Inclusion Criteria:
1. Patients must be fully informed about the study and sign the informed consent form (ICF) before any study specific assessment.
2. Patients ≥18 years old at the time of signing the informed consent.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 prior to study entry.
4. Have measurable disease per RECIST v1.1 or PCWG4 criteria (for mCRPC).
5. Adequate organ and bone marrow function as follows (subject must not have received any growth factor within 4 weeks or a blood transfusion within 7 days of the hematology laboratory):
1. Absolute neutrophil count (ANC) ≥ 1.5 x109/L;
2. Platelets ≥ 100 x109/L;
3. Hemoglobin ≥ 9.0 g/dl;
4. Prothrombin time (PT) or international normalised ratio (INR) ≤1.5 × ULN;
5. Total bilirubin level ≤ 1.5 x institutional upper limit of normal (ULN), except for patients with Gilbert's disease ≤ 5.0 x ULN;
6. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN;
7. Creatinine ≤ 1.5 x ULN;
8. creatinine clearance (CrCl) ≥ 30 mL/min;
9. Albumin \> 25 g/L.
Criteria Specific for Dose-escalation phase:
6. Patients with any histologically or cytologically confirmed solid tumor at advanced or metastatic stage.
Note: glioblastoma, cholangiocarcinoma, gastric, liver, or nasopharyngeal carcinomas are excluded given the potential negative impact of MAO-A inhibition and effect in reactive oxygen species (ROS) metabolism in these tumor types.
7. Disease progression to standard of care therapies within one month prior to study entry.
Note: Patients should have no available standard of care therapy likely to confer clinical benefit in the opinion of the investigator.
8. Life expectancy \> 6 months.
Criteria Specific for Dose-expansion phase:
9. Patients with histologically or cytologically confirmed mCRPC receiving ARPi treatment (including: abiraterone, apalutamide, enzalutamide or darolutamide) and experiencing PSA progression (any increase above 0.2 ng/mL in PSA level from baseline/nadir, confirmed by one additional rising PSA measurement at least 21 days apart) confirmed.
Note: the inclusion of patients will be limited to 50% with abiraterone and 50% with androgen receptor targeted agents (ARTAs).
Note: Patients should have castration resistant prostate cancer (CRPC) as defined by PCWG4 criteria.
Note: patients with prior therapies for locoregional disease and/or initiating ARPis in the hormone-sensitive that progressed to CRPC setting are eligible.
Note: Patients candidates for concurrent treatment with androgen deprivation therapy (ADT) according to the standard clinical practice are allowed.
10. Patients with a Charlson score ≤ 3 prior to study entry.
Contraceptive and other requirements:
11. Participants who have pregnant partners must use a condom and those with partners of childbearing potential must use a condom and another adequate birth control measure if engaging in sexual activities during the study treatment period and for at least 4 weeks after the last dose of ITR-251. A highly effective method of birth control is defined as those which result in low failure rate (i.e., less than 1% per year) when used consistently and correctly.
12. During the dose-escalation phase, women of childbearing potential (WOCBP) and their partners must agree to use a highly effective method of birth control during the study treatment period and for at least 4 weeks after the last dose of ITR-251.
13. Are willing and able to comply with scheduled visits, treatment schedule, the planned trial assessments, lifestyle restrictions, and other requirements of the trial. This includes that they are able to understand and follow trial-related instructions.
Exclusion Criteria:
1. For Dose-escalation phase only: women pregnant or breastfeeding.
2. For Dose-escalation phase only: Patients with glioblastoma, cholangiocarcinoma, gastric, liver, or nasopharyngeal carcinomas.
3. For dose-expansion phase only: patients with symptomatic or radiologic PD requiring or tributary for treatment with docetaxel or other concurrent anticancer therapies other than ADT and ARPi.
4. Patients with brain metastasis.
5. Required concurrent treatment with other investigational medicinal products or participation in other clinical trials.
6. Previous treatment with MAO-A inhibitors.
7. Treatment with antidepressant or psychostimulants, opioids or analgesics, antitussives and antihistaminics listed as prohibited concomitant medication within one month or 5 halflives, whichever is longer, prior to the study entry or patients with foreseen potential requirement of antidepressants during the study.
8. Previous systemic anticancer treatments should have been discontinued 15 days prior to study entry.
Note for dose-expansion phase: Continuous treatment with ADT and ARPi before start of study treatment is allowed.
9. Residual toxicity from prior anticancer therapy that are NCI-CTCAE v6.0 Grade ≥ 2, except for Grade ≥ 2 alopecia.
Note: Stable chronic Grade 2 toxicities from previous treatments may be eligible per the judgement of the investigator.
10. Have had major surgery (not including diagnostic surgery) within the 4 weeks prior to the first dose of trial treatment or are planned to undergo major surgery during the course of the trial.
11. Known secondary active malignancy requiring treatment within the last 2 years prior to study entry.
Note: Patients that have secondary malignancies that have undergone potentially curative therapy are eligible.
12. Body mass index (BMI) \< 15 kg/m2 or patients with symptomatic malnutrition (GLIM criteria).
13. Uncontrolled hypertension despite appropriate medical therapy (blood pressure \[BP\] \> 160 mmHg systolic and 90 mmHg diastolic at 2 separate measurements no more than 60 minutes apart during the screening visit).
Note: patients may be rescreened after adjustment of antihypertensive medications.
14. History of hypertensive crisis.
15. Known prior history of mania or major psychiatric illness (schizophrenia, bipolar disorder, severe major depression requiring hospitalization, psychosis, etc.).
16. Patients with a pre-existing diagnosis of severe insomnia (Grade 3 according to CTCAE v6.0) or primary sleep disorders (e.g., severe obstructive sleep apnea, narcolepsy) who have required adjustments to their pharmacological treatment in the 28 days prior to inclusion.
17. Patients at high risk (i.e. categories 4, 5, or any suicide behaviors \[6-9\]) of suicide according to the validated Columbia Scale (C-SSRS).
18. Patients with ongoing or active severe infections requiring treatment.
19. Patients with symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia.
20. History of stroke or significant cerebrovascular disease (ie, transient ischemic attack) within 6 months prior to initiation of study intervention.
21. History of clinically significant cardiac disease within 6 months prior to the initiation of study intervention, including but not limited to unstable angina, acute myocardial infarction, endoscopic or open-heart cardiac surgery, or heart failure classified as New York Heart Association Grade ≥ 2, left ventricular ejection fraction \<45% or interval corrected by Fridericia (QTcF) \>470 ms (for women) and \>450 ms (for men) or clinically significant arrhythmias.
22. History of clinically significant respiratory disease within 6 months prior to the initiation of study intervention, including severe chronic obstructive pulmonary disease or asthma.
23. History of noninfectious interstitial lung disease (ILD) /pneumonitis /radiation pneumonitis that required steroids or has current ILD/pneumonitis.
24. Clinically significant gastrointestinal disorder including bleeding, occlusion, diarrhoea \>Grade 1, malabsorption syndrome, ulcerative colitis, inflammatory bowel disease or partial bowel obstruction.
25. Any intercurrent gastrointestinal condition that may affect the ingestion and absorption of ITR-251.
26. History of allergic reactions attributed to compounds of similar chemical or biologic composition to ITR-251 or other monoamine oxidase inhibitors.
27. History or current drug abuse.
28. Uncontrolled intercurrent illness, or condition or psychiatric illness/social situations that would limit compliance with study requirements.
