PM534 Administered Intravenously to Patients With Advanced Solid Tumors

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

• Voluntarily signed and dated written informed consent, obtained prior to any specific study procedure.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1
• Patients must have:

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

• Patients with measurable or non-measurable disease according to the RECIST v.1.1.
• Recovery to grade ≤1 from drug-related adverse events (AEs) of previous disease treatments, excluding grade 2 alopecia.
• Laboratory values within seven days prior to first infusion:

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

• At least three weeks since the last chemotherapy.
• At least four weeks since the last monoclonal antibody (MAb)-containing therapy.
• At least two weeks since the last biological/investigational single-agent therapy (excluding MAbs) and/or palliative radiotherapy (RT).
• 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.
• Castrate-resistant prostate cancer (CRPC) patients may continue receiving hormone therapy prior to and during study treatment.
• Life expectancy ≥3 months

Exclusion criteria

• Concomitant diseases/conditions:

• 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.
• 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.
• Active infection requiring systemic treatment.
• Known human immunodeficiency virus (HIV) or known hepatitis C virus (HCV) infection or active hepatitis B.
• Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the patient's participation in this study
• Symptomatic, steroid-requiring, central nervous system (CNS) disease.
• Patients with carcinomatous meningitis.
• Prior bone marrow or stem cell transplantation.
• Current treatment with colchicine.
• Use of (strong or moderate) inhibitors or strong inducers of CYP3A4 activity within two weeks prior to the first infusion of PM534
• Known hypersensitivity to any of the components of the drug product.
• Limitation of the patient's ability to comply with the treatment or to follow the protocol procedures.
• Women who are pregnant or breast feeding and fertile patients (men and women) who are not using an effective method of contraception
• Patients with pulmonary lymphangitis.
• Use of medications with known risk of inducing torsades de pointes (TdP) within five half-lives prior to the first infusion of PM534