, and he should receive investigational therapy.

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International, randomized phase III study Untreated AML>60, Median age 67yrs High dose daunorubicin vs. standard dose

Only 10% of patients received alloHCT in CR1

Lowenberg B, et al. N Engl J Med. 2009;361(13):1235-1248.

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CALGB 100103/BMT CTN 0502 DFS

DFS 41% at 2 yrs DFS 38% in MUD Median follow up: 1,602 days

Devine SM, et al. J Clin Oncol. 2015;33(35):4167-4175.

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CALGB 100103/BMT CTN 0502 DFS

DFS 41% at 2 yrs DFS 38% in MUD Median follow up: 1,602 days

Devine SM, et al. J Clin Oncol. 2015;33(35):4167-4175.

Would we cure more patients if we took a higher proportion to transplant, faster? Or have we already taken the best of the best?

8 Winship Cancer Institute | Emory University

National Cancer Institute. Surveillance, Epidemiology, and End Results. SEER Cancer Statistics Review 1988-2004

Studies based on intensive induction may not accurately reflect realities for all

• lder AML patients

Klepin HD, et al. Oncologist. 2009;14(3):222.232.

INNOVATIVE TRIAL DESIGN FOR AML

THE BEAT AML TRIAL

“ONE DOES NOT FIT ALL”

PIs Byrd, Levine, Druker CoI Blum, Mims, Walker, Stein, Pollyea

10 Winship Cancer Institute | Emory University

BIOLOGY OF AML – COMPLEX AND HETEROGENOUS

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Growing number of gene mutations

• Relatively small number per case
• Significant differences between cases

including in co-mutational patterns

• However some groups of mutations

converge on common mechanisms of transformation (TET/IDH/WT1) Relapse represents more complex mixture of disease

• Presence of pre-existence and/or evolution
• f resistant subsets within single AML

cases Targeting early, untreated disease – potential therapeutic opportunity

Cancer Genome Atlas Research Network, et al. N Engl J Med. 2013;368(22):2059.

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RATIONALE FOR “MASTER TRIAL” CONCEPT IN AML

• Overall intent to yield measurable efficiencies in terms of
• Improving genomic screening of cancer patients for clinical trial entry
• Improved timelines for drug biomarker testing
• Precedent with Lung Map and i-SPY trials
• Multi-arm master protocol
• Each arm independent from one another with consistent eligibility
• Infrastructure facilitates opening new arms faster
• Provide network for junior and senior AML clinical investigators to lead trials
• Window design allows for testing of “large effects”
• Could lead to or support other trials for accelerated approval
• Bring safe and effective treatments to patients FASTER, not in opposition but in concert with getting patients to allo
• Designed to facilitate FDA approval of new drugs

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Outcomes for older AML patients w ho received 7 + 3 chemotherapy in CALGB trials

(excludes patients w ith death < 30 days, excludes CBF)

Mutation Group CR Rate 3-year DFS 3-year OS NPM1 mutated/FLT3 WT 82% 28% 35% CEPBPA Double Mutant 50% 33% 17% IDH1 mutated 60% 15% 19% IDH2 mutated 58% 15% 26% p53 mutated 33% 0% 0% FLT3-ITD positive 63% 8% 14% RAS or PTPN11 mutated 63% 9% 19% TET2 or WT1 mutated 53% 10% 11% EZH2 44% 14% 19% No mutation 63% 18% 16% All patients 57% 13% 15%

Best of the best….

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EXAMPLE CLINICAL TRIAL TIMELINE: PATIENT IDENTIFICATION

Patient Registration Consent Bone Marrow Sample

Genomic Screening < 1 Week (7 days)

Assign Treatment by Marker

Targeted Agent

Novel Agent Alternative therapy

Initiation

• f Trial

VAF>30%

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WHERE ARE WE NOW: CLINICAL SITES AND EXPANSION

Clinical Sites

• Memorial Sloan Kettering
• Oregon Health Sciences
• Ohio State University
• Dana Farber
• Mass General
• UT Southwestern
• Colorado
• Coming soon, Mayo, UChicago, Emory

Expand to at least 15-20 clinical sites by late 2017

• Additional sites will be selected via RFP process

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Initial Prioritization

• 1. CBF alterations
• 2. NPM1 mutation (No FLT3 mutation)
• 3. MLL balanced rearrangement or MLL-PTD
• 4. IDH2 mutations
• 5. IDH1 mutations
• 6. TP53 mutations
• 7. FLT3 mutations
• 8. TET2/WT1 mutations
• 9. DNMT3A mutations

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Beat AML version 1.0

• Now
• Samalizumab (CD200) plus 7+3 in CBF
• Entospletinib plus HMA in MLL-rearranged
• Aza plus AG-221 in IDH2 mutated
• Aza plus BI 836858 in “HMA sensitive” mutations
• Aza plus BI 836858 in marker negative
• Next wave
• Entospletinib plus 7+3 in NPM1 mutated
• FLT3 inhibitors
• IDH1 inhibitors
• BRD4
• Cdk inhibitors
• Many others---novel-novel combos for version 2.0

Targeting CD200 with Samalizumab, in combo with intensive induction chemotherapy in CBF+ AML

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Background

7% of elderly patients have t(8;21) and inv(16)

• 70% CR rate with 7+3 induction therapy
• 5-year DFS 25% and OS 30%

Decreased immune surveillance is a factor in AML

• NK cell function downregulated at baseline in AML (Stringaris et al. 2014)
• T cell recovery after induction with large peak of activated CD4+, CD25+, FOXP3+ T

regulatory cells, higher than in normal subjects (Kanakry et al. 2011)

CD200

• Increased expression associated with decreased activated NK cells, upreg of T regs
• CD200+ AML patients with 2x lower CR, decreased OS (Damiani, Tiribelli et al. 2015)

Stringaris K, et al. Haematologica. 2014; 99(5):836-847. Kanakry CG, et al. Blood. 2011;117(2):608-617.

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Approach

Hypothesis

• Inhibition of CD200 may augment the cytotoxic T-lymphocyte (CTL)

mediated immune response against CD200-expressing tumor cells

Samalizumab is a CD200 binding humanized mAb, blocking interaction of CD200 with CD200R on macrophages

• Samalizumab monotherapy well tolerated in B-cell malignancies

Patients will be given Samalizumab every 3 weeks, in combination with 7+3 and then with high dose cytarabine consolidation for 2 years

• Initial phase 1
• Followed by primary goal of improved 2 year PFS in expansion

N= 27 patients, assuming a true 2- year PFS rate of 70%, this expansion will have 90% power to rule out a PFS rate of <40%

Targeting Syk with entospletinib in combination with conventional therapy

• 1. MLL rearranged, plus HMA
• 2. mNPM1, plus 7+3

OSU 14251---Phase 1b/2 Study of Entospletinib (GS-9973) Monotherapy and in Combination w ith Chemotherapy in Patients w ith Acute Myeloid Leukemia

Alison R. Walker, Bhavana Bhatnagar, A. Mario Marcondes, Julie Di Paolo, Sumithra Vasu, Alice Mims, Rebecca Klisovic, Katherine Walsh, Renee Canning, Gregory K. Behbehani, Ramiro Garzon, James S. Blachly, Amy Johnson, Esteban Abella-Dominicis, John C. Byrd, William Blum

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Spleen Tyrosine Kinase and AML

Constitutive activation of SYK in AML has been observed

• Inhibition induces differentiation in vitro and has anti-leukemic activity in AML

mouse models

SYK has been shown to directly phosphorylate the FLT3 receptor

• FLT3-ITD mutated blasts exhibit increased levels of SYK activation and are

more sensitive to SYK inhibition than FLT3-wild type blasts

• 1. Hahn CK, et al. Cancer Cell. 2009;16(4):281-294. 2. Pussiant A, et al. Cancer Cell. 2014;25(2):226-242.

Phase 1b: Group A Dosing Schema and Subject Population

Group A Dosing Schema Subject Population

• Previously untreated AML
• Patients age > 18 and < 70 years with previously untreated AML
• Patients < 60 years of age must be negative on screening for CBF

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Phase 1b Results

• 11/12 patients enrolled achieved CR
• 9 completed all study treatments

3 discontinued (one due to CNS involvement and two withdrew consent)

• Monotherapy and combo both well tolerated, RP2D determined (400mg BID)
• Of patients evaluable for DLT (N=9), no DLT observed
• At ENTO 200mg BID, 2 of 3 required 2 cycles of induction (all 3 CR)
• At ENTO 400mg, BID 6 of 6 achieved CR after 1 cycle of induction
• Two patients initiated therapy early prior to completing monotherapy
• Based on PK and clinical results, RP2D was 400mg BID

WBC: 0.9 x K/uL; Hgb: 8.8 g/dL; Hct: 25.5%; Plt: 47 K/uL Cytogenetics, t(9;11)(p22;q23)

Progress Notes Date of Service: x/x/20xx 10:50 PM William G Blum, MD HEMATOLOGY - Notes Only CC Transfer for acute leukemia 18yo male, high school junior, with fatigue and headache especially over the last week is transferred from OSH with flow cytometry showing AML. He had BMBx today with results unknown and lumbar puncture (traumatic tap), LDH 1133, other results unknown.

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Overall survival of 1183 AML cases according to cytogenetics

Schoch C, et al. Blood. 2003;102(7):2395-2402).

TWO WEEKS LATER….

• Bone marrow, left posterior iliac crest, biopsy:

Normocellular marrow (85%) with erythroid and megakaryocytic hyperplasia, left-shifted myeloid hypoplasia, and no morphologic or immunophenotypic evidence of residual acute myeloid leukemia; see comment.

• --Comment---

Please correlate with the concurrent cytogenetics studies. The previous material S16-26221 to S16-26683 is noted.

• CBC data and smear review (200 cells):

WBC: 2.4 x K/uL; Hgb: 9.5 g/dL; Hct: 27.9%; Plt: 220 K/uL

• No circulating blasts are seen..

46,XY[20] *****INTERPRETATION***** FISH analysis on this sample was negative for KMT2A rearrangement. This is consistent with cytogenetic remission.

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Figure 1. Emerging Targeted Therapies in MLL and Its New Link with Itgb3/Syk Signaling

Zeisig BB, et al. Cancer Cell. 2013;24(1):5-7. Inhibition of the ITGB3/SYK axis upregulates transcriptional differentiation programs and downregulates LSC programs, leading to the suppression of MLL cell growth.

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Single agent activity in initial study in AML, monotherapy active and w ell tolerated… …Ento in Beat AML

• Window study of Ento (one cycle) followed by AZA in MLL rearranged

AML for patients ineligible (or unwilling) to receive intensive chemo

• Ento plus intensive chemotherapy in NPM1 mutated AML

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Single agent activity in initial study in AML, monotherapy active and w ell tolerated… …Ento in Beat AML

• Window study of Ento (one cycle) followed by AZA in MLL rearranged

AML for patients ineligible (or unwilling) to receive intensive chemo

• Ento plus intensive chemotherapy in NPM1 mutated AML

Simon’s two-stage design with N=27: This modified minimax design has 89% power for our alternative of a 50% CR/CRi rate (rule out <20%, composite response rate at 6 months)

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Single agent activity in initial study in AML, monotherapy active and w ell tolerated… …Ento in Beat AML

• Window study of Ento (one cycle) followed by AZA in MLL rearranged

AML for patients ineligible (or unwilling) to receive intensive chemo

• Ento plus intensive chemotherapy in NPM1 mutated AML

Simon’s two-stage design with N=27: This modified minimax design has 89% power for our alternative of a 50% CR/CRi rate (rule out <20%, composite response rate at 6 months) Phase 1 completed, Phase 2 under design

Targeting IDH1 and IDH2 mutations in

• lder AML patients

(monotherapy data courtesy E Stein)

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Introduction

• Somatic IDH1 and IDH2 mutations result

in accumulation of oncometabolite 2-HG

→epigenetic changes, impaired cellular differentiation

• mIDH identified in multiple solid and

hematologic tumors

• AG-120, AG-221: first-in-class, oral, potent, reversible, selective

inhibitors of mIDH1/2 enzymes (respectively)

• under evaluation in multiple clinical trials as a single agent and in

combinations 2-HG = D-2-hydroxyglutarate; IDH = isocitrate dehydrogenase; mIDH = mutant IDH

mIDH1 mIDH2 % of AML cases ~6–10% ~9–13%

Tumor cell

Mitochondrion αKG IDH2 Isocitrate Citrate Citrate Isocitrate αKG IDH1 mIDH2 mIDH1 NADPH NADPH 2-HG 2-HG 2-HG 2-HG 2-HG Epigenetic changes Impaired cellular differentiation

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Study design

R/R = relapsed or refractory; SCT = stem cell transplant; SOC = standard of care

Patients with mIDH advanced hematologic malignancies Oral Ag-x daily in continuous 28-day cycles R/R AML in 2nd+ relapse, relapse after SCT, refractory to induction or reinduction, or relapse within 1 year Untreated AML not eligible for SOC Other non-AML R/R advanced hematologic malignancies, Other R/R AML

Dose escalation Dose expansion

Single-arm, open-label, phase 1, multicenter studies (separate IDH1/2)

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Clinical activity

CR = complete response; CRi = CR with incomplete neutrophil recovery; CRp = CR with incomplete platelet recovery; PR = partial response; mCR/MLFS (marrow CR/morphologic leukemia-free state) = <5% blasts in bone marrow, no hematologic recovery; SD = stable disease; NE = not evaluable; ORR = overall response rate (CR + CRi + CRp + PR + mCR/MLFS)

Dose escalation mIDH1 R/R AML n=63 mIDH2 R/R AML n=109 CR, (%) 16 20.2 CRi/CRp, (%) 13 6.8 PR, (%) 2 2.8 mCR/MLFS, (%) 3 9.2 SD, (%) 43 53.2 ORR, (%) 33 38.5

Screening 44% blasts Cycle 1 Day 15 3% blasts Cycle 1 Day 28 2% blasts

Patient below achieved CR by end of Cycle 1-IDH1

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Single agent activity in initial studies in AML w ell tolerated… …AG-221 (Enasidenib) in Beat AML

• Window study of AG-221 monotherapy (CR/CRi by 5th cycle) followed

by combo with AZA in mIDH2 AML for patients ineligible (or unwilling) to receive intensive chemo (following phase 1 component)

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Single agent activity in initial studies in AML w ell tolerated… …AG-221 (Enasidenib) in Beat AML

• Window study of AG-221 monotherapy (CR/CRi by 5th cycle) followed

by combo with AZA in mIDH2 AML for patients ineligible (or unwilling) to receive intensive chemo (following phase 1 component)

Simon’s two-stage design with N=27: This modified minimax design has 89% power for our alternative of a 50% CR/CRi rate (rule

• ut <20%) for AG-221 alone

Secondary survival endpoints for patients who proceed to AZA plus AG-221

Can we improve response to HMA by selecting for “HMA- sensitizing” mutations?

• -Novel trials in combo

with a glycoengineered CD33 antibody

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Can w e “target” patients for HMA based

• n molecular data?
• Itzyson, 2011---In MDS/AML (20-30% blasts, N=86), TET2 mutation predicted

for higher response (and was assoc with better cytogenetic risk), RR including HI was 82% vs 45%.

• Bejar, 2014---In MDS (N=213), TET2 loss assoc with AZA sensitivity
• Emadi, 2015---In AML (N=42), IDH1 and IDH2 mutations may predict a

favorable response to HMAs.

• Meldi, 2015---In CMML, 167 differentially methylated regions (DMRs) of DNA

at baseline distinguished decitabine responders from nonresponders using next-generation sequencing. Distinct DNA methylation profiles associated with recurrent somatic mutations in DNMT3A, TET2, ASXL1, and SRSF2.

Itzykson R, et al. Leukemia. 2011;25(7):1147-1152. Bejar R, et al. Blood. 2014;124(17):2705-2712. Emadi A, et al. Am J Hematol. 2015;90(5):E77-79. Meldi K, et al. J Clin Invest. 2015;125(5):1857-1872.

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20 40 60 80 100 5 10 15 20 25 % surface expression time (h) BI 836858 HuM195

• 3
• 2
• 1

1 2 3 4

• 20

20 40 60 80

B I 8 3 6 8 5 8 H u M 195 lo g [m A b ] (n g /m l) % C y to ly s is

ADCC activity on HL60 cells at an E:T ratio of 20:1; peripheral blood mononuclear cells from healthy individuals were used as effectors. Incubation of HL60 cell lines with both antibodies (with anti-IgG ab label) results in decreased CD33 surface exposure over time, indicative of internalization

• f antibody/CD33
• complexes. BI 836858

shows significantly higher CD33 levels over time compared with HuM195.

BI 836858 is a fully human CD33 antibody

• 1. decelerated

internalization

• 2. binds a different

CD33 epitope than nonengineered HuM195

• 3. enhanced ADCC

Slides Courtesy of Sumi Vasu

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HMA plus BI 836858

• We observed higher BI 836858–mediated ADCC at day 28 after start of

HMA treatment compared with pre-Rx in ex vivo studies

• this time point coincided with upregulation of NKG2D ligand(s) in primary

leukemia samples from HMA-treated patients

• LLS study includes separate arms for BI plus AZA
• for “hypomethylating-sensitive” patients (TET2, WT1, IDH1)
• as well as a second arm for OTHER

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HMA plus BI 836858

• We observed higher BI 836858–mediated ADCC at day 28 after start of

HMA treatment compared with pre-Rx in ex vivo studies

• this time point coincided with upregulation of NKG2D ligand(s) in primary

leukemia samples from HMA-treated patients

• LLS study includes separate arms for BI plus AZA
• for “hypomethylating-sensitive” patients (TET2, WT1, IDH1)
• as well as a second arm for OTHER

Simon’s 2-stage design N=44: This design has 90% power to correctly rule out a CR rate <27% if the true rate is 47%.

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HMA plus BI 836858

• We observed higher BI 836858–mediated ADCC at day 28 after start of

HMA treatment compared with pre-Rx in ex vivo studies

• this time point coincided with upregulation of NKG2D ligand(s) in primary

leukemia samples from HMA-treated patients

• LLS study includes separate arms for BI plus AZA
• for “hypomethylating-sensitive” patients (TET2, WT1, IDH1)
• as well as a second arm for OTHER

Simon’s 2-stage design N=44: This design has 90% power to correctly rule out a CR rate <27% if the true rate is 47%. Simon’s 2-stage design N=39 This design has 90% power to correctly rule out a CR rate <19% if the true rate is 39%.

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Initial Prioritization

• 1. CBF alterations
• 2. NPM1 mutation (FLT3 wt)
• 3. MLL rearrangement
• 4. IDH2 mutation
• 5. IDH1 mutation
• 6. TP53 mutation
• 7. FLT3 mutation
• 8. TET2/WT1 mutation
• 9. DNMT3A mutation
• 10. None of the above (or no available trial)

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Initial Prioritization

• 1. CBF alterations--Samalizumab plus intensive chemo
• 2. NPM1 mutation (FLT3wt)--Ento plus intensive chemo
• 3. MLL rearrangement—Ento window followed by HMA
• 4. IDH2 mutation--AG-221 window followed by HMA
• 5. IDH1 mutation—pending
• 6. TP53 mutation—HMA plus Nedd8 inhibitor, HMA plus Ento
• 7. FLT3 mutation—FLT3i plus decitabine, FLT3i plus Bet inhib
• 8. TET2/WT1 mutation--HMA plus CD33
• 9. DNMT3A mutation—HMA plus CD33
• 10. None of the above (or no available trial)—HMA plus CD33

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Initial Prioritization

• 1. CBF alterations--Samalizumab plus intensive chemo
• 2. NPM1 mutation (FLT3wt)--Ento plus intensive chemo
• 3. MLL rearrangement—Ento window followed by HMA
• 4. IDH2 mutation--AG-221 window followed by HMA
• 5. IDH1 mutation—pending
• 6. TP53 mutation—HMA plus Nedd8 inhibitor, HMA plus Ento
• 7. FLT3 mutation—FLT3i plus decitabine, FLT3i plus Bet inhib
• 8. TET2/WT1 mutation--HMA plus CD33
• 9. DNMT3A mutation—HMA plus CD33
• 10. None of the above (or no available trial)—HMA plus CD33

Hopefully version 2.0 will be even more interesting as we convince pharma that this strategy is not just scientifically appealing, but feasible… So far N=70 since October, mainly from 3 sites until Jan 2017 Only 2/70 failures of mutational analysis in 7d to date