Clinical Trial of PM54 in Advanced Solid Tumors Patients.

Inclusion Criteria:

1. Voluntarily signed and dated written informed consent, obtained prior to anyspecific study procedure.

2. Age ≥18 years.

3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1.

4. Phase Ia (dose escalation) stage: patients must have:

5. Pathologically confirmed diagnosis of advanced solid tumors for whom nostandard therapy exists:

• Genitourinary tract tumors: urothelial carcinoma, clear cell renalcarcinoma and prostate adenocarcinoma.
• Cutaneous melanoma.
• Gastrointestinal: esophageal adenocarcinoma, gastric adenocarcinoma,pancreatic adenocarcinoma, and poorly differentiated (grade 3)gastroenteropancreatic Neuroendocrine Carcinoma (NEC )with Ki67 index >55%.
• Lung: non-small cell lung cancer (NSCLC) and Small Cell Lung Cancer (SCLC).
• Gynecological tumors: epithelial ovarian carcinoma (including primaryperitoneal disease and/or fallopian tube carcinomas), endometrialadenocarcinoma and carcinoma of cervix.
• Breast: ductal or lobular.
• Sarcoma: liposarcoma, leiomyosarcoma, synovial sarcoma and Ewing sarcoma.
• Deleterious germline BRCA1/2 mutation tumors.
• Other: MPM, extrapulmonary small cell carcinoma, adrenocortical carcinoma.Note: patients with measurable or non-measurable disease according to theResponse Evaluation Criteria In Solid Tumors (RECIST) v.1.1 (or mRECIST v.1.1in case of MPM) are eligible during this stage.

2. No more than three prior lines of chemotherapy.

3. Phase Ib (expansion) stage: patients must have:

4. Pathologically confirmed diagnosis of one of the following:

• High-grade Serous Ovarian Carcinoma (HGSOC) (including fallopian tube andprimary peritoneal carcinoma).
• Small cell carcinomas (SCLC or extrapulmonary small cell carcinoma) orpoorly differentiated grade 3 gastroenteropancreatic NEC with Ki67 index ≥55%.
• Cutaneous melanoma.
• Malignant pleural mesothelioma (MPM).
• HR+/HER2- breast cancer.

2. Measurable disease according to the RECIST v.1.1 (or mRECIST v.1.1 in case ofMPM) and/or evaluable disease byserum markers in case of prostate and ovariancancer (according to the Prostate-Specific Antigen Working GroupRecommendations (PSAWGR) and the Gynecologic Cancer Intergroup (GCIG) specificcriteria, respectively).

3. Progressive disease after last therapy at study entry.

4. Patients must have received standard treatments:

• HGSOC: no more than three prior lines of chemotherapy. Patients shouldhave received previous therapy with poly(ADP-ribose) polymerase inhibitors (PARPi) and anti-Vascular Endothelial Growth Factor (VEGF) (bevacizumab),unless contraindicated.
• Small cell carcinomas/NEC: no more than two prior lines of chemotherapy.
• Cutaneous melanoma:

1. BRAF wild-type (WT) melanoma: at least one prior line ofimmunotherapy for advanced disease. The patient may have receivedthis therapy in the adjuvant setting. No more than two prior lines ofsystemic therapy for advanced disease. Note: patients with diseaseprogression during adjuvant therapy or within the first six monthsafter the last dose of adjuvant therapy will be considered as havingbeen treated with one prior line of treatment.
2. BRAF-mutated melanoma: at least one prior line of target therapy foradvanced disease with BRAF inhibitor with or without MEK-inhibitor,and at least one prior line of immunotherapy for advanced disease.The patient may have received any of these therapies in the adjuvantsetting. No more than three prior lines of systemic therapy foradvanced disease.

• Malignant pleural mesothelioma (MPM): no more than two prior lines oftherapy; one of them should be a platinum containing line. Patients withnon-epithelioid MPM should have received a prior immunotherapy line.
• HR+/HER2- breast cancer: no more than three prior lines of chemotherapyfor advanced disease. Patients should have received the standardanticancer hormonal treatment including CDK4/6, and PI3K inhibitor ifindicated.

6. Recovery to grade ≤1 from drug-related AEs of previous treatments, excluding grade 2alopecia, according to the NCI-CTCAE v.5.

7. Laboratory values within seven days prior to first infusion:

8. Absolute Neutrophil Count (ANC) ≥1.5 x 10^9/L, platelet count ≥100 x 10^9/L andhemoglobin ≥9 g/dL (patients may be transfused for anemia as clinicallyindicated prior to study entry).

9. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤3.0 x ULN.

10. Total bilirubin ≤upper limit of normal (ULN) (up to 1.5 x ULN for patients withGilbert's syndrome).

11. Creatinine clearance ≥30 mL/min (calculated using the Cockcroft and Gault'sformula).

12. Serum albumin ≥3 g/dL. *

13. Creatine phosphokinase (CPK) ≤ 2.5 x ULN.

14. Washout periods:

15. At least three weeks since the last chemotherapy.

16. At least four weeks since the last monoclonal antibody (MAb)-containingtherapy.

17. At least two weeks since the last biological/investigational single-agenttherapy (excluding MAbs) and/or palliative radiotherapy (RT).

18. In patients with hormone-sensitive breast cancer progressing while on hormonetherapy (except for luteinizing hormone-releasing hormone [LHRH] analogues inpre-menopausal women or megestrol acetate), all other hormonal therapies mustbe stopped at least one week before study treatment start.

19. Castrate-resistant prostate cancer (CRPC) patients may continue receivinghormone therapy prior to and during study treatment. Note: washout periods willbe referred to the day of first cycle administration (Day 1), not to the day ofregistration.

20. Evidence of non-childbearing status for women of childbearing potential (WOCBP).WOCBP must agree to use a highly effective contraceptive measure during the courseof the trial and up to seven months after the last study drug infusion. Fertile malepatients with WOCBP partners should use condoms during treatment and for four monthsfollowing the last study drug infusion.

• Albumin infusion to increase the blood level in order to fulfill the inclusioncriterion is strictly forbidden.

Exclusion Criteria:

For both stages:

1. Concomitant diseases/conditions:

2. Increased cardiac risk:

• Uncontrolled arterial hypertension despite optimal management (≥160/100mmHg).
• Presence of clinically relevant valvular disease.
• History of long QT syndrome.
• Corrected QT interval (QTcF, Fridericia correction) ≥450 ms on screeningECG.
• History of ischemic heart disease, including myocardial infarction,unstable angina, coronary arteriography or cardiac stress testing withfindings consistent with coronary occlusion or infarction ≤6 months priorto study entry.
• History of heart failure or left ventricular dysfunction (left ventricularejection fraction [LVEF] ≤50%) by multiple-gated acquisition scan (MUGA)or echocardiography (ECHO).
• Clinically relevant ECG abnormalities, including any of the following:right bundle branch block with left anterior hemiblock, second (Mobitz II)or third degree atrioventricular block.
• Symptomatic arrhythmia.
• Concomitant medication with risk of inducing torsades de pointes, whichcannot be discontinued or switched to an alternative drug prior to startPM54 dosing.
• Use of a cardiac pacemaker.

2. Active infection requiring systemic treatment.

3. Known human immunodeficiency virus (HIV) or known chronic active hepatitis. ForHepatitis B, this includes positive tests for both Hepatitis B surface antigenand quantitative Hepatitis B polymerase chain reaction (PCR). For Hepatitis C,this includes positive tests for both Hepatitis C antibody and quantitativeHepatitis C PCR.

4. Any other major illness that, in the Investigator's judgment, willsubstantially increase the risk associated with the patient's participation inthis study (e.g., COVID-19).

5. Symptomatic, steroid-requiring, and progressing central nervous system (CNS)disease. Exceptions will be made for patients who have completed radiotherapy atleast four weeks prior to inclusion (asymptomatic patients taking steroids in theprocess of already being tapered within two weeks prior to inclusion).

6. Patients with carcinomatous meningitis.

7. Prior bone marrow or stem cell transplantation.

8. Prior treatment with trabectedin, lurbinectedin, or ecubectedin (PM14).

9. Use of (strong or moderate) inhibitors or strong inducers of CYP3A4 activity withintwo weeks prior to the first infusion of PM54.

10. Known hypersensitivity to any of the components of the drug product.

11. Limitation of the patient's ability to comply with the treatment or to follow theprotocol procedures.

12. Women who are pregnant or breast feeding and fertile patients (men and women) whoare not using a highly effective method of contraception (see inclusion criterionNo. 9).