First-in-Human Phase I Study of Iadademstat original reports (ORY-1001): A First-in-Class Lysine-Specific Histone Demethylase 1A Inhibitor, in Relapsed or Refractory Acute Myeloid Leukemia Olga Salamero, MD1; Pau Montesinos, MD2,3; Christophe Willekens, MD4; José Antonio Pérez-Simón, MD, PhD5,6; Arnaud Pigneux, MD, PhD7; Christian Récher, MD, PhD8; Rakesh Popat, MB, BS, PhD9; Cecilia Carpio, MD1; César Molinero, MD, PhD10; Cristina Mascaró, PhD10; Joaquim Vila10; M. Isabel Arévalo, PhD10; Tamara Maes, PhD10; Carlos Buesa, PhD10; Francesc Bosch, MD, PhD1; and Tim C. P. Somervaille, MBBS, PhD11,12 abstract PURPOSE Iadademstat is a novel, highly potent, and selective inhibitor of LSD1 (KDM1A), with preclinical in vitro and in vivo antileukemic activity. This study aimed to determine safety and tolerability of iadademstat as monotherapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML). METHODS This phase I, nonrandomized, open-label, dose-escalation (DE), and extension-cohort (EC) trial included patients with R/R AML and evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antileukemic activity of this orally bioavailable first-in-class lysine-specific demethylase 1 inhibitor. RESULTS Twenty-seven patients were treated with iadademstat on days 1 to 5 (5-220 mg/m2/d) of each week in 28-day cycles in a DE phase that resulted in a recommended dose of 140 mg/m2/d of iadademstat as a single agent. This dose was chosen to treat all patients (n 5 14) in an EC enriched with patients with MLL/KMT2A- rearranged AML. Most adverse events (AEs) were as expected in R/R AML and included myelosuppression and nonhematologic AEs, such as infections, asthenia, mucositis, and diarrhea. PK data demonstrated a dose- dependent increase in plasma exposure, and PD data confirmed a potent time- and exposure-dependent induction of differentiation biomarkers. Reductions in blood and bone marrow blast percentages were observed, together with induction of blast cell differentiation, in particular, in patients with MLL translocations. One complete remission with incomplete count recovery was observed in the DE arm. CONCLUSION Iadademstat exhibits a good safety profile together with signs of clinical and biologic activity as a single agent in patients with R/R AML. A phase II trial of iadademstat in combination with azacitidine is ongoing (EudraCT No.: 2018-000482-36). J Clin Oncol 38:4260-4273. © 2020 by American Society of Clinical Oncology Creative Commons Attribution Non-Commercial No Derivatives 4.0 License ASSOCIATED INTRODUCTION which facilitates recruitment of histone deacetylase to CONTENT sites on chromatin where SNAG domain transcription Data Supplement Acute myeloid leukemia (AML) is a hematologic ma- factors such as GFI1 and GFI1B are bound.16 LSD1 is Protocol lignancy characterized by a myeloid lineage differ- highly expressed in hematopoietic stem cells and Author affiliations entiation block.1-3 It remains, for the most part, an and support myeloblasts, and is necessary for proliferation and incurable disease, especially in the elderly, and new information (if terminal differentiation during normal hematopoie- approaches to treatment are required, including those applicable) appear sis.17 Preclinical studies have revealed that LSD1 at the end of this that promote differentiation.4-10 Epigenetic dysfunction sustains the differentiation block in certain molecular article. has a central role in AML pathology, as evidenced by subtypes of AML, in particular, MLL-translocated AML, Accepted on recurrent mutations in transcription factors and epi- and is required for leukemic stem cell potential.18-22 September 8, 2020 genetic regulators.11-14 Certain regulators are under and published at Targeting LSD1 in AML may serve to promote differ- evaluation as therapeutic targets, including lysine- ascopubs.org/journal/ entiation of leukemic blasts. specific demethylase 1 (LSD1), which serves a dual jco on October 14, 2020: DOI https://doi. role in hematopoiesis. It exhibits demethylase activity Iadademstat (ORY-1001) is a highly selective and org/10.1200/JCO.19. versus monomethylated and dimethylated lysine res- potent covalent inhibitor of LSD1, which induces dif- 03250 idues on histone tails15 as well as scaffolding activity, ferentiation of AML cells in vitro at low concentrations 4260 Volume 38, Issue 36 First-in-Human LSD1 Inhibitor Iadademstat in AML CONTEXT Key Objectives To evaluate the safety, pharmacokinetics, pharmacodynamics and preliminary antileukemic activity of iadademstat in acute myeloid leukemia. Knowledge Generated Iadademstat exhibits a good safety profile together with signs of clinical and biologic activity as a single agent in patients with relapsed or refractory AML. Relevance Current treatment options in AML fail to cure the majority of patients, in particular those not fit for intensive chemotherapy, and novel therapies are required. Ongoing studies are investigating the combinatorial use of iadademstat with azacitidine to further delineate its activity in AML. (, 1 nM) and compromises leukemic stem cell capacity in DE was performed in a traditional 3 1 3 design (Data preclinical models of AML. Iadademstat induces a mono- Supplement),24,25 with dosing administered until disease cyte/macrophage differentiation gene signature in AML cell progression, death, consent withdrawal, or adverse events lines, and induction of differentiation biomarkers correlates (AEs) that did not improve by standard of care (Data with reduction of tumor growth in rodent leukemia xeno- Supplement). The starting dose was based on preclinical grafts. Iadademstat has excellent oral bioavailability, ex- toxicology studies (Data Supplement). The escalation doses cellent target exposure, and promising antitumor activity were 5, 15, 30, 45, 60, 80, 140, and 220 mg/m2/d in in vivo.23 We report a first-in-human dose-escalation (DE) cohorts 1 to 8, the latter included after an amendment to and extension-cohort (EC) phase I study with iadademstat add an additional dose level (220 mg/m2/d). Iadademstat in patients with refractory or relapsed (R/R) acute leukemia was administered orally after a minimum of 2 hours of (EudraCT No.: 2013-002447-29). The primary objective fasting using a precharged syringe in a 28-day cycle (5 days was to assess safety and tolerability of iadademstat; sec- on/2 days off 3 4 weeks). Details regarding maximum ondary objectives were to study pharmacokinetics (PK), tolerated dose assessment, study monitoring, safety anal- pharmacodynamics (PD), and efficacy. ysis, sampling, PK/PD analysis, bone marrow (BM) biomarker analysis, response analysis, and statistical assessments are METHODS available in the Data Supplement. Participant Selection RESULTS Patients with relapsed or refractory acute leukemia (ex- cluding acute promyelocytic leukemia; age $ 16 years) not Patient Characteristics deemed suitable for standard therapies, with Eastern Co- Between February 2014 and April 2015, 27 patients with operative Oncology Group performance status # 2 and R/R acute leukemia were enrolled in the DE phase without an unstable or uncontrolled concurrent severe med- (1 with ALL in cohort 1; 26 with AML). Two patients failed ical condition, were eligible. Prior acute leukemia treat- screening. Between September 2015 and May 2016, 14 ment should have stopped at least 14 days before the patients were enrolled in the EC (140 mg/m2/d), which, first dose of iadademstat. Hydroxycarbamide was allowed guided by preclinical data, was restricted to patients with until 12 hours before the first dose of iadademstat and then MLL gene rearrangements or erythroleukemia. Median age after the fifth day (Data Supplement, online only). Patients was 67 years; 15 (42%) of 36 patients with karyotypes with MLL-rearranged AML or acute erythroblastic leukemia available exhibited adverse risk cytogenetics,26 and 7 were selected for the EC. (17%) of 41 patients were in second or third relapse. The median time since initial diagnosis to study enrollment was Study Design 9.8 months and since last treatment was 1.3 months. Of The protocol was approved by the institutional review board 41 patients, 30 completed cycle 1 (C1; Table 1; Data or independent ethics committee at each participating Supplement). center and by regulatory authorities, in accordance with the Declaration of Helsinki, the International Conference Safety and Tolerability on Harmonization–Good Clinical Practice, and local laws. All patients experienced treatment-emergent AEs; in total, Investigators obtained informed consent from each par- 497 were reported (Data Supplement). The most fre- ticipant before performing any study-specific procedures. quent nonhematologic AEs were infection, GI symptoms, Data were anonymized to protect patient identities. hemorrhagic manifestations, asthenia, musculoskeletal Journal of Clinical Oncology 4261 Salamero et al TABLE 1. Summary of Patient Characteristics at Screening Characteristics Dose-Escalation Cohort Extension Cohort All Patients No. of patients 27 14 41 Median age, years (range), 69 (40-81) 63 (30-78) 67 (30-81) Sex (F/M), % 30/70 36/64 32/68 ECOG performance status, No. 0 4 2 6 1 16 11 27 2 5 1 6 NA 2 0 2 Median WBC count 3 109/L, (range) 4.0 (0.6-104.9) 2.5 (0.2-26.3) 2.9 (0.2-104.9) Median platelet count 3 109/L, (range) 31 (4-335) 19 (4-266) 21 (4-335) Median Hgb, g/L (range) 89 (67-122) 86 (74-143) 88 (67-143) Median PB blast, % (range) 42 (0-92) 31 (0-95) 39 (0-95) Median BM blast, % (range), 49 (0-90) 32 (2-97) 47 (0-97) Cytogenetic risk,26 No. Favorable 1 0 1 Intermediate 12 8 20 Adverse 10 5 15 NA 4 1 5 Molecular abnormalities, No. MLL rearrangements 0 6 6 MLL, other abnormalities 2 4 6 FLT3-ITD mutations 3 0 3 NPM1 mutations 2 0 2 WT1 8 2 10 TP53 mutations 1 1 2 NA 14 4 18 WHO diagnosis,1-4 No. AML with recurrent genetic abnormalities 10 4 14 AML with multilineage dysplasia 6 5 11 AML, therapy related 2 2 4 AML, not otherwise specified 5 3 8 NA 4 0 4 FAB classification,1-4 No. M0 3 0 3 M2 4 3 7 M4 0 4 4 M5 1 3 4 M6 0 4 4 M7 2 0 2 NA 17 0 17 No. of relapses 0 (refractory) 8 5 13 1 14 7 21 $2 5 2 7 Median time from AML diagnosis months, (range) 9.8 (2-41) 9.9 (4-36) 9.8 (2-41) Abbreviations: AML, acute myeloid leukemia; BM, bone marrow; ECOG, Eastern Cooperative Oncology Group; Hgb, hemoglobin; NA, not available; PB, peripheral blood. 4262 © 2020 by American Society of Clinical Oncology Volume 38, Issue 36 First-in-Human LSD1 Inhibitor Iadademstat in AML TABLE 2. Grade 3 and 4 AEs and SAEs Grade 3 and 4 AEs Considered Possibly, Probably, or Definitely Total Grade 3 and 4 AEs Related to Iadademstat DE EC DE EC AE Description (n 5 27) (n 5 14) (n 5 27) (n 5 14) General Asthenia 2 4 — 2 Anorexia — 2 — 2 Mucositis 1 — — — Edema 1 1 — — Infection Fever of unknown origin or neutropenic fever 10 11 1 3 Septic shock or sepsis 2 3 — — Cutaneous/subcutaneous infection 3 2 — — Respiratory infection or pneumonia 5 2 — 1 Tonsillitis — 1 — — Hemorrhage Cutaneous 2 — — — Mucosal 1 — — — Intracranial 1 — — — Respiratory (other than mentioned) Respiratory failure or distress 1 — — — Pleural effusion 2 — — — GI (other than mentioned) Abdominal pain 1 — — — Neurologic Seizure or vasovagal episode 2 — — — Hematologic Thrombocytopenia 8 3 3 2 Leukocytosis 3 1 — — Leukopenia 1 — — — Neutropenia 3 1 2 — Anemia 1 1 — — Musculoskeletal disorders Musculoskeletal pain or discomfort — 1 — — Metabolism disorders Hyperglycemia 1 — — — Hypokalemia 7 — — — Cardiac Supraventricular tachycardia — 2 — — Hypotension 2 1 — — Urinary tract disorders Renal impairment — 1 — — (continued on following page) Journal of Clinical Oncology 4263 Salamero et al TABLE 2. Grade 3 and 4 AEs and SAEs (continued) Grade 3 and 4 AEs Considered Possibly, Probably, or Definitely Total Grade 3 and 4 AEs Related to Iadademstat DE EC DE EC AE Description (n 5 27) (n 5 14) (n 5 27) (n 5 14) Other Graft versus host disease 1 — — — Infusion reaction 1 — — — Total 62 37 6 10 SAEs Considered Possibly, Probably, Total SAEs or Definitely Related to Iadademstat DE EC DE EC SAE Description (n 5 27) (n 5 14) (n 5 27) (n 5 14) General Asthenia — 1 — 1 Infection Fever of unknown origin or neutropenic fever 7 9 1 3 Septic shock or sepsis 3 2 — — Cutaneous/subcutaneous 1 2 — 1 Respiratory infection or pneumonia 10 3 1 1 Sinusitis 1 — — — Bleeding Intracranial hemorrhage 3 — — — Respiratory (other than mentioned) Respiratory failure or distress 2 — — — GI (other than mentioned) Diarrhea — 1 — — Neurologic Depressed level of consciousness 1 — — — Hematologic Thrombocytopenia — 1 — 1 Leukocytosis — 3 — — Differentiation syndrome — 2 — 2 Disease progression 1 5 — — Musculoskeletal Musculoskeletal pain or discomfort — 1 — — Cardiac Pericarditis — 1 — — Supraventricular tachycardia — 2 — — Cardiac failure 1 — — — Hypotension — 1 — — Other Graft versus host disease (liver) 1 — — — Infusion reaction 1 — — — Total 32 34 2 9 NOTE. AEs that evolved from a lower to a higher grade or vice versa (n 5 21) are only counted once, at the highest grade. Abbreviations: AE, adverse event; DE, dose escalation; EC, extension cohort; SAE, serious adverse event. 4264 © 2020 by American Society of Clinical Oncology Volume 38, Issue 36 First-in-Human LSD1 Inhibitor Iadademstat in AML pain, mucositis, edema, skin rash, and anorexia. Of the hours postdose. Compound accumulation was observed AEs, 99 were grade 3 or 4; 66 were reported as serious AEs after repeated dosing, with an average accumulation ratio (SAEs), mainly infections (Table 2; Data Supplement). of approximately 3-6. The volume of distribution for iada- Sixty-six AEs were considered related to iadademstat (Data demstat was approximately 200 times total body water, and Supplement), 10 certainly, 21 probably, and 35 possibly, the half-life was 40-100 hours. PK curves and parameters according to investigator assessment. Of these, 16 were calculated for the EC (140 mg/m2/d) are summarized in grade 3 or 4, and 11 were SAEs (Table 2; Data Supple- Figures 1A, 1B, and 1E. ment). SAEs included neutropenic fever or fever of un- As expected from preclinical data,23 the PD biomarker known origin (n 5 4), cellulitis (n 5 1), pneumonia or response in the DE phase was heterogeneous. Nevertheless, respiratory infection (n 5 2), thrombocytopenia (n 5 1), selected biomarkers showed time and dose-dependent asthenia (n 5 1), and differentiation syndrome (n 5 2). response profiles in individual patients. PI16/CRISP9 was During the study, there were 27 recorded grade 5 AEs rapidly induced on day 1 (Fig 1B); maximal induction (where the AE was considered by the investigator to have (2DDCp max) was achieved after multiple dosing in patient contributed to death; Table 2; Data Supplement), and 25 11 (45 mg/m2/d) and patient 18 (80 mg/m2/d) but within patients died (DE, n 5 16; EC, n 5 9). The recorded causes 18 hours of the first dose in patient 22 (140 mg/m2/d), of death were as expected for patients with R/R acute reflecting saturation despite further increases in exposure leukemia: AML (n 5 12), lung infection or respiratory failure over the following days. Remarkably, induction was sus- (n 5 9), septic shock (n 5 1), sinusitis (n 5 1), and in- tained up to 1 week after the last administration. In the EC, tracranial hemorrhage with heart failure (n 5 1). Three patients with monocytic or monoblastic lineage leukemias grade 5 AEs were considered possibly related to iada- (FAB-M4 or -M5 AML) exhibited a potent response of many demstat: pneumonia in a patient in cohort VIII and episodes biomarkers, with the highest increase observed for VCAN, of cellulitis and differentiation syndrome in an EC patient S100A12, and LY96. whose recorded cause of death was AML. One EC patient Biomarker response correlated with morphologic differ- died as a result of complications arising from a differenti- entiation of blast cells in BM and/or peripheral blood (PB; ation syndrome (n 5 1), considered certainly related to Figs 2A-2C and Fig 3). A rapid and potent induction of iadademstat. VCAN and S100A12 was observed in two patients who Dose-Limiting Toxicity developed differentiation syndrome (patients 28 and 36). RNA sequencing of selected predose and post-treatment In cohort VIII (220 mg/m2/d), two SAEs were considered (C1D29) BM samples confirmed upregulation of PROCR possibly related to iadademstat—pneumonia (patient 24; and downregulation of erythroid biomarkers GYPA, GYPB, grade 5) and an episode of febrile neutropenia (patient 27; HBA1, and HBB in three patients with erythroleukemia grade 3), which did not meet the strict protocol criteria for (M6A) and confirmed the broad upregulation of biomarkers a dose-limiting toxicity (Data Supplement). However, in in PB in patient 29 (Data Supplement). Together, these view of evidence in cohort VII (140 mg/m2/d) of maximal surrogate biomarker data demonstrate target engagement biomarker induction within 24 hours of treatment, despite of iadademstat in leukemic cells and support their utility as subsequent accumulation of plasma iadademstat from D1- a tool to monitor response to LSD1 inhibition. D5 (Fig 1A and 1B; eg, patient 22), and evidence of potent hematopoietic target engagement (induction of grade 4 Iadademstat Efficacy thrombocytopenia by day 15-17 of treatment in two pa- tients; Figs 1C, and 1D), the Safety Monitoring Committee In the DE phase, patient 16 achieved a complete remission took the pragmatic view to establish the maximum tolerated with incomplete count recovery (CRi). This patient had dose as 220 mg/m2/d. The EC dose was set at 140 mg/m2/d. FAB-M2 AML (Data Supplement), which had relapsed The effects of iadademstat on platelet levels across cohorts 6 months after a sibling donor allogeneic stem cell trans- are shown in Fig 1C, and platelet dynamics for a cohort VII plantation. At relapse, the patient received a single cycle of patient with high baseline platelet levels are shown Fig 1D. 60 mg/m2/d iadademstat. At screening, the BM was infil- In the EC, one patient required a 25% dose reduction at trated with 40% blasts. After treatment, the neutrophil and cycle 1 day 15 (C1D15) after grade 4 thrombocytopenia platelet counts improved and were normal by D20; the and transient nonspecific deterioration in general health patient exhibited a progressive increase of the absolute (patient 32). neutrophil count (ANC) beginning at D5 (Fig 4A). Induction of CD86 started on D5, and expression of differentiation PK, PD, and Biomarkers genes VCAN, S100A12, and LY96 was observed at D12 At 5 and 15 mg/m2/d, plasma concentrations were typ- (Fig 4B-D). The D29 BM demonstrated morphologic re- ically below the lower limit of quantification. At higher mission that was sustained on D52 (both 2% blasts in doses, concentrations increased in an approximately linear a hypocellular BM with persistent thrombocytopenia). Of manner, with a tendency for overproportional exposure at note, on C1D11, the patient developed acute graft-versus- doses . 80 mg/m2/d. Tmax was generally observed 4-8 host disease of the liver and was treated with prednisolone Journal of Clinical Oncology 4265 Salamero et al A Iadademstat Plasma Concentration (pg/mL) 100 Day 1 Day 5 + 2 off Day 26 + washout 80 I II III 60 IV V VI VII 40 VIII E 20 0 0 6 12 18 24 96 108 120 132 144 600 624 648 672 696 720 744 768 Time (hours) B Day 1-8 Day 26 + washout 11 PK 100 8 18 PK 22 PK PK: Iadademstat Plasma 11 PD 80 4 18 PD PD:PI16-CP Conc. (pg/mL) 22 PD 60 0 40 –4 20 –8 0 –12 0 24 48 72 96 120 144 168 600 624 648 672 696 720 744 768 792 Time (hours) C D 0 Platelet CFB EoT (%) Platelet CFB EoT (%) 50 –25 25 0 –50 –25 –50 –75 –75 –100 –100 I II III IV V VI VII/E VIII 0 5 10 15 20 25 30 35 40 45 50 55 Treatment Day E Extension Cohort – 140 g/m /d 2 Parameters Day 1 Day 5 Day 26 AUC0-24 hr (pg hr/mL) 105 ± 85 (5-321) 475 ± 273 (70-1,058) 912 ± 521 (326-1,688) Cmax (pg/mL) 7.5 ± 6.5 (1.2-22.1) 35.0 ± 40.1 (5.5-166.0) 55.0 ± 32.4 (16.0-107.0) Tmax (hr) 5 (4.0-18.0) 5 (2-24) 6 (2-24) AUCinf (pg hr/mL) - - 3,715 ± 1,405 (2,722-4,709) Half-life (hr) - - 79.9 ± 29.7 (58.9-100.9) FIG 1. Pharmacokinetics (PK) and pharmacodynamics (PD) assessments of iadademstat. (A) Plasma levels of iadademstat were assessed by High-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS) in serial samples (day [D]1, D5, D26), trough samples, and washout samples. Mean 6 SEM plasma levels in cohorts I-VIII and the extension cohort (EC) are shown. (B) PK/PD relationship for PI16 (peptidase inhibitor 16) expression in patients 11 (cohort IV; triangles), 18 (cohort VI; squares), and 22 (cohort VII; dots) during week 1 of treatment (left panel) or washout (right panel). Black arrows indicate dosing occasions. (continued on following page) 4266 © 2020 by American Society of Clinical Oncology Volume 38, Issue 36 First-in-Human LSD1 Inhibitor Iadademstat in AML and antithymocyte globulin. A single dose of iadademstat on D5 of treatment, despite prompt treatment with high-dose was administered on D89 (C2D1). Death occurred in re- dexamethasone. Both patients were classified as having mission on D92 as a result of sepsis for reasons unrelated to drug-induced differentiation syndrome. iadademstat. There was modest evidence of promonocytic differentiation More modest hematologic improvements were also de- in patient 31 (FAB-M4 with t[9;11][q21;q23]; Fig 2A and tected in the DE phase in other patients. Patient 9 in cohort 2B), including induction of LY96 (Fig 3), and in patient III (30 mg/m2/d) showed a decrease in BM blasts from 38 (FAB-M2 AML with MLL–partial tandem duplication 38% to 24% after 1 cycle (D29), as did patient 13 in cohort [PTD]), who showed an increase in PB promonocytes from V (60 mg/m2/d; 51%-36% on C1D29). The modest plasma 0% to 10% on C2D23 (Fig 2B). Patient 33 (FAB-M4 AML levels (Data Supplement) were sufficient to induce robust with t[9;11][(q21;q23]) showed a 95% decrease in PB upregulation of differentiation genes VCAN, S100A12, and blasts (0.2 3 109/L at screening to 0.01 3 109/L at end of LY96 (Data Supplement). C1). However, the BM blast percentage was stable during treatment, and no morphologic evidence of blast cell dif- In the EC, no responses according to International Working ferentiation was observed. Differentiation markers upreg- Group criteria were observed, but a number of biologically ulated at the end of C1 included VCAN and CD86 (Fig 3). significant changes were seen, including induction of blast cell differentiation and reduction in blast cell burden. Blast cells in PB in patient 39 (FAB-M2 AML with MLL- Among patients with MLL translocations, patient 29 (FAB PTD) decreased from 75% to 51% on C1D8 (data not M4 AML with t[9;11][q21;q23]) showed reductions in BM shown), although no morphologic differentiation was evi- and PB blast percentages with a concomitant increase in dent; upregulation of LY96 and to a minor extent VCAN and differentiated cells across multiple treatment cycles. The CD86 were observed (Fig 3). maximum reduction of blasts in the BM was detected on Among the four erythroleukemia (FAB M6) patients, patient C3D29 (from 95% to 41%) and in PB on C2D29 (from 35 demonstrated a modest but consistent proportional 93% to 44%; Figs 2B and 2C). Induced expression of reduction in BM blasts (Data Supplement). There was no differentiation genes, including VCAN, S100A12, LY96, evidence of morphologic differentiation but upregulation of CD86, and ITGAM was detected in blood cells (Fig 3). VCAN at the end of C1 was observed in blood, and Although this patient received hydroxycarbamide 500 mg erythrocytic markers were downregulated in BM (Fig 3; three times daily from C1D6 (as permitted by protocol) and Data Supplement). Patient 32 showed stable disease, with hydroxycarbamide has been reported to potentiate differ- a transient blast reduction from 17% to 8% in BM observed entiation of other agents,27 the robust induction of PD between C1D15 and C1D29 of treatment (Figs 2C and 3). biomarkers was already observed on C1D5, in the absence of hydroxycarbamide. Patients 28 (FAB-M4 AML with [t10;11][q12;q23]) and 36 DISCUSSION (FAB-M5 AML with [t11,17][q23;q21) developed prominent Iadademstat was the first selective inhibitor of LSD1 to enter features of morphologic differentiation during treatment. PB clinical trials. Our study reveals that iadademstat exhibits smears revealed significant promonocytic and monocytic approximately linear PK and a half-life of 40-100 hours. differentiation, and biomarker analysis showed induction of Pharmacodynamic analyses demonstrate rapid target en- CD86, ITGAM, LY96, and especially VCAN and S100A12 gagement. Patients with R/R AML are difficult to treat, with (Figs 2A and 3). In the former case, the leukocyte count survival times typically in the range of weeks to months. The started to increase after 2 weeks of treatment. The patient majority of enrolled patients were . 65 years of age and developed breathlessness on D25 and was treated with presented with pancytopenia at screening, making it a antibiotics, intravenous steroids, and hydroxycarbamide. In particular challenge to discern drug-induced versus disease- the latter case, the patient developed fatal respiratory failure related AEs. FIG 1. (Continued). (C) Maximal impact of iadademstat on platelet levels, represented as % inhibition compared with baseline. Individual (symbols) and mean (bar) values are shown for each cohort. Blue symbols represent outlier values that were excluded for calculation of mean. (D) Example of the platelet dynamics in patient 21 (cohort VII), with a predose count of 149 3 109/L. A time-dependent reduction is followed by rebound. Black bars indicate iadademstat treatment blocks. (E) PK parameters for iadademstat in the EC. Area under the curve (AUC)0-24h indicates area under the plasma concentration time curve within time 0 to 24 hours (D1: n 5 13, D5: n 5 13, D26: n 5 9). Cmax indicates maximum (peak) plasma drug concentration (D1: n 5 14, D5: n 5 14, D26: n 5 9). Tmax indicates time to reach maximum (peak) plasma concentration (D1: n 5 14, D5: n 5 14, D26: n 5 9). AUCinf indicates area under the plasma concentration time curve from time zero to infinity and half-life (hours; D26: n 5 2). Values are shown as mean 6 standard deviation (median for Tmax) with range in brackets. CFB, change from baseline; EoT, end of treatment. Journal of Clinical Oncology 4267 Salamero et al A Screening Day 21 Patient No. 28 Screening Day 14 Patient No. 31 30m B C Metamyelocytes, % Lymphocytes, % Promyelocytes and Lymphocytes, % Promonocytes, % Neutrophils, % Monocytes, % myelocytes, % Promyelocytes, % Promonocytes, % erythroid, % WCC (× 10 /L) Neutrophils, % PLT (× 10 /L) Myelocytes, % Monocytes, % Nucleated Timepoint Timepoint HB (G/L) Karyotype Karyotype 9 Blasts, % Patient Blasts, % 9 Patient 28 t(10;11) 29 t(9;11) Screen 94 0.9 53 10 55 0 0 15 20 Screen 95 0 0 0 0 0 0 5 0 C1D29 85 30 13 79 0 12 9 0 0 C1D29 81 11 5 0 0 0 0 3 0 29 t(9;11) C2D29 69 12 7 8 0 0 0 4 0 Screen 96 23.5 47 93 0 0 0 0 7 C3D29 41 15 32 11 0 0 0 1 0 C1D29 82 8.6 24 79 0 0 0 0 21 33 t(9;11) C2D29 88 1.2 17 44 20 0 0 0 36 Screen 47 4 13 9 0 0 0 11 16 C3D29 92 4.6 57 53 36 0 0 0 11 C1D29 31 12 16 2 0 0 1 32 6 31 t(9;11) Screen 89 3.9 13 95 2 0 0 0 3 C1D14 81 6.7 11 89 5 5 0 0 1 33 t(9;11) Screen 92 1.4 25 15 6 0 6 34 39 C1D29 90 0.6 4 2 3 0 0 0 95 36 t(11;17) + trisomy 21 (constitutional) Screen 99 19.8 44 69 2 7 0 6 15 C1D7 65 28.8 91 61 2 31 0 0 6 FIG 2. Morphologic response to treatment with iadademstat. (A) Representative images of blood smears showing morphologic differentiation from patient 28 (top) at screening (left) and cycle 1(C1), day 21 (D21) (right) and patient 31 (bottom) at (continued on following page) 4268 © 2020 by American Society of Clinical Oncology Volume 38, Issue 36 First-in-Human LSD1 Inhibitor Iadademstat in AML Maximum response (–Cp) Morph. differ.a (hours; range) FAB subtypeb Blasts, % at t0 Time period Patient No. CAMSAP2 variationa S100A12 Blast, % ANXA2 CRISP9 ITGAM GPR65 VCAN CTSG CD86 LY96 VIM LYZ c 28d M4 600-768 6.6 4.9 3.2 7.1 7.0 5.2 3.1 2.6 1.9 4.6 5.3 4.0 52  29 M4 600-768 2.2 0.9 4.8 2.8 5.9 2.3 3.2 4.4 0.7 3.0 3.9 3.7 95  36d M5a 98-168 9.1 1.2 0.9 5.0 3.3 –3.3 2.6 3.5 0.5 –1.2 2.9 2.3 74 = 31 M4 98-168 1.2 –2.4 –4.4 –3.9 4.1 2.5 –3.2 –2.5 –1.3 2.9 2.8 2.8 81 = 33 M4 600-768 4.3 1.4 6.4 –3.2 –1.1 na na na na na 6.0 –1.2 7 = 37 M5a 600-768 –2.9 –4.0 –4.8 –3.5 –4.6 –4.7 –1.1 3.3 –2.0 –2.3 –2.8 –1.8 na n/a 30 M5b 98-168 –1.6 na na na 1.6 na na na na na na na na  39 M2 98-168 2.2 2.3 3.0 –2.4 3.1 1.8 2.0 3.5 2.4 3.7 2.0 1.3 75  41 M2 98-168 2.1 2.2 2.3 –2.1 –2.4 na 1.6 3.1 na 2.5 –0.8 –3.2 3.4  38 M2 600-768 –4.5 –5.5 –4.7 –5.3 –2.6 2.9 –2.8 –5.2 2.8 –3.4 –4.0 –5.4 31 c 32 M6a 98-168 –1.2 –1.2 1.5 2.1 1.5 0.7 1.4 1.1 0.6 1.4 –1.3 –1.8 0  35 M6a 600-768 3.7 –3.1 –2.6 –3.2 –2.0 –3.9 2.3 3.9 2.7 2.6 –0.9 –1.6 1  34 M6a 600-768 –2.6 –2.6 –3.4 –3.5 5.1 –3.0 –0.1 5.0 –3.3 2.8 3.8 3.0 na  40 M6a 600-768 2.6 2.5 2.3 –3.6 3.4 –9.1 2.5 –3.3 3.5 4.8 2.8 1.3 20 FIG 3. Molecular response to treatment with iadademstat. Relative gene expression levels in nucleated blood cells of a differentiation biomarker panel in the extension cohort (EC). Magenta values show gene upregulation and pink values show gene downregulation. The maximum response and its timing within the treatment period is shown. Data are expressed as 2DDCp, calculated relative to expression of the endogenous gene HPRT1 and to the predose sample. Information on the occurrence of blast cell differentiation in bone marrow (BM) or blood and the percentage variation is also shown. The final column shows blast percentage in peripheral blood at baseline. (a) In bone marrow and/or peripheral blood. (b) Grey background indicates chromosome alterations involving MLL; dark grey, MLL fusion. (c) Between D5 and D12 of treatment (patient 28) or between D15 and D29 of treatment (patient 32). (d) Differentiation syndrome diagnosed. Morph. differ., morphologic differentiation. Iadademstat was largely well tolerated with a good safety an MLL gene rearrangement: 80% of evaluable patients (4 profile. The majority of AEs were as expected for this patient of 5) exhibited iadademstat-induced morphologic and population and included infections and cytopenias, many molecular blast cell differentiation in blood or BM, and the of which predated the start of treatment. Drug-related AEs remaining patient with a MLL fusion gene exhibited clear- such as fatigue, dysgeusia, diarrhea, and anorexia were ance of circulating blasts. managed with standard supportive care. Thrombocytope- nia, managed with platelet transfusions where necessary, The particular sensitivity of patients with MLL-translocated was frequent and an anticipated on-target effect of treat- AML to iadademstat may relate to their dependency on ment with an LSD1 inhibitor based on preclinical studies. the transcription factor GFI1.16 GFI1 knockdown in MLL- translocated patient blasts robustly induces differentia- Although efficacy was not the main endpoint, there were tion16 and, in addition to inactivating histone demethylase nonetheless encouraging signs of activity. The most fre- activity, LSD1 inhibitors may also inactivate GFI1 through quent finding was that of induction of differentiation of impeding the physical interaction of LSD1 with GFI1.16 leukemic blast cells, with responses observed in PD ana- lyses within the first hours or days of treatment. Indeed, In two patients, drug-induced differentiation was vigorous. gene expression analysis allowed monitoring of the early In patient 28, toward the end of C1, hyperleukocytosis pharmacologic response to treatment. Induced differenti- developed with respiratory failure and cellulitis; the syn- ation was most notable in patients with AML associated with drome responded to hydroxycarbamide, antibiotics, and FIG 2. (Continued). screening (left) and C1D14 (right; two images from the same slide and patient are shown, separated by a dotted line). Charts show results of morphologic analysis of (B) blood smears and (C) bone marrow smears from selected MLL-translocated patients in the extension cohort (EC). HB, hemoglobin; WCC, white cell count; PLT, platelets. Journal of Clinical Oncology 4269 Salamero et al A Treatment (cycle 1) Washout 200 10 ANC Platelets (× 109/L) Platelets 8 ANC (× 109/L) 150 6 100 4 50 2 0 0 0 3 5 8 12 15 17 19 22 24 26 29 33 43 Day of Treatment B C 2 2 CD86 VCAN 1 1 –Cp –Cp 0 0 96 192 288 384 480 576 672 768 96 192 288 384 480 576 672 768 –1 Time (hours) –1 Time (hours) –2 –2 D E 4 4 S100A12 LY96 2 2 –Cp –Cp 0 0 96 192 288 384 480 576 672 768 96 192 288 384 480 576 672 768 –2 Time (hours) –2 Time (hours) –4 –4 FIG 4. Hematologic and biomarker response in patient 16. (A) Absolute neutrophil count (ANC) and platelet dynamics after treatment (cycle 1) and during the washout period in patient 16 of cohort V. Time course of changes in expression of differentiation biomarkers analyzed by quantitative reverse transcriptase–polymerase chain reaction shows that iadademstat induced expression of (B) CD86, (C) VCAN, (D) S100A12, and (E) LY96 in blood cells of patient 16. steroids. In the second patient (patient 36), onset of provide clear evidence of the activity of iadademstat as a differentiation syndrome was early (C1D5) and fulminant, a differentiating agent in patients with AML. resulting in death from respiratory failure despite treatment Of particular interest in the DE cohort was the patient in with high-dose steroid. The severity of the response may be whom iadademstat induced a CRi after a relapse of disease related to the high blast cell count in blood at the start of after allogeneic stem cell transplantation. It is unclear therapy (14.6 3 10^9/l). More modest features of mor- whether the remission was induced as a consequence of phologic or molecular differentiation, or reduction in blast a leukemia cell intrinsic effect of iadademstat or a noncell cells, were also observed in 50% of patients (2 of 4) intrinsic effect. Pertaining to the latter, inhibitors of LSD1, exhibiting an MLL-PTD and 50% (2 of 4) of patients with including iadademstat, induce expression of CD86, a pro- erythroleukemia. Resting periods (2-4 weeks) scheduled tein expressed on antigen-presenting cells that provides between cycles for safety reasons may have allowed pro- costimulatory signals for T-cell activation and survival.28-31 gression in some patients (eg, patient 35). Overall, the data Expression of CD86 in murine AML cells stimulated a graft- 4270 © 2020 by American Society of Clinical Oncology Volume 38, Issue 36 First-in-Human LSD1 Inhibitor Iadademstat in AML versus-leukemia (GVL) effect and survival in a murine al- other inhibitors of LSD1 may be further enhanced by com- logeneic transplant model.32 CD86 levels are often low or binatorial use of all-trans-retinoic acid, azacitidine, rapamycin, nonreactive to stimulation in AML.33 We hypothesize that BCL2, and DOT1L inhibitors, among others.23,35-37 Inhibition induction of CD86 in AML blasts by iadademstat might have of LSD1 has also been proposed as an approach to overcome stimulated a GVL effect raising the possibility that iada- Bromodomain and Extra-Terminal motif (BET) protein in- demstat may stimulate antileukemic immunity and could hibitor resistance in AML.38 In next-phase combination trials, be used as an adjunct to immune therapies. LSD1 ablation concomitant use of agents with antiproliferative or cytotoxic has recently been reported to enable checkpoint blockade activity will likely mitigate the risk of differentiation syndrome. and overcome resistance to anti–programmed death-1 Related to that, a phase IIa clinical trial with iadademstat and therapy in a mouse melanoma model.34 azacitidine in patients with de novo AML ineligible for intensive In summary, iadademstat is a well-tolerated compound with chemotherapy and regardless of molecular subtype is on- a good safety profile without significant extrahematologic going (ALICE study; EudraCT No.: 2018-000482-36) with toxicity that acts as a potent differentiating agent in AML. preliminary data indicating an above-expected proportion of Additional LSD1 inhibitors are under early phase evaluation patients achieving CRi and no evidence of differentiation for efficacy in cancer, including INCB059872, bomedemstat syndrome.39 Which molecular subtypes of AML are most (IMG-7289), and CC-90011. In the setting of leukemia, sensitive to combination antileukemic approaches, including preclinical data suggest that the activity of iadademstat or LSD1 inhibitors, remains to be determined. AFFILIATIONS SUPPORT 1 Hospital Vall d’Hebron, Vall D’Hebron Institute of Oncology, Supported by Oryzon Genomics and IPT-2012-0673-010000 of the Departament de Medicina, Universitat Autònoma de Barcelona, UAB, INNPACTO program of the Spanish Ministry of Economy and Barcelona, Spain Competitiveness, with contribution of Fondo Europeo de Desarrollo 2 Hospital Universitari I Politécnic La Fe, València, Spain Regional (FEDER) from the European Union and CDTI_CIIP-20131005/ 3 Centro de Investigación Biomédica en Red de Cáncer, Instituto Carlos EUROSTAR_E18159. T.C.P.S. is supported by Cancer Research UK III, Madrid, Spain Grant No. C5759/A20971. R.P. is supported by the National Institute for 4 Institut Gustave Roussy, Villejuif Cedex, France Health Research, University College London Hospitals, Biomedical 5 Hospital Universitario Virgen del Rocı́o, Sevilla, Spain Research Centre. 6 Instituto de Biomedicina de Sevilla (Insitituto de Biomedicina De Sevilla/Consejo Superior De Investigaciones Cientı́ficas/Centro de CLINICAL TRIAL INFORMATION Investigación Biomédica en Red de Cáncer), Universidad de Sevilla, EudraCT No.: 2013-002447-29 Sevilla, Spain 7 Centre Hospitalier Universitaire CHU Bordeaux, Hôpital du Haut Lévêque, Pessac, France AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF 8 Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer INTEREST de Toulouse Oncopole, Université Toulouse III Paul Sabatier, Toulouse, Disclosures provided by the authors are available with this article at DOI France https://doi.org/10.1200/JCO.19.03250. 9 National Institute for Health Research UCLH Clinical Research Facility, University College London Hospitals NHS Foundation Trust, London, United Kingdom AUTHOR CONTRIBUTIONS 10 Oryzon Genomics, Barcelona, Spain Conception and design: Olga Salamero, César Molinero, Tamara Maes, 11 The Christie NHS Foundation Trust, Manchester, United Kingdom Carlos Buesa, Francesc Bosch, Tim C. P. Somervaille 12 Cancer Research UK Manchester Institute, The University of Financial support: Rakesh Popat, Tamara Maes, Carlos Buesa, Tim C. P. Manchester, Manchester, United Kingdom Somervaille Administrative support: M. Isabel Arévalo, Tamara Maes Provision of study materials or patients: Olga Salamero, Pau Montesinos, CORRESPONDING AUTHOR Christophe Willekens, José Antonio Pérez Simón, Arnaud Pigneux, Tim C. P. Somervaille, MB BS, PhD, Cancer Research UK Manchester Christian Récher, Rakesh Popat, Cecilia Crespo, Carlos Buesa, Francesc Institute, The University of Manchester, Manchester, M20 4GJ, United Bosch, Tim C. P. Somervaille Kingdom; e-mail: tim.somervaille@cruk.manchester.ac.uk. Collection and assembly of data: Olga Salamero, Pau Montesinos, Christophe Willekens, José Antonio Pérez-Simón, Arnaud Pigneux, EQUAL CONTRIBUTION Christian Récher, Rakesh Popat, Cecilia Carpio, César Molinero, Joaquim F.B. and T.C.P.S. contributed equally to this work. Vila, Francesc Bosch, Tim C. P. Somervaille Data analysis and interpretation: Olga Salamero, Arnaud Pigneux, Christian Récher, Rakesh Popat, César Molinero, Cristina Mascaró, M. PRIOR PRESENTATION Isabel Arévalo, Tamara Maes, Carlos Buesa, Francesc Bosch, Tim C. P. Presented in part at the 58th Annual Meeting of the American Society of Somervaille Hematology, December 3-6, 2016, San Diego, CA. Manuscript writing: All authors Final approval of manuscript: All authors Accountable for all aspects of the work: All authors Journal of Clinical Oncology 4271 Salamero et al ACKNOWLEDGMENT and sponsored the study, and worked with investigators to design the The authors thank the patients who participated in this trial, their study, as well as collect, analyze, and interpret the pharmacokinetics/ families, and the co-investigators, nurses, and study coordinators at each pharmacodynamics data. The authors also thank Roser Vives Vilagut and of the sites and referral centers. 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Blood 134:3839, 2019 (suppl 1) n n n Journal of Clinical Oncology 4273 Salamero et al AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST First-in-Human Phase I Study of Iadademstat (ORY-1001): A First-in-Class Lysine-Specific Histone Demethylase 1A Inhibitor, in Relapsed or Refractory Acute Myeloid Leukemia The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Olga Salamero Cecilia Carpio Honoraria: Celgene, Astellas Pharma, Jazz Pharmaceuticals, Pfizer, Daiichi Consulting or Advisory Role: Regeneron Sankyo Speakers’ Bureau: Takeda Consulting or Advisory Role: Pfizer, Celgene, Astellas Pharma Travel, Accommodations, Expenses: Gilead Sciences, Novartis Speakers’ Bureau: Pfizer César Molinero Expert Testimony: Astellas Pharma, Jazz Pharmaceuticals, Novartis Employment: Oryzon Genomics Travel, Accommodations, Expenses: Celgene, Astellas Pharma, Pfizer, Jazz Leadership: Oryzon Genomics Pharmaceuticals, Novartis Stock and Other Ownership Interests: Oryzon Genomics Pau Montesinos Honoraria: Oryzon Genomics Consulting or Advisory Role: AbbVie, Pfizer, Shire, Daiichi Sankyo, Novartis, Consulting or Advisory Role: Marketing Y Comunicación Atril Celgene, Jazz Pharmaceuticals, Roche-Offman Uncompensated Relationships: Oryzon Genomics Speakers’ Bureau: Otsuka, Celgene, Daiichi Sankyo Cristina Mascaró Research Funding: Celgene (Inst), Janssen-Cilag (Inst), Pfizer (Inst) Employment: Oryzon Genomics Travel, Accommodations, Expenses: Amgen Joaquim Vila Christophe Willekens Employment: Oryzon Genomics Travel, Accommodations, Expenses: CHUGAI M. Isabel Arévalo José Antonio Pérez-Simón Employment: Oryzon Genomics Consulting or Advisory Role: Novartis, Janssen, Roche, Jazz Pharmaceuticals, Amgen, Novartis, Janssen, Gilead Sciences, Roche, Jazz Pharmaceuticals Tamara Maes Research Funding: Novartis, Janssen, Pfizer, Roche, Takeda Employment: Oryzon Genomics, Oryzon Genomics (I) Patents, Royalties, Other Intellectual Property: Patent licensed by Entourage Leadership: Oryzon Genomics, Oryzon Genomics (I) Bioscience on cannabinoid derivatives Stock and Other Ownership Interests: Oryzon Genomics, Oryzon Genomics (I), Travel, Accommodations, Expenses: Roche, Gilead Sciences, Janssen Mendelion Lifesciences, Mendelion Lifesciences (I), Palo Biofarma, Palo Biofarma (I) Arnaud Pigneux Consulting or Advisory Role: Roche, AbbVie, Astellas Pharma, Amgen, Daiichi Carlos Buesa Sankyo, Jazz Pharmaceuticals, Pfizer Employment: Oryzon Genomics Travel, Accommodations, Expenses: Sanofi Leadership: Oryzon Genomics (Inst) Stock and Other Ownership Interests: Oryzon Genomics Christian Récher Patents, Royalties, Other Intellectual Property: Inventor in some of Oryzon’s Consulting or Advisory Role: Celgene, Amgen, Novartis, Jazz Pharmaceuticals, patents AbbVie, Janssen, Astellas Pharma, Macrogenics, Daiichi Sankyo, Astellas Pharma, Otsuka, Novartis, Incyte, Pfizer, Roche Francesc Bosch Research Funding: Celgene (Inst), Amgen (Inst), Novartis (Inst), Jazz Consulting or Advisory Role: AstraZeneca, Genentech, Janssen-Cilag, Lilly, Pharmaceuticals (Inst), Astellas Pharma (Inst), Chugai Pharma (Inst), Agios AbbVie (Inst), Daiichi Sankyo (Inst), MaatPharma (Inst), Roche (Inst), AbbVie Speakers’ Bureau: AbbVie, Janssen, Roche, AstraZeneca Travel, Accommodations, Expenses: Incyte, Celgene, Sanofi, Amgen, Novartis, Tim C. P. Somervaille Daiichi Sankyo, Gilead Sciences Honoraria: Novartis Rakesh Popat Consulting or Advisory Role: Novartis Honoraria: Janssen, Takeda, Celgene, GlaxoSmithKline Research Funding: Imago Biosciences, Cellcentric Consulting or Advisory Role: Takeda, AbbVie, GlaxoSmithKline, Celgene No other potential conflicts of interest were reported. Research Funding: Takeda (Inst) Travel, Accommodations, Expenses: Janssen, Takeda © 2020 by American Society of Clinical Oncology Volume 38, Issue 36