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

original reports 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 Olga Salamero, MD 1 ; Pau Montesinos, MD 2,3 ; Christophe Willekens, MD 4 ; Jos´ e Antonio P´ erez-Sim´ on, MD, PhD 5,6 ; Arnaud Pigneux, MD, PhD 7 ; Christian R´ echer, MD, PhD 8 ; Rakesh Popat, MB, BS, PhD 9 ; Cecilia Carpio, MD 1 ;C´ esar Molinero, MD, PhD 10 ; Cristina Mascar´ o, PhD 10 ; Joaquim Vila 10 ; M. Isabel Ar´ evalo, PhD 10 ; Tamara Maes, PhD 10 ; Carlos Buesa, PhD 10 ; Francesc Bosch, MD, PhD 1 ; and Tim C. P. Somervaille, MBBS, PhD 11,12 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/m 2 /d) of each week in 28-day cycles in a DE phase that resulted in a recommended dose of 140 mg/m 2 /d of iadademstat as a single agent. This dose was chosen to treat all patients (n 514) 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 dosedependent 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 INTRODUCTION Acute myeloid leukemia (AML) is a hematologic malignancy characterized by a myeloid lineage differentiation block. 1-3 It remains, for the most part, an incurable disease, especially in the elderly, and new approaches to treatment are required, including those that promote differentiation. 4-10 Epigenetic dysfunction has a central role in AML pathology, as evidenced by recurrent mutations in transcription factors and epigenetic regulators. 11-14 Certain regulators are under evaluation as therapeutic targets, including lysinespecific demethylase 1 (LSD1), which serves a dual role in hematopoiesis. It exhibits demethylase activity versus monomethylated and dimethylated lysine residues on histone tails 15 as well as scaffolding activity, which facilitates recruitment of histone deacetylase to sites on chromatin where SNAG domain transcription factors such as GFI1 and GFI1B are bound. 16 LSD1 is highly expressed in hematopoietic stem cells and myeloblasts, and is necessary for proliferation and terminal differentiation during normal hematopoiesis. 17 Preclinical studies have revealed that LSD1 sustains the differentiation block in certain molecular subtypes of AML, in particular, MLL-translocated AML, and is required for leukemic stem cell potential. 18-22 Targeting LSD1 in AML may serve to promote differentiation of leukemic blasts. Iadademstat (ORY-1001) is a highly selective and potent covalent inhibitor of LSD1, which induces differentiation of AML cells in vitro at low concentrations ASSOCIATED CONTENT Data Supplement Protocol Author affiliations and support information (if applicable) appear at the end of this article. Accepted on September 8, 2020 and published at ascopubs.org/journal/ jco on October 14, 2020: DOI https://doi. org/10.1200/JCO.19. 03250 4260 Volume 38, Issue 36 Downloaded from ascopubs.org by 150.214.182.238 on November 3, 2023 from 150.214.182.238 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. (,1 nM) and compromises leukemic stem cell capacity in preclinical models of AML. Iadademstat induces a monocyte/macrophage differentiation gene signature in AML cell lines, and induction of differentiation biomarkers correlates with reduction of tumor growth in rodent leukemia xenografts. Iadademstat has excellent oral bioavailability, excellent target exposure, and promising antitumor activity in vivo. 23 We report a first-in-human dose-escalation (DE) and extension-cohort (EC) phase I study with iadademstat in patients with refractory or relapsed (R/R) acute leukemia (EudraCT No.: 2013-002447-29). The primary objective was to assess safety and tolerability of iadademstat; secondary objectives were to study pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. METHODS Participant Selection Patients with relapsed or refractory acute leukemia (excluding acute promyelocytic leukemia; age $16 years) not deemed suitable for standard therapies, with Eastern Cooperative Oncology Group performance status #2 and without an unstable or uncontrolled concurrent severe medical condition, were eligible. Prior acute leukemia treatment should have stopped at least 14 days before the first dose of iadademstat. Hydroxycarbamide was allowed until 12 hours before the first dose of iadademstat and then after the fifth day (Data Supplement, online only). Patients with MLL-rearranged AML or acute erythroblastic leukemia were selected for the EC. Study Design The protocol was approved by the institutional review board or independent ethics committee at each participating center and by regulatory authorities, in accordance with the Declaration of Helsinki, the International Conference on Harmonization–Good Clinical Practice, and local laws. Investigators obtained informed consent from each participant before performing any study-specific procedures. Data were anonymized to protect patient identities. DE was performed in a traditional 3 13 design (Data Supplement), 24,25 with dosing administered until disease progression, death, consent withdrawal, or adverse events (AEs) that did not improve by standard of care (Data Supplement). The starting dose was based on preclinical toxicology studies (Data Supplement). The escalation doses were 5, 15, 30, 45, 60, 80, 140, and 220 mg/m 2 /d in cohorts 1 to 8, the latter included after an amendment to add an additional dose level (220 mg/m 2 /d). Iadademstat was administered orally after a minimum of 2 hours of fasting using a precharged syringe in a 28-day cycle (5 days on/2 days off 34 weeks). Details regarding maximum tolerated dose assessment, study monitoring, safety analysis, sampling, PK/PD analysis, bone marrow (BM) biomarker analysis, response analysis, and statistical assessments are available in the Data Supplement. RESULTS Patient Characteristics Between February 2014 and April 2015, 27 patients with R/R acute leukemia were enrolled in the DE phase (1 with ALL in cohort 1; 26 with AML). Two patients failed screening. Between September 2015 and May 2016, 14 patients were enrolled in the EC (140 mg/m 2 /d), which, guided by preclinical data, was restricted to patients with MLL gene rearrangements or erythroleukemia. Median age was 67 years; 15 (42%) of 36 patients with karyotypes available exhibited adverse risk cytogenetics, 26 and 7 (17%) of 41 patients were in second or third relapse. The median time since initial diagnosis to study enrollment was 9.8 months and since last treatment was 1.3 months. Of 41 patients, 30 completed cycle 1 (C1; Table 1; Data Supplement). Safety and Tolerability All patients experienced treatment-emergent AEs; in total, 497 were reported (Data Supplement). The most frequent nonhematologic AEs were infection, GI symptoms, hemorrhagic manifestations, asthenia, musculoskeletal 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. Journal of Clinical Oncology 4261 First-in-Human LSD1 Inhibitor Iadademstat in AML Downloaded from ascopubs.org by 150.214.182.238 on November 3, 2023 from 150.214.182.238 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. 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. 0426 1161127 2516 NA 2 0 2 Median WBC count 310 9 /L, (range) 4.0 (0.6-104.9) 2.5 (0.2-26.3) 2.9 (0.2-104.9) Median platelet count 310 9 /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 114721 $2527 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 Salamero et al Downloaded from ascopubs.org by 150.214.182.238 on November 3, 2023 from 150.214.182.238 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. TABLE 2. Grade 3 and 4 AEs and SAEs AE Description Total Grade 3 and 4 AEs Grade 3 and 4 AEs Considered Possibly, Probably, or Definitely Related to Iadademstat DE (n 527) EC (n 514) DE (n 527) EC (n 514) 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 First-in-Human LSD1 Inhibitor Iadademstat in AML Downloaded from ascopubs.org by 150.214.182.238 on November 3, 2023 from 150.214.182.238 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. TABLE 2. Grade 3 and 4 AEs and SAEs (continued) AE Description Total Grade 3 and 4 AEs Grade 3 and 4 AEs Considered Possibly, Probably, or Definitely Related to Iadademstat DE (n 527) EC (n 514) DE (n 527) EC (n 514) Other Graft versus host disease 1 ——— Infusion reaction 1 ——— Total 62 37 6 10 SAE Description Total SAEs SAEs Considered Possibly, Probably, or Definitely Related to Iadademstat DE (n 527) EC (n 514) DE (n 527) EC (n 514) 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 521) 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 Salamero et al Downloaded from ascopubs.org by 150.214.182.238 on November 3, 2023 from 150.214.182.238 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. pain, mucositis, edema, skin rash, and anorexia. Of the AEs, 99 were grade 3 or 4; 66 were reported as serious AEs (SAEs), mainly infections (Table 2; Data Supplement). Sixty-six AEs were considered related to iadademstat (Data Supplement), 10 certainly, 21 probably, and 35 possibly, according to investigator assessment. Of these, 16 were grade 3 or 4, and 11 were SAEs (Table 2; Data Supplement). SAEs included neutropenic fever or fever of unknown origin (n 54), cellulitis (n 51), pneumonia or respiratory infection (n 52), thrombocytopenia (n 51), asthenia (n 51), and differentiation syndrome (n 52). During the study, there were 27 recorded grade 5 AEs (where the AE was considered by the investigator to have contributed to death; Table 2; Data Supplement), and 25 patients died (DE, n 516; EC, n 59). The recorded causes of death were as expected for patients with R/R acute leukemia: AML (n 512), lung infection or respiratory failure (n 59), septic shock (n 51), sinusitis (n 51), and intracranial hemorrhage with heart failure (n 51). Three grade 5 AEs were considered possibly related to iadademstat: pneumonia in a patient in cohort VIII and episodes of cellulitis and differentiation syndrome in an EC patient whose recorded cause of death was AML. One EC patient died as a result of complications arising from a differentiation syndrome (n 51), considered certainly related to iadademstat. Dose-Limiting Toxicity In cohort VIII (220 mg/m 2 /d), two SAEs were considered possibly related to iadademstat—pneumonia (patient 24; grade 5) and an episode of febrile neutropenia (patient 27; grade 3), which did not meet the strict protocol criteria for a dose-limiting toxicity (Data Supplement). However, in view of evidence in cohort VII (140 mg/m 2 /d) of maximal biomarker induction within 24 hours of treatment, despite subsequent accumulation of plasma iadademstat from D1- D5 (Fig 1A and 1B; eg, patient 22), and evidence of potent hematopoietic target engagement (induction of grade 4 thrombocytopenia by day 15-17 of treatment in two patients; Figs 1C, and 1D), the Safety Monitoring Committee took the pragmatic view to establish the maximum tolerated dose as 220 mg/m 2 /d. The EC dose was set at 140 mg/m 2 /d. The effects of iadademstat on platelet levels across cohorts are shown in Fig 1C, and platelet dynamics for a cohort VII patient with high baseline platelet levels are shown Fig 1D. In the EC, one patient required a 25% dose reduction at cycle 1 day 15 (C1D15) after grade 4 thrombocytopenia and transient nonspecific deterioration in general health (patient 32). PK, PD, and Biomarkers At 5 and 15 mg/m 2 /d, plasma concentrations were typically below the lower limit of quantification. At higher doses, concentrations increased in an approximately linear manner, with a tendency for overproportional exposure at doses .80 mg/m 2 /d. T max was generally observed 4-8 hours postdose. Compound accumulation was observed after repeated dosing, with an average accumulation ratio of approximately 3-6. The volume of distribution for iadademstat was approximately 200 times total body water, and the half-life was 40-100 hours. PK curves and parameters calculated for the EC (140 mg/m 2 /d) are summarized in Figures 1A, 1B, and 1E. As expected from preclinical data, 23 the PD biomarker response in the DE phase was heterogeneous. Nevertheless, selected biomarkers showed time and dose-dependent response profiles in individual patients. PI16/CRISP9 was rapidly induced on day 1 (Fig 1B); maximal induction (2DDCp max) was achieved after multiple dosing in patient 11 (45 mg/m 2 /d) and patient 18 (80 mg/m 2 /d) but within 18 hours of the first dose in patient 22 (140 mg/m 2 /d), reflecting saturation despite further increases in exposure over the following days. Remarkably, induction was sustained up to 1 week after the last administration. In the EC, patients with monocytic or monoblastic lineage leukemias (FAB-M4 or -M5 AML) exhibited a potent response of many biomarkers, with the highest increase observed for VCAN, S100A12, and LY96. Biomarker response correlated with morphologic differentiation of blast cells in BM and/or peripheral blood (PB; Figs 2A-2C and Fig 3). A rapid and potent induction of VCAN and S100A12 was observed in two patients who developed differentiation syndrome (patients 28 and 36). RNA sequencing of selected predose and post-treatment (C1D29) BM samples confirmed upregulation of PROCR and downregulation of erythroid biomarkers GYPA,GYPB, HBA1, and HBB in three patients with erythroleukemia (M6A) and confirmed the broad upregulation of biomarkers in PB in patient 29 (Data Supplement). Together, these surrogate biomarker data demonstrate target engagement of iadademstat in leukemic cells and support their utility as a tool to monitor response to LSD1 inhibition. Iadademstat Efficacy In the DE phase, patient 16 achieved a complete remission with incomplete count recovery (CRi). This patient had FAB-M2 AML (Data Supplement), which had relapsed 6 months after a sibling donor allogeneic stem cell transplantation. At relapse, the patient received a single cycle of 60 mg/m 2 /d iadademstat. At screening, the BM was infiltrated with 40% blasts. After treatment, the neutrophil and platelet counts improved and were normal by D20; the patient exhibited a progressive increase of the absolute neutrophil count (ANC) beginning at D5 (Fig 4A). Induction of CD86 started on D5, and expression of differentiation genes VCAN, S100A12, and LY96 was observed at D12 (Fig 4B-D). The D29 BM demonstrated morphologic remission that was sustained on D52 (both 2% blasts in a hypocellular BM with persistent thrombocytopenia). Of note, on C1D11, the patient developed acute graft-versus- host disease of the liver and was treated with prednisolone Journal of Clinical Oncology 4265 First-in-Human LSD1 Inhibitor Iadademstat in AML Downloaded from ascopubs.org by 150.214.182.238 on November 3, 2023 from 150.214.182.238 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. Parameters Extension Cohort – 140   g/m 2 /d Day 1 Day 5 Day 26 AUC 0-24 hr (pg hr/mL) 105 ± 85 (5-321) 475 ± 273 (70-1,058) 912 ± 521 (326-1,688) C max (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) T max (hr) 5 (4.0-18.0) 5 (2-24) AUC inf (pg hr/mL) - - 3,715 ± 1,405 (2,722-4,709) Half-life (hr) - - 79.9 ± 29.7 (58.9-100.9) 6 (2-24) E B 100 PK: Iadademstat Plasma Conc. (pg/mL) 80 60 40 20 0 Time (hours) 0 24 48 72 96 120 144 168 600 624 648 696672 720 744 768 792 8 4 0 PD:PI16-CP –4 –8 –12 Day 1-8 Day 26 + washout A 100 Iadademstat Plasma Concentration (pg/mL) 80 60 40 20 0 Time (hours) 0 6 12 18 24 96 108 120 132 144 600 624 648 672 696 720 744 768 Day 1 Day 5 + 2 off Day 26 + washout I II III IV V VI VII VIII E 11 PK 18 PK 22 PK 11 PD 18 PD 22 PD C Platelet CFB EoT (%) –100 –75 –50 –25 0 I II III IV V VI VII/E VIII D 50 Platelet CFB EoT (%) 25 0 –25 –50 –75 –100 0 5 10 15 20 25 30 35 40 45 50 55 Treatment Day 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 6SEM 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 Salamero et al Downloaded from ascopubs.org by 150.214.182.238 on November 3, 2023 from 150.214.182.238 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. and antithymocyte globulin. A single dose of iadademstat was administered on D89 (C2D1). Death occurred in remission on D92 as a result of sepsis for reasons unrelated to iadademstat. More modest hematologic improvements were also detected in the DE phase in other patients. Patient 9 in cohort III (30 mg/m 2 /d) showed a decrease in BM blasts from 38% to 24% after 1 cycle (D29), as did patient 13 in cohort V (60 mg/m 2 /d; 51%-36% on C1D29). The modest plasma levels (Data Supplement) were sufficient to induce robust upregulation of differentiation genes VCAN,S100A12, and LY96 (Data Supplement). In the EC, no responses according to International Working Group criteria were observed, but a number of biologically significant changes were seen, including induction of blast cell differentiation and reduction in blast cell burden. Among patients with MLL translocations, patient 29 (FAB M4 AML with t[9;11][q21;q23]) showed reductions in BM and PB blast percentages with a concomitant increase in differentiated cells across multiple treatment cycles. The maximum reduction of blasts in the BM was detected on C3D29 (from 95% to 41%) and in PB on C2D29 (from 93% to 44%; Figs 2B and 2C). Induced expression of differentiation genes, including VCAN,S100A12,LY96, CD86, and ITGAM was detected in blood cells (Fig 3). Although this patient received hydroxycarbamide 500 mg three times daily from C1D6 (as permitted by protocol) and hydroxycarbamide has been reported to potentiate differentiation of other agents, 27 the robust induction of PD biomarkers was already observed on C1D5, in the absence of hydroxycarbamide. Patients 28 (FAB-M4 AML with [t10;11][q12;q23]) and 36 (FAB-M5 AML with [t11,17][q23;q21) developed prominent features of morphologic differentiation during treatment. PB smears revealed significant promonocytic and monocytic differentiation, and biomarker analysis showed induction of CD86,ITGAM, LY96, and especially VCAN and S100A12 (Figs 2A and 3). In the former case, the leukocyte count started to increase after 2 weeks of treatment. The patient developed breathlessness on D25 and was treated with antibiotics, intravenous steroids, and hydroxycarbamide. In the latter case, the patient developed fatal respiratory failure on D5 of treatment, despite prompt treatment with high-dose dexamethasone. Both patients were classified as having drug-induced differentiation syndrome. There was modest evidence of promonocytic differentiation in patient 31 (FAB-M4 with t[9;11][q21;q23]; Fig 2A and 2B), including induction of LY96 (Fig 3),andinpatient 38 (FAB-M2 AML with MLL–partial tandem duplication [PTD]), who showed an increase in PB promonocytes from 0% to 10% on C2D23 (Fig 2B). Patient 33 (FAB-M4 AML with t[9;11][(q21;q23]) showed a 95% decrease in PB blasts (0.2 310 9 /L at screening to 0.01 310 9 /L at end of C1). However, the BM blast percentage was stable during treatment, and no morphologic evidence of blast cell differentiation was observed. Differentiation markers upregulated at the end of C1 included VCAN and CD86 (Fig 3). Blast cells in PB in patient 39 (FAB-M2 AML with MLLPTD) decreased from 75% to 51% on C1D8 (data not shown), although no morphologic differentiation was evident; upregulation of LY96 and to a minor extent VCAN and CD86 were observed (Fig 3). Among the four erythroleukemia (FAB M6) patients, patient 35 demonstrated a modest but consistent proportional reduction in BM blasts (Data Supplement). There was no evidence of morphologic differentiation but upregulation of VCAN at the end of C1 was observed in blood, and erythrocytic markers were downregulated in BM (Fig 3; Data Supplement). Patient 32 showed stable disease, with a transient blast reduction from 17% to 8% in BM observed between C1D15 and C1D29 of treatment (Figs 2C and 3). DISCUSSION Iadademstat was the first selective inhibitor of LSD1 to enter clinical trials. Our study reveals that iadademstat exhibits approximately linear PK and a half-life of 40-100 hours. Pharmacodynamic analyses demonstrate rapid target engagement. Patients with R/R AML are difficult to treat, with survival times typically in the range of weeks to months. The majority of enrolled patients were .65 years of age and presented with pancytopenia at screening, making it a particular challenge to discern drug-induced versus diseaserelated 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 149 310 9 /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 513, D5: n 513, D26: n59). C max indicates maximum (peak) plasma drug concentration (D1: n 514, D5: n 514, D26: n 59). T max indicates time to reach maximum (peak) plasma concentration (D1: n 514, D5: n 514, D26: n 59). AUC inf indicates area under the plasma concentration time curve from time zero to infinity and half-life (hours; D26: n 52). Values are shown as mean 6standard deviation (median for T max ) with range in brackets. CFB, change from baseline; EoT, end of treatment. Journal of Clinical Oncology 4267 First-in-Human LSD1 Inhibitor Iadademstat in AML Downloaded from ascopubs.org by 150.214.182.238 on November 3, 2023 from 150.214.182.238 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. B Patient Karyotype Timepoint HB (G/L) WCC (× 109/L) PLT (× 109/L) Blasts, % Promyelocytes and myelocytes, % Promonocytes, % Monocytes, % Neutrophils, % Lymphocytes, % 28 t(10;11) Screen 94 0.9 53 10 55 0 0 15 20 C1D29 85 30 13 79 0 12 9 0 0 29 t(9;11) Screen 96 23.5 47 93 0 0 0 0 7 C1D29 82 8.6 24 79 0 0 0 0 21 C2D29 88 1.2 17 44 20 0 0 0 36 C3D29 92 4.6 57 53 36 0 0 0 11 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 C Patient Karyotype Timepoint Blasts, % Promyelocytes, % Myelocytes, % Metamyelocytes, % Neutrophils, % Promonocytes, % Monocytes, % Lymphocytes, % 29 t(9;11) Screen 95 0 0 0 0 0 0 5 0 C1D29 81 11 5 0 0 0 0 3 0 C2D29 69 12 7 8 0 0 0 4 0 C3D29 41 15 32 11 0 0 0 1 0 33 t(9;11) Screen 47 4 13 9 0 0 0 11 16 C1D29 31 12 16 2 0 0 1 32 6 A 30m Screening Screening Day 21 Day 14 Patient No. 28Patient No. 31 Nucleated erythroid, % 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 Salamero et al Downloaded from ascopubs.org by 150.214.182.238 on November 3, 2023 from 150.214.182.238 Copyright © 2023 American Society of Clinical Oncology. All rights reserved.