Single-centre, open-label, dose escalation phase I clinical trial, designed to evaluate mainly the safety and tolerability of the antitumor drug THE-0504 in patients with different types of solid tumors.

The primary aim of the Phase 1 study is to define the Recommended Phase 2 dose and the Maximum Tolerated Dose of THE-0504, as well as to assess the safety and tolerability of escalating doses of THE-0504 administered intravenously to patients with different types of solid tumors. The study will also provide first data in humans concerning safety, tolerability, antitumor activity, pharmacokinetics, pharmacodynamics and immunogenicity of THE-0504. For the first-in-human study, a model based on a classic 3+3 design following a modified Fibonacci sequence for dose escalation will be implemented. THE-0504 will be administered IV on day 1 and day 8 of a 21-day cycle. At the end of 21 days from the first treatment of the first patient, the treatment of the second patient of the first Cohort will begin (according to the dose-escalation schedule of the specific Cohort). Intra-patient dose escalation will be permitted to minimize the chance of sub-optimal dosing. The results of the Phase 1 study will drive the future clinical development of THE-0504 in Phase 2 and Phase 3 studies.

Inclusion Criteria:

Patients will be enrolled in the study if they meet all the following criteria:

1. written informed consent obtained;

2. both gender adult (≥ 18 years) patients;

3. diagnosis of solid tumor. Preferably, but non-limited, tumor types are the following: Small Cell Lung Cancer (SCLC), Colorectal Carcinoma (CRC), Pancreas Adenocarcinoma (PaAdCa), Gastric Cancer (GC) and Triple Negative Breast Cancer (TNBrCa);

4. measurable metastatic disease or locally advanced unresectable tumors;

5. have exhausted all EMA-approved treatment options;

6. ECOG Performance Status graded as 0 or 1;

7. patients able to understand the full nature and the purpose of the trial, including possible risks and side effects, able to cooperate with the Investigator and to comply with the requirements of the entire trial (ability to attend all the planned trial visits according to the time limits included) based on Investigator's judgement;

8. adequate liver function as assessed by following laboratory tests to be conducted within 28 days before the first dose of study treatment:

   • Total bilirubin ≤ 1.5 × ULN (or ≤ 3 X ULN for patients with documented Gilbert-Meulengracht Syndrome, or for patients with hyperbilirubinemia considered due to liver metastasis).
   • Aspartate transaminase and alanine transaminase ≤ 2.5 × ULN (or ≤ 5 × ULN if due to liver involvement by tumor);

9. adequate kidney function as assessed by following laboratory test to be conducted within 28 days before the first dose of study treatment:

   • Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min per 1.73 m2 according to the CKD-EPI formula.

10. adequate bone marrow function as defined as:

    • Hgb ≥ 9 g/dL
    • ANC ≥1.5x109/L
    • PLT≥100.0 x109/L

11. Female patients of childbearing potential and male patients who are sexually active with women of childbearing potential will have to mandatorily use an appropriate method of contraception, according to the definition of Note 3 of ICH M3 Guideline, for the entire duration of the trial and for a minimum of 12 months after last administration of the IMP.

Exclusion Criteria:

Patients will not be enrolled if they meet any of the following criteria:

1. pregnant (as determined by a blood pregnancy test at the screening visit) or lactating women;

2. male patients who are willing to father children during the trial or in the 12 months after the end of IMP administration;

3. additional malignancy in the last 5 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy;

4. have any unresolved toxicity of Grade ≥ 2 from previous anti-cancer treatment, except for alopecia and skin pigmentation. Patients with chronic, but stable Grade 2 toxicities may be allowed to enrol after agreement between the Investigator and Sponsor;

5. ECOG Performance Status > 2;

6. had not tolerated previously administered Top1 inhibitor treatments;

7. known active CNS metastatic disease (patients with CNS metastases that are treated with radiotherapy and are stable for at least 28 days before study treatment start could be considered eligible);

8. serious concurrent illness;

9. Hgb < 9 g/dL;

10. Transfusion dependent anemia with transfusion dependency of ≥3 months;

11. Clinically significant iron metabolism disorders (e.g., sickle cell anemia) or use of iron chelators treatments;

12. Iron overload, hereditary hemochromatosis and similar;

13. Moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment;

14. Prolonged QTc interval;

15. Multiple Sclerosis (MS) or other demyelinating disease, Eaton-Lambert syndrome, history of haemorrhagic or ischemic stroke within the last 6 months, or alcoholic liver disease;

16. Non-healing wound(s), except for ulcerative lesions caused by the underlying neoplasm;

17. History of severe allergic or anaphylactic reactions to previous protein-based therapy;

18. Currently receiving anticoagulation therapy with warfarin;

19. Known history of HIV infection, unless all the following are applicable:

    • receiving an approved, stable, effective combination antiretroviral therapy regimen for ≥ 3 months prior to the planned first study intervention;
    • CD4 T-cell count > 350 cells/μL
    • CD4 T-cell nadir (lowest historical count) > 350 cells/μL, and • viral load confirmed as < 50 copies/mL.

20. HBV infection, unless on stable anti-viral therapy for > 4 weeks prior to the planned first dose of study intervention and viral load confirmed as undetectable; and HCV infection, unless the participant has received curative treatment and viral load was confirmed as undetectable;

21. Known autoimmune disease, uncontrolled diabetes, vitiligo, or stable thyroid disease;

22. Patients on chronic (more than 10 days) administration of systemic, high-dose corticosteroids (≥4 mg Dexamethasone or equivalent), not amenable for reduction or suspension;

23. Other concurrent medical or psychiatric conditions that, in the Investigator's opinion, may be likely to confound study interpretation or prevent completion of study procedures and follow-up examinations;

24. History of drugs and/or alcohol abuse;

25. Patients considered to be unsuitable to participate, in the Investigator's opinion, for any other reason (e.g. consequences of previous medical and/or surgical procedures or other medical or ethical reasons);

26. Planned relocation during the study, which would make impossible to attend the scheduled visits and follow-ups;

27. Concomitant participation in other clinical trials or participation in the evaluation of any investigational drugs/products up to 4 weeks before this trial (in any case, enrolment procedure should start only after the complete washout of the drugs/products under investigation**); or previous participation in the same trial or planned to receive other investigational products during the study.

To the present date, only the sharing of the summary of the clinical results after 30 months from the study completion can be guaranteed.

Complete data from individual participants cannot be shared in scientific publications until intellectual property of the Investigational Medicinal Product is granted in all countries currently under evaluation.