First-in-human Study of BAY2287411 Injection, a Thorium-227 Labeled Antibody-chelator Conjugate, in Patients With Tumors Known to Express Mesothelin

Study Overview
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Brief Summary
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The purpose of this study is to evaluate, in patients with tumors known to express the protein mesothelin, the following properties of BAY2287411 injection: safety (to identify, assess, minimize, and appropriately manage the risks associated to the study drug) tolerability (the degree to which side effects can be tolerated by your body) maximum tolerated dose pharmacokinetics (the effect of your body on the study drug) anti-tumor activity recommended dose for further clinical development

Official Title
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An Open-label, First-in-human, Multi-center Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Anti-tumor Activity of a Thorium-227 Labeled Antibody-chelator Conjugate, BAY2287411 Injection, in Patients With Solid Tumors Known to Express Mesothelin

Conditions
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Advanced Recurrent Malignant Pleural Epithelioid Mesothelioma, Advanced Recurrent Malignant Peritoneal Epithelioid Mesothelioma, Advanced Recurrent Serous Ovarian Cancer, Advanced Pancreatic Ductal Adenocarcinoma (Optional, Dose Expansion, Not Initiated)

Intervention / Treatment
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* Drug: BAY2287411
* Drug: BAY2287411


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent Male or female subjects ≥ 18 years of age ECOG PS (Eastern Cooperative Oncology Group Performance Status) of 0 or 1 Patients with advanced malignant epithelioid mesothelioma or advanced recurrent serous ovarian cancer, who have exhausted available therapeutic options; in addition, in the dose expansion part of the study, patients with metastatic pancreatic adenocarcinoma, who have exhausted available therapeutic options Availability of fresh or archival tumor tissue samples Adequate bone marrow, liver and renal function, as assessed by pre-defined laboratory requirements (within 28 days before start of study drug treatment) A negative serum pregnancy test in women of childbearing potential (WOCBP) performed within 7 days before the start of study drug administration. Women and men of reproductive potential must agree to use highly effective methods of contraception, when sexually active. Exclusion Criteria: Impaired cardiac function, clinically significant cardiac disease or cardiac arrhythmias Pericarditis (any CTCAE grade) or pericardial effusion (CTCAE Grade ≥ 2) Left Ventricular Ejection Fraction (LVEF) < 50% (as measured at screening by echocardiogram). History of anaphylactic reactions to monoclonal antibody therapy History of Myelodysplastic syndrome (MDS)/treatment-related acute myeloid leukemia (t-AML) or with features suggestive of MDS/AML Infections of CTCAE (Common Terminology Criteria for Adverse Events) version 5.0 Grade 2 not responding to therapy or active clinically serious infections of CTCAE Grade >2; known human immunodeficiency virus (HIV) infection; active hepatitis B virus (HBV) or hepatitis C virus (HCV)infection requiring treatment. Patients with chronic HBV or HCV infection are eligible at the investigator's discretion provided that the disease is stable and sufficiently controlled under treatment Known brain, spinal or meningeal metastases

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose escalation cohort a<br>Subjects with either advanced recurrent epithelioid mesothelioma or serous ovarian cancer who have exhausted available therapeutic options. The dose of Thorium-227 will start at 1.5 MBq and increase in steps of 1.0 or 1.5 MBq, with antibody doses of 10 mg. | Drug: BAY2287411<br>* Dose Escalation part: A single dose will be administered intravenously on Day 1 of each cycle lasting 6 weeks (42 days).<br>|
| Experimental: Dose escalation cohort b<br>Subjects with either advanced recurrent epithelioid mesothelioma or serous ovarian cancer who have exhausted available therapeutic options. The dose of Thorium-227 will start at 1.5 MBq and increase in steps of 1.0 or 1.5 MBq, with a total antibody dose within the range of 10 - 50 mg. | Drug: BAY2287411<br>* Dose Escalation part: A single dose will be administered intravenously on Day 1 of each cycle lasting 6 weeks (42 days).<br>|
| Experimental: Dose Expansion Cohort 1<br>Subjects with advanced recurrent epithelioid mesothelioma or serous ovarian cancer, who have exhausted available therapeutic options Dose / Regimen 1 (to be determined after completion of the dose escalation) | Drug: BAY2287411<br>* Dose Expansion part: The selection of the dose level(s) /regimen(s) to be evaluated will be based on the overall benefit / risk and PK profile observed in the dose escalation.<br>|
| Experimental: Dose Expansion Cohort 2<br>Subjects with advanced recurrent epithelioid mesothelioma or serous ovarian cancer, who have exhausted available therapeutic options Dose / Regimen 2 (to be determined after completion of the dose escalation) | Drug: BAY2287411<br>* Dose Expansion part: The selection of the dose level(s) /regimen(s) to be evaluated will be based on the overall benefit / risk and PK profile observed in the dose escalation.<br>|
| Experimental: Dose expansion Cohort 3 (optional)<br>Subjects with histologically or cytologically confirmed unresectable, metastatic or locally advanced pancreatic ductal adenocarcinoma Dose / Regimen to be determined | Drug: BAY2287411<br>* Dose Expansion part: The selection of the dose level(s) /regimen(s) to be evaluated will be based on the overall benefit / risk and PK profile observed in the dose escalation.<br>|
| Experimental: Dose escalation cohort c<br>Subjects with either advanced recurrent epithelioid mesothelioma or serous ovarian cancer who have exhausted available therapeutic options. The dose of Thorium-227 will start at 1.5 MBq and increase in steps of 1.0 or 1.5 MBq, with antibody doses of 10 - 150 mg mg. | Drug: BAY2287411<br>* Dose Escalation part: A single dose will be administered intravenously on Day 1 of each cycle lasting 6 weeks (42 days).<br>|
| Experimental: Dose escalation cohort d<br>Subjects with either advanced recurrent epithelioid mesothelioma or serous ovarian cancer who have exhausted available therapeutic options. The dose of Thorium-227 will start at 1.5 MBq and increase in steps of 1.0 or 1.5 MBq, with antibody doses of 10 - 400 mg. | Drug: BAY2287411<br>* Dose Escalation part: A single dose will be administered intravenously on Day 1 of each cycle lasting 6 weeks (42 days).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of DLTs (dose-limiting toxicity) |  | 6 weeks (42 days) | 
| Proportion of participants with treatment-emergent adverse events (TEAEs), drug-related adverse events (AEs), and serious adverse events (SAEs) |  | 6 months after the end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of Thorium-227 after single dose of Cycle 1 |  | From Day 1 to 43 | 
| Cmax of Radium-223 after single dose of Cycle 1 |  | From Day 1 to 43 | 
| Cmax of Total antibody after single dose of Cycle 1 |  | From Day 1 to 43 | 
| AUC(0-42 days) of Radium-223 after single dose of Cycle 1 |  | From Day 1 to 43 | 
| AUC(0-42 days) of Total antibody after single dose of Cycle 1 |  | From Day 1 to 43 | 
| AUC(0-42 days) of Thorium-227 after single dose of Cycle 1 |  | From Day 1 to 43 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malignant Mesothelioma, Malignant Pleural Epithelioid Mesothelioma, Malignant Peritoneal Epithelioid Mesothelioma