PM534 Administered Intravenously to Patients With Advanced Solid Tumors

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

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

Conditions
-----------------
Patients With Advanced Solid Tumors

Intervention / Treatment
-----------------
* Drug: PM534


Participation Criteria
=================
Eligibility Criteria
-----------------
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. 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. 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 ischemic heart disease, including myocardial infarction, unstable angina, coronary arteriography or cardiac stress testing with findings consistent with coronary occlusion or infarction ≤ 6 months prior to study entry 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. Symptomatic arrhythmia. Use of a cardiac pacemaker. 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PM534<br>Patients will be included in cohorts of a minimum of three or six patients to receive PM534 at successively increasing dose levels. | Drug: PM534<br>* PM534 drug product is provided as a powder for concentrate for solution for infusion, is a sterile, preservative-free, lyophilized white cake in a single-dose vial for reconstitution prior to intravenous infusion.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of the Maximum Tolerated Dose and the Recommended Dose | A fully evaluable patient is a patient evaluable for the primary objective (i.e., determination of the MTD and the RD). | From the date of first infusion of PM534 to the date of study termination, up to 27 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety AEs of PM534 | AEs will be graded according to the NCI-CTCAE v.5. | From the date of first infusion of PM534 to the date of study termination, up to 27 months | 
| Safety Hb of PM534 | Parameters Labs will be graded according to the NCI-CTCAE v.5. | From the date of first infusion of PM534 to the date of study termination, up to 27 months | 
| Safety neutrophils of PM534 | Parameters Labs will be graded according to the NCI-CTCAE v.5. | From the date of first infusion of PM534 to the date of study termination, up to 27 months | 
| Safety platelets of PM534 | Parameters Labs will be graded according to the NCI-CTCAE v.5. | From the date of first infusion of PM534 to the date of study termination, up to 27 months | 
| Safety BT of PM534 | Parameters Labs will be graded according to the NCI-CTCAE v.5. | From the date of first infusion of PM534 to the date of study termination, up to 27 months | 
| Safety ALT/AST of PM534 | Parameters Labs will be graded according to the NCI-CTCAE v.5. | From the date of first infusion of PM534 to the date of study termination, up to 27 months | 
| Safety ALK of PM534 | Parameters Labs will be graded according to the NCI-CTCAE v.5. | From the date of first infusion of PM534 to the date of study termination, up to 27 months | 
| Safety creatinine of PM534 | Parameters Labs will be graded according to the NCI-CTCAE v.5. | From the date of first infusion of PM534 to the date of study termination, up to 27 months | 
| QT Assessment | The direct relationship between PM534 plasma concentration C and the change from baseline in QT corrected according to Fridericia's formula (ΔQTcF) will be assessed using linear mixed effects (LME) models. | During Day of Cycle 1 (each cycle lasts 21 days) | 
| Pharmacokinetics Cmax of PM534 | Maximum Plasma Concentration (Cmax). Pharmacokinetic analyses will be evaluated in plasma and urine by standard noncompartmental analysis. Compartmental modeling may be performed if appropriate. | Cycle 1 from all patients, and also in Cycle 2 from treated patients once the MTD has been determined(each cycle is 21 days). | 
| Pharmacokinetics AUC of PM534 | Area Under The Concentration-time Curve (AUC). Pharmacokinetic analyses will be evaluated in plasma and urine by standard noncompartmental analysis. Compartmental modeling may be performed if appropriate. | Cycle 1 from all patients, and also in Cycle 2 from treated patients once the MTD has been determined(each cycle is 21 days). | 
| Pharmacogenomics Plasma AUC(0-t) of PM534 | To analyze the expression levels of Plasma AUC(0-t) of response and/or resistance to treatment with PM534 | Cycle 1 from all patients, and also in Cycle 2 from patients treated once the MTD has been determined) (each cycle is 21 days) | 
| Pharmacogenomics Plasma Cmax of PM534 | To analyze the expression levels of Plasma Cmax of response and/or resistance to treatment with PM534 | Cycle 1 from all patients, and also in Cycle 2 from patients treated once the MTD has been determined) (each cycle is 21 days) | 
| Pharmacogenomics Plasma half life of PM534 | To analyze the expression levels of Plasma half life of response and/or resistance to treatment with PM534 | Cycle 1 from all patients, and also in Cycle 2 from patients treated once the MTD has been determined) (each cycle is 21 days) | 
| Pharmacogenomics Total body plasma clearance of PM534 | To analyze the expression levels of Total body plasma clearance of response and/or resistance to treatment with PM534 | Cycle 1 from all patients, and also in Cycle 2 from patients treated once the MTD has been determined) (each cycle is 21 days) | 
| Pharmacogenomics Volume of distribution of PM534 | To analyze the expression levels of Volume of distribution of response and/or resistance to treatment with PM534 | Cycle 1 from all patients, and also in Cycle 2 from patients treated once the MTD has been determined) (each cycle is 21 days) | 
| Pharmacogenomics Percentage of dose recovered in urine of PM534 | To analyze the expression levels of Percentage of dose recovered in urine of response and/or resistance to treatment with PM534 | Cycle 1 from all patients, and also in Cycle 2 from patients treated once the MTD has been determined) (each cycle is 21 days) | 
| Efficacy of PM534 | To analyze the response rates will be determined in patients with measurable or evaluable disease specific tumor types, time-to-event parameter will also be analyzed ORR. | From the date of first infusion of PM534 to the date of study termination, up to 27 months |