AML in 2017: the molecular therapeutic era finally arrives William Blum, MD 1
Beat AML A new trial sponsored by LLS William Blum, MD 2
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… Winship Cancer Institute | Emory University 3
? • 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. Winship Cancer Institute | Emory University 4
Only 10% of patients received alloHCT in CR1 International, randomized phase III study Untreated AML>60, Median age 67yrs High dose daunorubicin vs. standard dose Lowenberg B, et al. N Engl J Med. 2009;361(13):1235-1248. Winship Cancer Institute | Emory University 5
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. Winship Cancer Institute | Emory University 6
CALGB 100103/BMT CTN 0502 DFS Would we cure more patients if we took a higher proportion to transplant, faster? DFS 41% at 2 yrs Or have we already DFS 38% in MUD taken the best of the best? Median follow up: 1,602 days Devine SM, et al. J Clin Oncol. 2015;33(35):4167-4175. Winship Cancer Institute | Emory University 7
Studies based on intensive induction may not accurately reflect realities for all older AML patients National Cancer Institute. Surveillance, Epidemiology, and End Results. SEER Cancer Statistics Review 1988-2004 Klepin HD, et al. Oncologist. 2009;14(3):222.232. Winship Cancer Institute | Emory University 8
INNOVATIVE TRIAL DESIGN FOR AML THE BEAT AML TRIAL “ONE DOES NOT FIT ALL” PIs Byrd, Levine, Druker CoI Blum, Mims, Walker, Stein, Pollyea
BIOLOGY OF AML – COMPLEX AND HETEROGENOUS 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 of resistant subsets within single AML cases Targeting early, untreated disease – potential therapeutic opportunity 10 Cancer Genome Atlas Research Network, et al. N Engl J Med. 2013;368(22):2059. Winship Cancer Institute | Emory University 10
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 11 Winship Cancer Institute | Emory University 11
Outcomes for older AML patients w ho received 7 + 3 chemotherapy in CALGB trials Best of the best…. (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% Winship Cancer Institute | Emory University 12
EXAMPLE CLINICAL TRIAL TIMELINE: PATIENT IDENTIFICATION VAF>30% Assign Targeted Treatment Initiation by Marker Agent of Trial Bone Patient Genomic Screening Marrow Registration < 1 Week (7 days) Sample Consent Alternative therapy Novel Agent Winship Cancer Institute | Emory University 13
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 14 • Additional sites will be selected via RFP process Winship Cancer Institute | Emory University 14
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 Winship Cancer Institute | Emory University 15
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 Winship Cancer Institute | Emory University 16
Targeting CD200 with Samalizumab, in combo with intensive induction chemotherapy in CBF+ AML
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. Winship Cancer Institute | Emory University 18
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 N= 27 patients, assuming a true 2- CD200 with CD200R on macrophages year PFS rate of 70%, this • Samalizumab monotherapy well tolerated in B-cell malignancies expansion will have 90% power to rule out a PFS rate of <40% 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 Winship Cancer Institute | Emory University 19
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
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. Winship Cancer Institute | Emory University 22
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 23
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 Winship Cancer Institute | Emory University 24
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