American Society of Hematology Annual Meeting, San Diego, CA USA, 2 Dec 2018

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Uproleselan (GMI-1271), an E-selectin antagonist, improves efficacy and safety of chemotherapy in R/R and newly diagnosed older patients with AML: final, correlative, and subgroup analyses Daniel J.

1 Uproleselan (GMI-1271), an E-selectin antagonist, improves efficacy and safety of chemotherapy in R/R and newly diagnosed older patients with AML: final, correlative, and subgroup analyses Daniel J. DeAngelo, Brian A. Jonas, Jane L. Liesveld, Dale L. Bixby, Anjali S. Advani, Paula Marlton, Michael E. O Dwyer, William E. Fogler, Curt D. Wolfgang, John L. Magnani, Helen M. Thackray, Pamela S. Becker Dana-Farber Cancer Institute, Boston, MA; UC Davis Comprehensive Cancer Center, Sacramento, CA; U of Rochester School of Medicine and Dentistry, Rochester, NY; University of Michigan, Ann Arbor, MI; Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH; Princess Alexandra Hospital, University of Queensland School of Medicine, Brisbane, Australia; National University of Ireland Galway, Galway, Ireland; GlycoMimetics, Rockville, MD; University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA American Society of Hematology Annual Meeting, San Diego, CA USA, 2 Dec 2018

Uproleselan (GMI-1271), an E-selectin Antagonist, Disrupts the Relationship Between Tumor Cells and Bone Marrow Microenvironment E-selectin Constitutively expressed in the bone marrow

2 Uproleselan (GMI-1271), an E-selectin Antagonist, Disrupts the Relationship Between Tumor Cells and Bone Marrow Microenvironment E-selectin Constitutively expressed in the bone marrow microvasculature Binds to the E-selectin ligands on AML cells Promotes environment-mediated drug resistance (EMDR) of leukemic cell Uproleselan, an E-selectin antagonist Inhibits activation of cancer survival pathways (e.g. NF-KB), disrupting EMDR within bone marrow Prolongs survival over chemotherapy alone in animal models Protects normal HSCs by enhancing quiescence and ability for self-renewal Reduces chemotherapy-associated mucositis

3 Uproleselan in Combination with Chemotherapy Prolongs Survival in AML Tumor Models Clinical course may be predicted by expression of E-selectin ligand (sialyl Le x ) on leukemic blasts Addition of uproleselan to chemotherapy hypothesized to improve clinical outcomes, including survival Treatment Survival (days) % survival (day 120) Saline 33 0 Prolonged Survival Replicated in 4 Separate AML in vivo Models (e.g. syngeneic, xenogeneic and patient blasts) Percent Survival *p=0.03 Uproleselan IP 40 mg/kg bid x 10 days 26 0 AraC/DNR Uproleselan + AraC/DNR > Female NOD SCID mice injected iv with 5x10 6 human tumor cells (n=10-11/group) R x 3 days U937 injection Rx Days Post Tumor Implant Aref S, et al. Hematology 2002, 7(2): Noguchi m, et al. Leuk Res. 2001, 25(10): *Winkler IG et al. Blood 2016, 128:2823. Chien S, et al. Blood 2012;120:4092.

Uproleselan Protects against Chemotherapy-Induced Mucosal Injury 5FU 5FU 0 20 14 days Uproleselan

4 Saline Uproleselan Untreated 5FU-treated F4/80 Macrophage Staining of Murine Small Intestine

4 Uproleselan Protects against Chemotherapy-Induced Mucosal Injury 5FU 5FU days Uproleselan Saline Saline Uproleselan Small Intestine Weight (g) Saline Uproleselan Untreated 5FU-treated F4/80 Macrophage Staining of Murine Small Intestine Blockade of E-selectin significantly reduced intestinal mucositis and therapy-induced weight loss *Winkler et al. Blood. 2014;122:21.

$Study Schema RP2D 10 mg/kg Eligible patients Relapsed/refractory 18 years old Primary refractory AML, 2 prior inductions (one$ organ function *Amended to include up to 3 cycles of consolidation in Phase 2 Eligible patients Newly diagnosed Patients 60

organ function *Amended to include up to 3 cycles of consolidation in Phase 2 Eligible patients Newly diagnosed Patients 60

5 Study Schema RP2D 10 mg/kg Eligible patients Relapsed/refractory 18 years old Primary refractory AML, 2 prior inductions (one with anthracyclines) OR in first or second relapse HSCT was allowed, >4 months prior (no GVHD) Hemodynamically stable/adequate organ function *Amended to include up to 3 cycles of consolidation in Phase 2 Eligible patients Newly diagnosed Patients 60 years with newly diagnosed AML Prior treatment for MDS, CMML was allowed ECOG 0-2 Hemodynamically stable/adequate organ function

6 Demographics Relapsed/Refractory Patients N=66 Age, median (range) 59 (26-84) Refractory, n (%) 22 (33) Relapsed, n (%) 44 (67) Duration of prior remission <6 mos 22 (33) Prior Therapies HSCT 11 (17) 2 Induction Regimens 22 (33) ELN Risk Category Intermediate 11 (17) Adverse 33 (50) Unknown 15 (23) Mutations FLT3-ITD 3 (5) TP53 mutation; del (17p) 4 (6)

7 Grade 3/4 Adverse Events Relapsed/Refractory Patients Total RP2D Adverse Event Type N=66 N=54 Cardiac 6 (9) 5 (9) Colitis 2 (3) 1 (2) GI 7 (11) 4 (7) Hepatic 3 (5) 3 (6) Infectious 50 (76) 39 (72) Bacteraemia 8 (12) 8 (15) Febrile neutropenia 31 (47) 27 (50) Sepsis 12 (18) 8 (15) Oral Mucositis Events Grades 1/2, n (%) 14 (21) 9 (17) Grades 3/4, n (%) 2 (3) 1 (2)

8 Response Data Relapsed/Refractory Patients Relapsed/Refractory Outcomes, n (%) Total (N=66) RP2D (N=54) CR/CRi 26 (39) 22 (41) CR 22 (33) 19 (35) ORR (CR/CRi/MLFS/PR) 32 (48) 27 (50) Mortality, All-Cause 30 days 1 (2) 1 (2) 60 days 6 (9) 5 (9) Outcomes by Subgroup (CR/CRi Rate and %) Primary Refractory 8/22 (36) 5/17 (29) Relapsed (total) 18/44 (41) 17/37 (46) Duration, prior remission <6 mos 5/22 (23) 5/19 (26) Duration, prior remission 12 mos 9/12 (75) 9/12 (75) MRD Rates MRD Negative* (N=16 evaluable) 11 (69) 11 (69) Proceeded to SCT 17 (26) 16 (30) *MRD negative = <10-3 leukemic cells at end of induction by local assessment using multicolor flow, RT-PCR, or NGS

9 Survival Outcomes Relapsed/Refractory Patients Median OS 8.8 mos (95% CI ) 28% censored at last follow-up Median follow up 8.9 mos 1-year OS: For all patients 35% For MRD negative 73% 10 longest survivors ( 16 mos) all had either HSCT or MEC/uproleselan consolidation All were MRD negative # at risk RP2D shown, N=54.

10 Subgroup Outcomes Relapsed/Refractory Patients Primary Refractory Uproleselan with MEC resulted in promising survival outcomes for each subgroup evaluated - Primary refractory disease (N=22) - Median OS 6.7 mos ( ) - Early relapse - Late relapse Primary Refractory

11 Subgroup Outcomes Relapsed/Refractory Patients Primary Refractory Early Relapse Uproleselan with MEC resulted in promising survival outcomes for each subgroup evaluated - Primary refractory disease (N=22) - Median OS 6.7 mos ( ) - Early relapse (<6 mo., N=22) - Median OS 5.1 mos ( ) - Late relapse Primary Refractory Early Relapse

12 Subgroup Outcomes Relapsed/Refractory Patients Primary Refractory Early Relapse Late Relapse Primary Refractory Early Relapse Late Relapse Uproleselan with MEC resulted in promising survival outcomes for each subgroup evaluated - Primary refractory disease (N=22) - Median OS 6.7 mos ( ) - Early relapse (<6 mo., N=22) - Median OS 5.1 mos ( ) - Late relapse (>12 mo., N=12) - Median OS NA (9.6-NA)

13 Subgroup Outcomes Relapsed/Refractory Patients Adverse Uproleselan with MEC resulted in promising survival outcomes for each subgroup evaluated - Adverse risk by ELN (N=39) - Median OS 5.9 mos ( ) - All other Adverse

14 Subgroup Outcomes Relapsed/Refractory Patients Adverse All other Uproleselan with MEC resulted in promising survival outcomes for each subgroup evaluated - Adverse risk by ELN (N=39) - Median OS 5.9 mos ( ) - All other (N=27) - Median OS 11.4 mos (5.8-NA) - p=0.018 by log rank, Kaplan-Meier method Adverse All other

$E-selectin Ligand Detectable on Blasts in All Patients Relapsed/Refractory Relapsed/Refractory Higher E-sel ligand expression on blasts associated with poor prognosis Chien et al, ASH 2018 abstract$

15 E-selectin Ligand Detectable on Blasts in All Patients Relapsed/Refractory Relapsed/Refractory Higher E-sel ligand expression on blasts associated with poor prognosis Chien et al, ASH 2018 abstract #1513 E-sel ligand expression is detected in 100% of the trial population, and the majority of patients have E-sel ligand on >10% of leukemic blasts E-sel ligand expression on blast population correlates with LSC population

16 Overall Survival Based on E-selectin Ligand Expression E-sel-L 10% E-sel-L <10% E-sel-L 10% E-sel-L <10% N=36 Evaluable for E-sel ligand at baseline High expressers (E-sel ligand 10% of LSCs or blasts) have poor prognosis (Chien abstract #1513) Addition of uproleselan to MEC reverses this: high expresser group survives longer than the low expresser group (E-sel ligand <10% of LSCs or blasts) Median OS 12.7 mos (8.3-NA) for High expressers Median OS 5.2 mos ( ) Low expressers p= by log rank, Kaplan- Meier method Data verify E-selectin/ligand as a target in AML

17 Demographics Newly Diagnosed Patients N=25 Age, median (range) 67 (60-79) Newly diagnosed de novo 12 (48) Secondary AML 13 (52) ELN Risk Category Favorable 3 (12) Intermediate 7 (28) Adverse 12 (48) Unknown 3 (12)

18 Grade 3/4 Adverse Events Newly Diagnosed Patients Adverse Event Type N=25 Colitis 3 (12) Infectious 19 (76) Febrile neutropenia 17 (68) Sepsis 4 (16) Pneumonia 3 (12) Respiratory 7 (28) Oral Mucositis Events Grades 1/2, n (%) 5 (20) Grades 3/4, n (%) 0

19 Response Data Newly Diagnosed Patients Newly Diagnosed Outcomes, n (%) N=25 CR/CRi 18 (72) CR 13 (52) ORR (CR/CRi/MLFS/PR) 20 (80) Mortality, All-Cause 30 days 2 (8) 60 days 3 (12) Outcomes by Subgroup (CR/CRi Rate and %) AML Type de novo 9/12 (75) Secondary AML 9/13 (69) MRD Rates MRD Negative* (N=9 evaluable) 5 (56) Proceeded to SCT 11 (44%) *MRD negative = <10-3 leukemic cells at end of induction by local assessment using multicolor flow, RT-PCR, or NGS

20 Survival Outcomes Newly Diagnosed Patients All All All All Median EFS 9.2 mos (3-12.6) 16% censored at last follow-up Median OS 12.6 mos (9.9-NA) Median follow up 13.0 mos 1-year OS: All patients 52% MRD negative 60%

21 Subgroup Outcomes Newly Diagnosed Patients All Secondary All Secondary All Secondary All Secondary Uproleselan with 7+3 resulted in promising survival outcomes for each subgroup evaluated All newly diagnosed (N=25): Median EFS 9.2 mos (3-12.6). Median OS 12.6 mos (9.9-NA). saml (N=13): Median EFS 7.7 mos ( ). Median OS 10.5 (4.4-NA). de novo AML

22 Subgroup Outcomes Newly Diagnosed Patients All Secondary De Novo All Secondary De Novo All Secondary De Novo All Secondary De Novo Uproleselan with 7+3 resulted in promising survival outcomes for each subgroup evaluated All newly diagnosed (N=25): Median EFS 9.2 mos (3-12.6). Median OS 12.6 mos (9.9-NA). saml (N=13): Median EFS 7.7 mos ( ). Median OS 10.5 (4.4-NA). de novo AML (N=12): Median EFS 13.2 mos (0.8-NA). Median OS NA (0.8-NA).

23 Subgroup Outcomes Newly Diagnosed Patients Adverse Adverse Adverse Adverse Uproleselan with 7+3 resulted in promising survival outcomes for each subgroup evaluated Adverse risk by ELN (N=8): Median EFS 3.1 mos ( ). Median OS NA (0.1-NA). All other

24 Subgroup Outcomes Newly Diagnosed Patients Adverse All other Adverse All other Adverse All other Adverse All other Uproleselan with 7+3 resulted in promising survival outcomes for each subgroup evaluated Adverse risk by ELN (N=8): Median EFS 3.1 mos ( ). Median OS NA (0.1-NA). All other (N=17): Median EFS 11.3 mos ( ). Median OS 12.6 (7.8-NA).

25 Conclusions Uproleselan, an E-selectin antagonist, can be safely added to chemotherapy MEC as well as standard 7+3 Selective disruption of the bone marrow niche with uproleselan is associated with: Low rates of severe oral mucositis Encouraging clinical outcomes High remission rates (CR/CRi) Relapsed/refractory and elderly newly diagnosed High rates of MRD negativity Promising survival outcomes across all subgroups assessed Correlative studies support biological and clinical rationale for targeting E-selectin Confirmatory trials underway in relapsed/refractory AML and frontline AML Breakthrough Therapy Designation granted by FDA for R/R population NCT (Relapsed/Refractory AML), NCT (Newly Diagnosed AML)

26 Acknowledgements Patients and their families Study Research Staff at our institutions Dana-Farber Cancer Institute, UC Davis Comprehensive Cancer Center, University of Rochester School of Medicine and Dentistry, University of Michigan Comprehensive Cancer Center, Taussig Cancer Center Cleveland Clinic, Princess Alexandra Hospital Brisbane, National University of Ireland Galway, University of Washington/Fred Hutchinson Cancer Research Center University of Washington Becker Lab correlative biomarkers Sylvia Chien, Jin Dai Rho, Inc. Shane Rosanbalm, statistician GlycoMimetics, Inc. Mary Chen, Martina Hemmer, Christine Nietubicz, Henry Flanner, Shanti Rodriguez, Britney Brown Novella Clinical Richard Gams, Rebecca Light

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