BI 6727 (Volasertib) Human ADME Trial in Various Solid Tumours

Study Overview
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Brief Summary
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Investigation of absorption, distribution, metabolism and excretion (ADME) and assessment of safety, tolerability and preliminary therapeutic effects of [14C]volasertib in patients with advanced solid tumours.

Official Title
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Investigation of the Metabolism, Excretion and Pharmacokinetics of an Openlabel Single Dose of 300 mg [14C]Volasertib Administered Intravenously in Patients With Various Solid Tumours With a Possible Extension Phase With Nonlabelled Drug

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: BI 6727


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Inclusion Criteria 1. Patients with histologically or cytologically confirmed diagnosis of advanced, non resectable and / or metastatic solid tumour Inclusion Criteria 2. Male Inclusion Criteria 3. Age >=18 and =<70 years Inclusion Criteria 4. Written informed consent Inclusion Criteria 5. Eastern Cooperative Oncology Group (ECOG) performance score =<2 Inclusion Criteria 6. Recovery from Common Terminology Criteria for Adverse Events (CTCAE) Grade >=2 therapy-related toxicities from previous chemo-, hormone-, immuno-, or radiotherapy Exclusion criteria: Exclusion Criteria 1. Serious concomitant non-oncological disease considered by the investigator Exclusion Criteria 2. Active infectious disease Exclusion Criteria 3. Viral hepatitis, Human Immunodeficiency Virus (HIV) infection Exclusion Criteria 4. Clinical evidence of active brain metastasis during the past 6 months Exclusion Criteria 5. Second malignancy currently requiring active therapy Exclusion Criteria 6. Absolute neutrophil count less than 1,500/mm3 Exclusion Criteria 7. Platelet count less than 100,000/mm3 Exclusion Criteria 8. Total bilirubin greater than 1.5 mg/dL Exclusion Criteria 9. Aspartate amino transferase (AST) and / or alanine amino transferase (ALT) greater than 2.5 times the upper limit of normal (if related to liver metastases greater than five times the upper limit of normal) Exclusion Criteria 10. Serum creatinine greater than 1.5x Upper Limit of Normal (ULN). Exclusion Criteria 11. Known history of QT/QTcF-prolongation Exclusion Criteria 12. Patients who are sexually active and having a partner with childbearing potential and unwilling to use a medically acceptable method of contraception Exclusion Criteria 13. Treatment with other investigational drugs or participation in another clinical trial Exclusion Criteria 14. Chemo-, radio- immuno-, or molecular-targeted cancer-therapy within the past four weeks prior to start of therapy or concomitantly with this trial. This restriction does not apply to steroids and bisphosphonates. Exclusion Criteria 15. Alcohol abuse Exclusion Criteria 16. Life expectancy less than 12 weeks Exclusion Criteria 17. Potent Cytochrome P450 enzyme (CYP) 3A4 and P-glycoprotein inhibitors or inducers Exclusion Criteria 18. History of allergy/hypersensitivity

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Male

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 6727<br>BI 6727 cycles in every 21 days | Drug: BI 6727<br>* PLK-1 inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Individual Time Course Profiles of 14C-radioactivity in Whole Blood and Plasma: Cmax of 14C Labelled Volasertib | Individual time course profiles of 14C-radioactivity in whole blood and plasma: Cmax of 14C labelled Volasertib. | Whole blood: Pre-dose (-0.5 hours (h)) and 1.0h, 1.983h, 4h, 6h, 8h and 24h after start of the 2h drug infusion.Plasma: Pre-dose (-0.5h) and 1.0h, 1.983h, 4h, 6h, 8h, 24h,48h. 96h, 168h and 336h after start of drug infusion. | 
| Individual Time Course Profiles of 14C-radioactivity in Urine: Cumulative Fraction of 14C-ratioactivity Excreted in Urine | Percentage of administered dose excreted in urine as 14C-radioactivity over time | Every 24 hours, up to 504 hours | 
| Individual Time Course Profiles of 14C-radioactivity in Faeces: Cumulative Fraction of 14C-radioactivity Excreted in Faeces | Percentage of administered dose excreted in faeces as 14C-radioactivity over time | Every 24 hours, up to 504 hours | 
| Individual Time Course Profiles of Volasertib and CD 10899 in Plasma: Cmax of Volasertib and CD 10899 (a Metabolite of Volasertib). | Individual time course profiles of volasertib (BI 6727) and a metabolite of volasertib (CD 10899), in plasma: Cmax of Volasertib and CD 10899. | Plasma: Pre-dose (-0.5h) and 1.0h, 1.983h, 4h, 6h, 8h, 24h,48h. 96h, 168h and 336h after start of drug infusion. | 
| Individual Time Course Profile of Volasertib in Urine:Cumulative Fraction of Volasertib Excreted in Urine | Percentage of administered dose excreted in urine as volasertib (BI 6727) over time | Every 24 hours, up to 504 hours | 
| Individual Time Course Profile of CD 10899 in Urine: Cumulative Amount of CD 10899 Excreted in Urine | Cumulative amounts of CD 10899, a metabolite of volasertib, excreted in urine over time | Every 24 hours, up to 504 hours | 
| Rate and Extent of Excretion Mass Balance Based on the Total Radioactivity in Urine and Faeces: Cumulative Fraction of Excretion 504 Hours After Start of Drug Infusion. | Cumulative Percentage of 14C-radioactivity excreted in urine and faeces at 504 hours after start of drug infusion related to total [14C] volasertib administered. | up to 504 hours | 
| Cmax of Volasertib and CD 10899 in Plasma | Maximum measured concentration of volasertib and CD 10899, a metabolite of volasertib, in plasma (Cmax). | 30 minutes (min) before start of infusion and 1 hour (h), 1h 59min, 4h, 6h, 8h, 24h, 48h, 96h, 168h and 336h after start of infusion | 
| AUC0-inf of Volasertib and CD10899 in Plasma | Area under the concentration-time curve of volasertib and CD 10899, a metabolite of volasertib, in plasma over the time interval from 0 to infinity (AUC0-inf). | 30 minutes (min) before start of infusion and 1 hour (h), 1h 59min, 4h, 6h, 8h, 24h, 48h, 96h, 168h and 336h after start of infusion | 
| CL/R of Volasertib and CD 10899 in Urine | Renal clearance of the analyte in urine (CL/R) within the time interval 0 hours to 504 hours of volasertib and CD 10899, a metabolite of volasertib. | Every 24 hours, up to 504 hours | 
| Ae(0-tz) of Volasertib and CD 10899 in Urine | Amount of analyte eliminated in urine within the time interval 0 hours to last quantifiable data point (Ae(0-tz)) for volasertib and CD 10899, a metabolite of volasertib. | Every 24 hours, up to 504 hours | 
| AUC0-tz of 14C Radioactivity in Plasma and Whole Blood | Area under the concentration-time curve of 14C radioactivity in plasma and whole blood over the time interval from 0 to the last quantifiable data point (AUC0-tz). | 30 minutes (min) before start of infusion and 1 hour (h), 1h 59min, 4h, 6h, 8h, 24h, 48h, 96h, 168h and 336h after start of infusion for plasma; 30 min before start of infusion and 1h, 1h 59min, 4h, 6h, 8h and 24h after start of infusion for whole blood | 
| Ae(0-tz) of 14C Radioactivity in Urine | Amount of analyte eliminated in urine within the time interval 0 to to the last quantifiable data point (Ae(0-tz)) of 14C radioactivity | Every 24 hours, up to 504 hours | 
| Ae,Faeces(0-tz) of 14C Radioactivity | Amount of analyte excreted in faeces within the time interval 0 to to the last quantifiable data point (Ae(0-tz)) of 14C radioactivity | Every 24 hours, up to 504 hours | 
| Time Dependency of Cblood Cells/Cplasma Ratio and Cblood/Cplasma Ratio of 14C-radioactivity | Time dependency of Cblood cells/Cplasma ratio and Cblood/Cplasma ratio of 14C-radioactivity. | 1.983 hours and 6 hours | 
| Elucidation of Metabolite Structures and Identification of Major Metabolites in Plasma, Urine, and Faeces | Elucidation of mb structures and identification of major metabolites in plasma, urine, and faeces. This endpoint was not analysed in the study report. The contribution of volasertib and the metabolite CD 10899 to total radioactivity in plasma in the time interval 0 to 8 h after drug administration supports the suggestion that other metabolites in addition to CD 10899 are present in plasma. However, different methods used for the quantification of volasertib and CD 10899 (HPLC MS/MS) and total 14C-radioactivity (liquid scintillation counting) have to be taken into account for the interpretation of the difference between total 14C-radioactivity and analysis of volasertib and CD 10899 in plasma and the plasma metabolite pattern remains to be categorized. | 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Drug Related Adverse Events | Percentage of participants with drug related adverse events (AEs) | From first intake of study drug until 21 days after last intake of the study drug, up to 63 days | 
| Percentage of Participants With Clinically Relevant Abnormalities for Clinical Assessments, ECG, Vital Signs and Laboratory Tests | Percentage of participants with clinically relevant abnormalities for clinical assessments, electrocardiogram (ECG), vital signs and clinical laboratory test parameters. New abnormal findings or worsening of baseline conditions were reported as adverse events. | From first intake of study drug until 21 days after last intake of the study drug, up to 63 days | 
| Percentage of Participants With Clinical Benefit | The endpoint tumour response was was analysed as the percentage of participants with clinical benefit after each treatment cycle based on the Investigator's response assessment (with clinical assessment being conducted after every cycle and radiological assessment at the Investigator's discretion). | 21, 42 and 63 days |