PM534 Administered Intravenously to Patients With Advanced Solid Tumors

Phase I, Open-label, Dose-escalating, Clinical and Pharmacokinetic Study of PM534 Administered Intravenously to Patients With Advanced Solid Tumors

The goals of this trial are to identify the dose limiting toxicities, to determine the maximum tolerated dose and the recommended dose of PM534 in patients with advanced solid tumors. All Patients will receive PM534 via intravenous.

This is a prospective, open-label, dose-escalating phase I study in patients with advanced solid tumors. Patients will be included in cohorts of a minimum of three or six patients to receive PM534 at successively increasing dose levels.

Inclusion Criteria:

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

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

3. Patients must have:

   3.1 Pathologically confirmed diagnosis of advanced solid tumors 3.2 No more than three prior chemotherapy lines.

4. Patients with measurable or non-measurable disease according to the RECIST v.1.1.

5. Recovery to grade ≤1 from drug-related adverse events (AEs) of previous disease treatments, excluding grade 2 alopecia.

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

   1. Absolute neutrophil count (ANC) ≥1.5 x 10⁹/L, platelet count ≥100 x 10⁹/L and hemoglobin ≥9 g/dL
   2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 x upper limit of normal (ULN).
   3. Total bilirubin ≤ULN (up to 1.5 x ULN for patients with Gilbert's syndrome).
   4. Creatinine clearance ≥30 mL/min or serum creatinine ≤1.5 x ULN.
   5. Serum albumin ≥3 g/dL.
   6. Serum potassium ≥3.5 mmol/L.
   7. Serum magnesium ≥1.6 mg/dL.

7. Wash-out periods:

   1. At least three weeks since the last chemotherapy.
   2. At least four weeks since the last monoclonal antibody (MAb)-containing therapy.
   3. At least two weeks since the last biological/investigational single-agent therapy (excluding MAbs) and/or palliative radiotherapy (RT).
   4. In patients with hormone-sensitive breast cancer progressing while on hormone therapy (except for luteinizing hormone-releasing hormone [LHRH] analogues in pre-menopausal women or megestrol acetate), all other hormonal therapies must be stopped at least one week before study treatment start.
   5. Castrate-resistant prostate cancer (CRPC) patients may continue receiving hormone therapy prior to and during study treatment.

8. Life expectancy ≥3 months

Exclusion Criteria:

1. Concomitant diseases/conditions:

   1. Increased cardiac risk:

      • History of long QT syndrome.
      • Corrected QT interval (QTcF, Fridericia correction) ≥450 msec on screening electrocardiogram (ECG).
      • History of or current ischemic heart disease, including myocardial infarction, stable/unstable angina, coronary arteriography or cardiac stress testing with findings consistent with coronary occlusion or infarction or symptomatic arrhythmia.
      • History of heart failure or left ventricular dysfunction (left ventricular ejection fraction [LVEF] ≤50%) by multiple-gated acquisition scan (MUGA) or echocardiography (ECHO).
      • Clinically significant ECG abnormalities, including any of the following: right bundle branch block with left anterior hemiblock, second (Mobitz II) or third degree atrioventricular block and findings suggestive of ischemic heart disease.
      • Symptomatic arrhythmia.
      • Use of a cardiac pacemaker.
      • History of or current peripheral vascular disease or cerebrovascular disease.

   2. Presence of:

      • Any grade of peripheral neuropathy (any etiology) at study entry.
      • Prior history of grade ≥ 2 peripheral neuropathy due to any chemotherapeutic or investigational agent.
      • Clinical or radiological signs of subocclusion/bowel obstruction.

   3. Active infection requiring systemic treatment.

   4. Known human immunodeficiency virus (HIV) or known hepatitis C virus (HCV) infection or active hepatitis B.

   5. Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the patient's participation in this study

2. Symptomatic, steroid-requiring, central nervous system (CNS) disease.

3. Patients with carcinomatous meningitis.

4. Prior bone marrow or stem cell transplantation.

5. Current treatment with colchicine.

6. Use of (strong or moderate) inhibitors or strong inducers of CYP3A4 activity within two weeks prior to the first infusion of PM534

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

8. Limitation of the patient's ability to comply with the treatment or to follow the protocol procedures.

9. Women who are pregnant or breast feeding and fertile patients (men and women) who are not using an effective method of contraception

10. Patients with pulmonary lymphangitis.

11. Use of medications with known risk of inducing torsades de pointes (TdP) within five half-lives prior to the first infusion of PM534