Phase I Dose Escalation Study of BAY94-9343 Given by Intravenous Infusion Every 3 Weeks in Japanese Subjects With Advanced Malignancies

Study Overview
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Brief Summary
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The primary objectives of the Phase I study 15404 are to evaluate the safety, tolerability and pharmacokinetics of BAY94-9343 given once every 3 weeks in Japanese subjects with advanced, refractory solid tumors. The secondary objectives are to investigate the efficacy, biomarkers and immunogenicity.

Official Title
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An Open Label, Phase I Study to Evaluate the Safety, Tolerability and Pharmacokinetics of BAY94-9343 Given by Intravenous Infusion Every 3 Weeks (Q3W) in Japanese Subjects With Advanced Malignancies

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: BAY94-9343


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Japanese subjects ≥ 20 years of age ECOG Performance Status of 0 to 1 Life expectancy of at least 12 weeks Subjects with advanced, histologically or cytologically confirmed solid tumors, not amenable to any standard therapy, have no standard therapy available Subjects whose fresh or archival tumor tissues are available Measurable disease with at least one lesion that can be accurately measured in at least one dimension according to RECIST criteria (Version 1.1 or modified version) Adequate bone marrow, liver, and renal function Exclusion Criteria: Anticancer chemotherapy, experimental cancer therapy, or immunotherapy within 2 weeks of start of the first dose Impaired cardiac function or clinically significant cardiac disease (i.e., congestive heart failure (CHF) NYHA Class III or IV) Myocardial infarction or onset of unstable angina < 3 months prior to general screening Cardiac arrhythmias in the electrocardiogram that would interfere with QT/QTc interval measurement (LBBB (left bundle branch block), AV block, atrial fibrillation) QTc >470 ms, derived as the average of the 3 values measured by the ECG recorder's algorithm on the ECG triplicate LVEF (left ventricular ejection fraction) <50 % Uncontrolled hypertension defined as systolic blood pressure > 150 mm Hg and/or diastolic blood pressure > 90 mmHg, despite optimal medical management Known human immunodeficiency virus (HIV) infection Subjects with an active hepatitis B or C infection requiring treatment Personal or family history of Long QT Syndrome (LQTS) Subject with clinically significant eye disorders

Ages Eligible for Study
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Minimum Age: 20 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BAY94-9343<br>Cohort 1: Safety, tolerability and PK of 4.5 mg/kg dose given Q3W. Proceeding to Cohort 2 or not will be decided based on both safety variables during Cycle 1 (21 days) of 3 to 6 subjects in Cohort 1 and PK obtained from Cycle 1 (at least Day 1 to Day 5). Cohort 2: Safety, tolerability and PK of 6.5 mg/kg dose given Q3W. Whether recruitment will be continued up to 9 subjects for Cohort 2 or not will be decided based on safety variables during Cycle 1 (21 days) of the first 3 subjects in Cohort 2. The safety and tolerability of 6.5 mg/kg will be assessed based on the data of 9 subjects during Cycle 1 in Cohort 2, and considering long term toxicity, the safety and tolerability of BAY94-9343 will be assessed all safety data by the end of 3 cycles in Cohort 2. | Drug: BAY94-9343<br>* Cohort 1: 4.5 mg/kg of BAY 94-9343 at Q3W dose regimen. Cohort 2: 6.5 mg/kg of BAY 94-9343 at Q3W dose regimen.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Treatment-emergent Adverse Events (TEAEs) as a measure of safety and tolerability |  | Up to 9 weeks | 
| Intensity of TEAEs acc. to NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) v.4.03 |  | Up to 9 weeks | 
| Cmax (maximum drug concentration in plasma after single dose administration ) for BAY94-9343, total antibody compound, DM4, metabolite DM4-Me |  | Cycle 1, 3 ,6: pre, 30, 60min, 1.5, 2, 3, 5, 8, 48, 96, 168 and 504 hours after the start of dosing; Cycle1,2 only: 336 hours; Cycle1 only: 24 hours (each cycle is 21 days) | 
| Cmax,norm (Cmax divided by dose (mg) per kg body weight) for BAY94-9343, total antibody compound, DM4, metabolite DM4-Me |  | Cycle 1, 3 ,6: pre, 30, 60min, 1.5, 2, 3, 5, 8, 48, 96, 168 and 504 hours after the start of dosing; Cycle1,2 only: 336 hours; Cycle1 only: 24 hours (each cycle is 21 days) | 
| Cmax/D (Cmax divided by dose (mg)) for BAY94-9343, total antibody compound, DM4, metabolite DM4-Me |  | Cycle 1, 3 ,6: pre, 30, 60min, 1.5, 2, 3, 5, 8, 48, 96, 168 and 504 hours after the start of dosing; Cycle1,2 only: 336 hours; Cycle1 only: 24 hours (each cycle is 21 days) | 
| AUC(0-tlast) (area under the plasma concentration vs time curve from time 0 to the last data point) for BAY94-9343, total antibody compound, DM4, metabolite DM4-Me |  | Cycle 1, 3 ,6: pre, 30, 60min, 1.5, 2, 3, 5, 8, 48, 96, 168 and 504 hours after the start of dosing; Cycle1,2 only: 336 hours; Cycle1 only: 24 hours (each cycle is 21 days) | 
| AUC(0-tlast)norm (AUC(0-tlast) divided by dose (mg) per kg body weight) for BAY94-9343, total antibody compound, DM4, metabolite DM4-Me |  | Cycle 1, 3 ,6: pre, 30, 60min, 1.5, 2, 3, 5, 8, 48, 96, 168 and 504 hours after the start of dosing; Cycle1,2 only: 336 hours; Cycle1 only: 24 hours (each cycle is 21 days) | 
| AUC(0-tlast)/D (AUC(0-tlast) divided by dose (mg)) for BAY94-9343, total antibody compound, DM4, metabolite DM4-Me |  | Cycle 1, 3 ,6: pre, 30, 60min, 1.5, 2, 3, 5, 8, 48, 96, 168 and 504 hours after the start of dosing; Cycle1,2 only: 336 hours; Cycle1 only: 24 hours (each cycle is 21 days) | 
| tmax (time to reach maximum drug concentration in plasma) for BAY94-9343, total antibody compound, DM4, metabolite DM4-Me |  | Cycle 1, 3 ,6: pre, 30, 60min, 1.5, 2, 3, 5, 8, 48, 96, 168 and 504 hours after the start of dosing; Cycle1,2 only: 336 hours; Cycle1 only: 24 hours (each cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor response based on RECIST (Response Evaluation Criteria in Solid Tumors) |  | Up to 9 weeks | 
| Level of mesothelin expression using IHC (Immunohistochemistry) staining for the tumor tissue obtained from fresh or archival tumor tissue |  | Up to 9 weeks | 
| Plasma levels of soluble mesothelin |  | Up to 9 weeks | 
| Immunogenicity evaluation based on anti-BAY94-9343 antibody count |  | Up to 9 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BAY 94-9343, Anetumab ravtansine, ADC (Antibody Drug Conjugate), Phase I, Japan, solid cancers, Advanced, refractory solid tumors, mesothelin, endometrial, adenocarcinoma of lung, gastrointestinal, ovarian, pancreatic, cholangio, mesothelioma and triple negative breast cancers