Clinical Trial of PM54 in Advanced Solid Tumors Patients.

Study Overview
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Brief Summary
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The first part of the study (phase Ia - dose escalation) will evaluate the safety and tolerability and identify the dose-limiting toxicities (DLTs) of PM54. The second part of the study (phase Ib - expansion) will be to evaluate the antitumor activity of PM54 in terms of clinical benefit (response or stable disease [SD] ≥4 months associated with tumor shrinkage), according to the RECIST v.1.1 and/or serum markers as appropriate, in patients with selected advanced solid tumors.

Official Title
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Phase I/Ib, Open-label, Dose-escalating, Clinical and Pharmacokinetic Study of PM54 Administered Intravenously to Patients With Selected Advanced Solid Tumors.

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: PM54


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntarily signed and dated written informed consent, obtained prior to any specific study procedure. Age ≥18 years. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1. Phase Ia (dose escalation) stage: patients must have: Pathologically confirmed diagnosis of advanced solid tumors for whom no standard therapy exists: Genitourinary tract tumors: urothelial carcinoma, clear cell renal carcinoma 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 primary peritoneal disease and/or fallopian tube carcinomas), endometrial adenocarcinoma and carcinoma of cervix. Breast: ductal or lobular. Sarcoma: liposarcoma, leiomyosarcoma, synovial sarcoma and Ewing sarcoma. Deleterious germline BRCA1/2 mutation tumors. Other: malignant pleural mesothelioma, extrapulmonary small cell carcinoma, adrenocortical carcinoma. Note: patients with measurable or non-measurable disease according to the Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1 are eligible during this stage. No more than three prior lines of chemotherapy. Phase Ib (expansion) stage: patients must have: Pathologically confirmed diagnosis of one of the following: High-grade Serous Ovarian Carcinoma (HGSOC) (including fallopian tube and primary peritoneal carcinoma). Sarcomas (including liposarcoma, leiomyosarcoma [uterine or soft tissue], synovial sarcoma and Ewing sarcoma). Small cell carcinomas (SCLC or extrapulmonary small cell carcinoma) or poorly differentiated grade 3 gastroenteropancreatic NEC with Ki67 index ≥55%. Tumors with deleterious germline BRCA1/2 mutations. Cutaneous melanoma. Measurable disease according to the RECIST v.1.1 and/or evaluable disease by serum markers in case of prostate and ovarian cancer (according to the Prostate-Specific Antigen Working Group Recommendations (PSAWGR) and the Gynecologic Cancer Intergroup (GCIG) specific criteria, respectively). Progressive disease after last therapy at study entry. Patients must have received standard treatments: HGSOC: no more than three prior lines of chemotherapy. Patients should have received previous therapy with poly(ADP-ribose) polymerase inhibitors (PARPi) and anti-Vascular Endothelial Growth Factor (VEGF) (bevacizumab), unless contraindicated. In case of germline BRCA1/2 mutation, the patient will be included in the cohort of tumors with deleterious germline BRCA1/2 mutations (see below). Sarcomas: at least one but no more than two prior lines of chemotherapy. Small cell carcinomas/NEC: no more than two prior lines of chemotherapy. Tumors with deleterious germline BRCA1/2 mutations: Breast cancer: no more than three prior lines of chemotherapy. Standard therapies for hormone receptor (HR)-positive disease and/or anti-Her2 therapies (in the event of Her2-positive disease) should have been completed. One line of immunotherapy is allowed in triple negative disease. Epithelial ovarian/fallopian tube/primary peritoneal carcinoma: no more than three prior lines of chemotherapy. Pancreatic adenocarcinoma: no more than two prior lines of chemotherapy. Prostate adenocarcinoma: no more than one prior line of chemotherapy. Patients must have received one line of next-generation androgen pathway inhibitors (i.e., enzalutamide, apalutamide, abiraterone or darolutamide). Tumors of other anatomical locations: no more than two prior lines of chemotherapy. Prior use of PARPi is required for those indications where use of PARPi has been approved by regulatory agencies. Cutaneous melanoma: BRAF wild-type (WT) melanoma: at least one prior line of immunotherapy for advanced disease. The patient may have received this therapy in the adjuvant setting. No more than two prior lines of systemic therapy for advanced disease. Note: patients with disease progression during adjuvant therapy or within the first six months after the last dose of adjuvant therapy will be considered as having been treated with one prior line of treatment. BRAF-mutated melanoma: at least one prior line of target therapy for advanced 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 adjuvant setting. No more than three prior lines of systemic therapy for advanced disease. Recovery to grade ≤1 from drug-related AEs of previous treatments, excluding grade 2 alopecia, according to the NCI-CTCAE v.5. Laboratory values within seven days prior to first infusion: Absolute Neutrophil Count (ANC) ≥1.5 x 10^9/L, platelet count ≥100 x 10^9/L and hemoglobin ≥9 g/dL (patients may be transfused for anemia as clinically indicated prior to study entry). Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤3.0 x ULN. Total bilirubin ≤upper limit of normal (ULN) (up to 1.5 x ULN for patients with Gilbert's syndrome). Creatinine clearance ≥30 mL/min (calculated using the Cockcroft and Gault's formula). Serum albumin ≥3 g/dL. * Washout 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. Note: washout periods will be referred to the day of first cycle administration (Day 1), not to the day of registration. Albumin transfusion to increase the blood level in order to fulfill the inclusion criterion is strictly forbidden. Exclusion Criteria: For both stages: Concomitant diseases/conditions: Increased cardiac risk: Uncontrolled arterial hypertension despite optimal management (≥160/100 mmHg). Presence of clinically relevant valvular disease. History of long QT syndrome. Corrected QT interval (QTcF, Fridericia correction) ≥450 ms on screening 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. History of heart failure or left ventricular dysfunction (left ventricular ejection 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, which cannot be discontinued or switched to an alternative drug prior to start PM54 dosing. Use of a cardiac pacemaker. 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 (e.g., COVID-19). Symptomatic, steroid-requiring, and progressing central nervous system (CNS) disease. Exceptions will be made for patients who have completed radiotherapy at least four weeks prior to inclusion (asymptomatic patients taking steroids in the process of already being tapered within two weeks prior to inclusion). Patients with carcinomatous meningitis. Prior bone marrow or stem cell transplantation. Prior treatment with trabectedin, lurbinectedin, or PM14. Use of (strong or moderate) inhibitors or strong inducers of CYP3A4 activity within two weeks prior to the first infusion of PM54. 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. Women of childbearing potential (WOCBP) must agree to use an effective contraception method to avoid pregnancy during the course of the trial (and for at least six months after the last infusion). Fertile male patients must agree to refrain from fathering a child or donating sperm during the trial and for four months after the last infusion.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PM54<br>Phase Ia (dose escalation) stage: Patients will receive PM54 i.v. at a starting dose of 0.3 mg/m2. Phase Ib (expansion) stage: Patients will receive PM54 i.v. at the RD determined during the Phase Ia stage. | Drug: PM54<br>* PM54 powder for concentrate for solution for infusion (3 mg/vial) is a sterile, preservative-free, lyophilized white to yellowish cake in a single-dose vial for reconstitution prior to intravenous infusion. Each vial contains 3 mg PM54. Route of administration: Intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1a: Dose-limiting toxicities (DLTs) |  | Day 1 Cycle 1 up to end of first cycle of treatment (Cycle 1 is 21 days) | 
| Phase 1a: Treatment-emergent Adverse Events (TEAEs) |  | Day 1 Cycle 1 up to end of first cycle of treatment (Cycle 1 is 21 days) | 
| Phase 1a: Drug-related Adverse Events (AEs) |  | Day 1 Cycle 1 up to end of first cycle of treatment (Cycle 1 is 21 days) | 
| Phase 1a: Drug-related deaths |  | Day 1 Cycle 1 up to end of first cycle of treatment (Cycle 1 is 21 days) | 
| Phase 1a: Serious adverse events (SAEs) |  | Screening up to end of first cycle of treatment (Cycle 1 is 21 days) | 
| Phase 1a: Drug-related delays |  | Day 1 Cycle 1 up to end of first cycle of treatment (Cycle 1 is 21 days) | 
| Phase 1a: Dose reductions |  | Day 1 Cycle 1 up to end of first cycle of treatment (Cycle 1 is 21 days) | 
| Phase 1a: Treatment discontinuations |  | Day 1 Cycle 1 up to end of first cycle of treatment (Cycle 1 is 21 days) | 
| Phase 1a: Maximum tolerated dose (MTD) | Lowest dose level explored during dose escalation in which one third (i.e., 33%) or more of evaluable patients develop a DLT in Cycle 1. | Day 1 Cycle 1 up to end of first cycle of treatment (Cycle 1 is 21 days) | 
| Phase 1a: Recommended dose (RD) | Once the maximum tolerated dose (MTD) is reached, lower dose level will be confirmed as the RD if less than one third (i.e., 33%) of all evaluable patients at the dose level develop DLT during Cycle 1. | Day 1 Cycle 1 up to end of first cycle of treatment (Cycle 1 is 21 days) | 
| Phase 1b: Percentage of evaluable patients with clinical benefit | Clinical benefit defined as confirmed response (either complete [CR] or partial [PR]) or stable disease (SD) ≥4 months associated with tumor shrinkage | Start of treatment to the date of progression or the start of a subsequent therapy or end of patient's follow-up, according to the RECIST v.1.1 and/or serum markers, as appropriate. (Up to approximately 36 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Adverse events (AEs) | AEs will be graded according to the NCI-CTCAE v.5. | Screening to end of study (up to approximately 36 months) | 
| Phase 1b: Treatment discontinuation |  | Day 1 up to end of study (up to approximately 36 months) | 
| Phase 1b: Dose reductions |  | Day 1 up to end of study (up to approximately 36 months) | 
| Phase 1b: Treatment delays due to adverse events (AEs) |  | Day 1 up to end of study (up to approximately 36 months) | 
| Phase 1b: QT Assessment | The QT assessment will evaluate the risk of prolongation of the QT interval by PM54. | Day 1 of Cycle 1 for all patients participating in the QT assessment, and on Day 1 of Cycle 2 for patients treated during the Phase Ia stage once the MTD has been determined, will be used in this substudy. | 
| Phase 1b: Maximum Plasma Concentration (Cmax) |  | Cycle 1 and Cycle 2 during the Phase Ia (dose expansion) stage once the MTD has been determined. Each cycle is 21 days. | 
| Phase 1b: Concentration in urine samples |  | Day 1 of Cycle 1 and Cycle 2 during the Phase Ia (dose expansion) stage once the MTD has been determined. Each Cycle is 21 days. | 
| Phase 1b: Percentage of patients with clinical benefit (overall response rate (ORR) or stable disease (SD) ≥4 months associated with tumor shrinkage) |  | Day 1 up to end of study (up to approximately 36 months) | 
| Phase 1b: Response rate | Response rate defined as percentage of patients with partial response (PR), with complete response (CR), or the sum of both [overall response rate (ORR)]. | Day 1 up to end of study (up to approximately 36 months) | 
| Phase 1b: Percentage of patients with stable disease (SD) ≥4 months |  | Day 1 up to end of study (up to approximately 36 months) | 
| Phase 1b: Duration of Response (DoR) |  | From the date of the first documentation of response to the date of documented progression or death, assessed up to 36 months | 
| Phase 1b: Progression-free Survival (PFS) |  | From the date of first infusion of study treatment to the date of first documented progression or date of death from any cause, assessed up to 36 months | 
| Phase 1b: Overall survival (OS) |  | From the date of first infusion of study treatment to the date of death (due to any cause) or last contact (in this case, survival will be censored on the date of last contact), assessed up to 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced Solid Tumor