Phase 2 Study of iadademstat for the treatment of patients with essential thrombocythemia resistant/intolerant to hydroxyurea.

Prior treatment

• Uncontrolled or untreated infection with Human immunodeficiency virus (HIV) or hepatitis B or C virus (HBV, HCV) • HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial • For patients with evidence of chronic HBV infection, the HBV viral load must be undetectable on suppressive therapy to be eligible for this trial • History of HCV infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Current use of prohibited medication (i.e., cytotoxic agents, hematopoietic growth factors, monoamine oxidase A and B inhibitors (MAOIs) like Tranylcypromine or Phenelzine) or expected to require any of these medications during treatment with the investigational drug. Previous use requires a washout period at least 5 half-lives of that agent or 14 days if half-live unknown prior to the study D1
• Prior use of an investigational agent requires a washout period of at least 5 half-lives of that agent or 14 days if half-live unknown, prior to the study D1
• Patients refractory to bomedemstat or other LSD-1 inhibitors for the treatment of ET
• Known current drug or alcohol abuse
• Other co-morbidity that substantially increases subject's risk for the study per the Investigator discretion. Subjects with a concurrent second active but stable malignancy, such as non-melanoma skin cancers, are eligible
• Patients may not receive administration of live or live-attenuated vaccines. Administration of non-live vaccines including RNA- based vaccines is allowed and is recommended for pneumococcal, coronavirus and influenza vaccines
• Has undergone major surgery ≤4 weeks prior to starting study drug or has not recovered from the side effects of such surgery
• Unresolved treatment-related toxicities from prior therapies (unless resolved to ≤ Grade 1)
• Known fever > 38.5°C in the week prior to first administration of study medication

Other illness

• Current diagnosis of pulmonary hypertension requiring oxygen therapy
• Congestive heart failure New York Heart Association (NYHA) class 3 or 4
• Known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to drugs chemically related to MAOIs
• History of any illness/impairment of gastrointestinal (GI) function that might interfere with drug absorption (e.g., chronic diarrhea, patients with gastric bypass)
• History of splenectomy
• Uncontrolled active infection (bacterial, viral, fungal, or parasitic) in the last 72h before starting study treatment

Lab values

• Transfusion dependency, defined as requiring 2 or more units of packed red blood cells (RBC) per month for more than 3 months or a hemoglobin level of ≤ 8g/dL in the preceding 8 weeks before the start of dosing
• Left ventricular ejection fraction (LVEF) < 45% by echocardiogram or MUGA
• Mean of triplicate corrected QT interval (mQTcF) > 450ms at Screening
• Evidence at the time of Screening of increased risk of bleeding, including any of the following: • Activated partial thromboplastin time (aPTT) > 1.3 x the upper limit of normal (ULN) • International normalized ratio (INR) > 1.3 x the local ULN • History of severe thrombocytopenia or platelet dysfunction unrelated to a myeloproliferative disorder or its treatment • Known bleeding disorder (e.g., dysfibrinogenemia, factor IX deficiency, hemophilia, Von Willebrand’s disorder (e.g. patients diagnosed with Acquired von Willebrand syndrome [AVWS]), Disseminated Intravascular Coagulation [DIC], fibrinogen deficiency, or other clotting factor deficiency)
• Evidence at the time of Screening of significant renal or hepatic insufficiency as defined by any of the following local lab parameters: • Calculated glomerular filtration rate (GFR; using the Cockcroft-Gault equation) < 40 mL/min/1.73 m2 or serum creatinine > 1.5 x ULN • Aspartate transaminase (AST) or alanine aminotransferase (ALT) ≥2 x ULN • Bilirubin > 1.5 x ULN Total and direct bilirubin > 3 x ULN, if the elevation is associated with choledocholithiasis, cholecystitis, biliary obstruction, or hepatocellular disease. Elevated bilirubin attributed to hemolysis or Gilbert’s syndrome is not exclusionary • History of cirrhosis or any evidence of bridging fibrosis, or active hepatitis on liver biopsy

Other

• Eastern Cooperative Oncology Group (ECOG) questionnaire score of 3 or greater at Screening
• Patients with known sensitivity to iadademstat
• Currently pregnant or breastfeeding or plan to become pregnant or breastfeed during the study
• Unable to comply with the study procedures outlined in the protocol as judged by the investigator

• Age ≥ 18 years
• Able and willing to give consent and comply with all study procedures including bone marrow (BM) evaluation and peripheral blood (PB) sampling during the study [BM is only required at screening and week 48 of treatment for those patients in the extension phase or as medically indicated]
• Women of childbearing potential, must have a documented negative pregnancy test prior to entry and agree to use one or more locally medically accepted methods of contraception from consent, through the entire study period and 4 months after last dose of iadademstat
• Men of reproductive capacity must agree to use effective contraception from the start of treatment through 4 months after last dose of iadademstat
• Agreement to not to donate or freeze egg(s) or sperm during the course of this study or within 4 months after receiving their last dose of study drug
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible
• Body weight of at least 50 kg
• Diagnosis of ET per revised WHO 2016 with High-risk per the revised IPSET-t diagnostic criteria for myeloproliferative neoplasms (either thrombosis history at any age or JAK2-mutated patients who are > 60 years old before treatment starts)
• Patients who had previously been treated with HU and are intolerant to HU or had inadequate response as per the European Leukemia Net (ELN) criteria: • Platelet count > 600×109/L after a daily dose of at least 2g HU for at least 3 months (2.5 g/day in patients with a body weight over 80 kg) or maximally tolerated dose if < 2g/day after at least 3 months of HU • Platelet count > 400 × 109/L and WBC < 2.5 ×109/L at any dose and duration of HU • Platelet count > 400 × 109/L and hemoglobin < 10 g/dL at any dose and duration of HU • Presence of HU-non hematologic related toxicities at any dose and duration of therapy (e.g., fever, pneumonitis, mucocutaneous manifestations or leg ulcers)
• Must have discontinued previous ET therapy at least for: • 24h if prior anagrelide or hydroxyurea • 4 weeks if prior interferon • 7 days for all other prior therapies
• Blood parameters pre-dose at screening should be: • Platelet count > 450x109/L • ANC ≥ 0.5x109/L • Hb ≥ 10g/dL CONFIDENTIAL 15 • Peripheral blast count < 1%
• Fibrosis Score < grade 2, as per a slightly modified version of the European Consensus Criteria for Grading Myelofibrosis [MF-0 or MF-1 fibrosis consistent with low-grade reticulin deposition and prefibrotic myelofibrosis]
• Life expectancy > 9 months
• Able to swallow oral medications