DOT1L Inhibitor EPZ-5676: Safety and Activity in Relapsed/Refractory Patients with MLL-Rearranged Leukemia Stein EM, Garcia-Manero, G, Rizzieri DA, Savona MR, Tibes R, Altman JK, Jongen-Lavrencic M, Döhner H, Armstrong S, Pollock RM, Waters NJ, Legler M, Thomson B, Daigle SR, McDonald A, Campbell C, Olhava E, Hedrick EE, Löwenberg B, Copeland RA, Tallman MS Participating Institutions Memorial Sloan Kettering Cancer Center MD Anderson Cancer Center Duke University Health System Sarah Cannon Research Institute Mayo Clinic Scottsdale Northwestern University Erasmus University Medical Center, Netherlands Universitätsklinikum, Ulm, Germany
DOT1L Promotes MLL-r Leukemia via Aberrant 2013 Accomplishments H3K79 Methylation Normal H3K79 Normal gene No MLL Fusion Differentiation methylation expression normal MLL Aberrant gene Aberrant H3K79 activation MLL-Fusion Leukemogenesis methylation (e.g. HOXA9, MEIS1) Kristov and Armstrong (2007) Nature Rev Cancer: 823 Kristov et al (2008) Cancer Cell: 355 2 Courtesy, Dr. P. Ho and Dr. K. Maloney
EPZ-5676 is a Potent and Highly Selective 2013 Accomplishments DOT1L Inhibitor Tumor Response in MLL-r EPZ-5676 MV4-11(AF4) Xenograft Biochemical Selectivity SMYD2 EZH1 PRMT5 SMYD3 EZH2 SETD7 PRMT3 PRMT1 DOT1L CARM1 EHMT1 PRMT8 EHMT2 WHSC1L1 WHSC1 - 11 - 10 - 9 - 8 - 7 - 6 > 1.0 X 10 - 5 10 10 10 10 10 10 Daigle et al. (2013) Blood 122: 1017 3
2013 Accomplishments EPZ-5676-12-001 (NCT01684150) First-in-Human phase 1 study • Objectives – Primary: Determine Maximum Tolerated Dose (MTD) or Recommended Phase 2 Dose (RP2D) with a 21 or 28 day infusion – Secondary: Describe safety, pharmacokinetics & pharmacodynamics • Study Design – Part 1: Dose Escalation • 3+3 design • Adult patients with advanced hematologic malignancies • Initial cohorts not MLL-r restricted ‒ Part 2: Expansion • Restricted to MLL-r (translocations and Partial Tandem Duplications: PTD) 4
2013 Accomplishments Definitions • Dose Limiting Toxicity DLT (per CTCAE v4.03) – Occurrence within 28 days of cycle 1 – Grade > 3 non-hematologic clinically significant suspected adverse reaction assessed as: • Unrelated to disease progression • Inter-current illness or • Concomitant medications – Prolonged (> 42 days) grade 4 neutropenia or thrombocytopenia • Maximum Tolerated Dose (MTD) – Dose level below which > 1 of 3 patients or > 2 of 6 patients experiences a DLT • Data cut-off: 6-Oct-2014 5
2013 Accomplishments Patient Characteristics Total patients n=42 (%) Median age, years (range) 52 (19 to 81 ) Sex Female 17 (40) Disease at study entry ALL 6 (14) AML / MDS 34 / 1 (81 / 2) MPN (CMML) 1 (2) MLL rearrangement t(6;11) 8 (19) t(11;19) 8 (19) PTD 5 (12) t(4;11) 4 (10) other MLL-r 4 (10) t(9;11) 3 (7) t(10;11) 2 (5) No MLL rearrangement 8 (19) Prior attempts at remission 1 13 (31) 2 13 (31) 3 10 (24) >4 6 (14) Number of patients with prior allogeneic hematopoietic cell 16* (38) 6 transplants (*one patient with two prior HCTs)
2013 Accomplishments Drug Exposure and Pharmacokinetics • Median number of cycles completed: 2 (range 1 – 7) • Median duration of treatment in weeks: 4.5 (range: 1 – 27) • Concentration at steady state (Css) achieved by 24 hours and AUC dose proportional – Low total body clearance and short half life (t 1/2 ) 7
2013 Accomplishments Pharmacodynamics • Evidence of target H3K79me2 inhibition in PBMC observed at all dose exposures • Clinical response and leukocytosis/differentiation associated with >30% methyl mark reduction N=23 Leukocytosis or Differentiation Complete Remission Non-responder 8 8 8 8 8 8 8
2013 Accomplishments Safety: Treatment Related Adverse Events • Total incidence (all grades): 16 patients (38%) – 10 patients < grade 2 • Majority gastrointestinal – 4 patients with grade 3 • Leukocytosis (n=3) • Anemia (n=1) • Dose Limiting Toxicities – 90 mg/m 2 /d dose escalation cohort (n=6) • None – 90 mg/m 2 /d expansion cohort (n=17) • Grade 4 reversible cardiac failure with concurrent sepsis • Grade 4 reversible hypophosphatemia during rapid WBC drop • MTD not reached 9
Safety: Most Frequent Adverse Events (≥15%) 2013 Accomplishments Regardless of Attribution Grade ≥3 All Grades Adverse event n=42 (%) n=42 (%) Febrile neutropenia 10 (24) 8 (19) Fatigue 14 (33) 4 (10) Anemia 7 (17) 5 (12) Pneumonia 7 (17) 5 (12) Dyspnea 8 (19) 2 (5) Mucosal inflammation 8 (19) 2 (5) Constipation 10 (24) 1 (2) Fever 10 (24) 1 (2) QTcF prolongation (total n=34) 11 (34) 0 Nausea 13 (31) 0 Peripheral edema 9 (21) 0 Chills 7 (17) 0 Diarrhea 7 (17) 0 Vomiting 7 (17) 0 PR prolongation (total n=34) 5 (15) 0 10
2013 Accomplishments Clinical Activity • 9 patients (8/34 MLL-r) had either: – marrow response and/or – resolution of leukemia cutis and/or – leukocytosis or differentiation Number Leukemia Marrow Leukocytosis or Dose of cutis Response Differentiation mg/m 2 /day patients resolved (n=3) (n=8) (n=42) (n=2) 12 1 - - - 24 5 - - 1 36 4 - 1 2 54 6 2 CR 1 1 80 3 - - 2 90 23 1 PR - 2 (28 day CIV) 11 11
Clinical Activity: Marrow Response 2013 Accomplishments and Leukemia Cutis Response Extra- Disease MLL-r Dose (weeks on medullary study) Disease Cytogenetic MPN (CMML) Resolved 54 mg/m 2 /day t(11;19) CR 01-101 leukemia cutis (27) Morphologic AML 54 mg/m 2 /day t(11;19) CR NA 04-401 (16*) AML Other: PR trisomy 11 90 mg/m 2 /day NA 01-105 (12) AML 36 - Resolved t(6;11) 03-300 mg/m2/day (6) leukemia cutis * Off-study for Hematopoietic Cell Transplant 12
Clinical Activity: Resolution of Leukemia Cutis 2013 Accomplishments Patient 01-101: CMML, t(11;19) at 54 mg/m 2 /day Cycle 1 day 1 Cycle 2 day 1 Cycle 3 day 1 Cycle 4 day 1 Cycle 4 day 1 13 Courtesy, Dr. Klaus Busum
Clinical Activity: Leukocytosis and Differentiation 2013 Accomplishments Patient 01-103: AML, t(11;19) at 90 mg/m 2/ day Rise of absolute monocyte/neutrophil Neutrophils 25% 50% above baseline and above ULN blasts Monocytes 14% lymphocytes C1D22 Baseline WBC 38.4 X 10 9 /L C2D1 WBC 13.2 X 10 9 /L C1D15 MLL FISH: neutrophil t(11;19) FISH positive neutrophil Neutrophils 47% Median day of onset: C1D15 (range: 8-28 days) Monocytes 16% 14
2013 Accomplishments Conclusions and Next Steps • Dose escalation through 90 mg/m 2 /d without reaching protocol-defined MTD • Acceptable safety profile • Clinical activity, including CRs and clonal differentiation, observed in heavily pre-treated MLL-r patients • Currently enrolling up to 20 patients at 54 mg/m 2 /d based on observed clinical responses and clinical activity • Molecular characterization of patient samples to identify patient selection and response biomarkers – myAML panel – 193 commonly mutated genes in AML – Whole genome RNA-Seq – Pathway analysis 15
2013 Accomplishments Acknowledgements We thank the investigators and their teams and most importantly the patients and families who participated in the study. 16
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