Dose Finding Study of BI 6727 (Volasertib) in Patients With Various Solid Cancers

Study Overview
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Brief Summary
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The primary objective of this trial is to identify the maximum tolerated dose (MTD) of BI 6727 in Asian cancer patients, and to provide safety data in terms of drug-related adverse events.

Official Title
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A Phase I Single Dose Escalation Study of Two Dosing Schedules of BI 6727 Administered Intravenously in Asian Patients With Various Solid Cancers With Repeated Administration in Patients With Clinical Benefit

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: Patients with histologically or cytologically confirmed diagnosis of advanced solid cancer Age 18 years or older Written informed consent Eastern Cooperative Oncology Group (ECOG) performance score 2 or less Exclusion criteria: Serious illness or concomitant non-oncological disease. Pregnancy or breast feeding Active infectious disease Absolute neutrophil count less than 1,500/cubic millimeter Platelet count less than 100,000/cubic millimeter Bilirubin greater than 1.5 mg/dL (> 26 µmol/L, SI unit equivalent) Aspartate amino transferase (AST) and / or alanine amino transferase (ALT) greater than 2.5 times the upper limit of normal Serum creatinine greater than 1.5x ULN.

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 6727<br>Schedule A | Drug: BI 6727<br>* Dose level 1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Dose Limiting Toxicities (DLT) in Cycle 1 for the Determination of the Maximum Tolerated Dose (MTD) of Volasertib | Primary objective for this trial was to identify the MTD of volasertib for 2 dosing schedules. The MTD was defined as the highest volasertib dose studied for which the incidence of DLT was less than 2/6 patients. The MTD was defined on the basis of DLTs observed during the first treatment course only. In this outcome measure the percentage of participants with DLTs in cycle 1 is presented. | From first administration of study drug up to 3 weeks | 
| MTD of Volasertib | Primary objective for this trial was to identify the MTD of volasertib for 2 dosing schedules. The MTD was defined as the highest volasertib dose studied for which the incidence of DLT was less than 2/6 patients. This outcome measure shows the MTD. | From the first administration of study drug up to 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Incidence and Intensity of Drug-related AEs According to CTCAE v.3.0 | Percentage of participants with incidence and intensity of drug-related AEs according to Common Terminology Criteria for Adverse Events (CTCAE) v.3.0. This endpoint will be presented as a percentage of patients with adverse event by treatment and the highest CTCAE grade of the related AE. | From first administration of volasertib to 21 days after the last dose, up to 548 days | 
| Change From Baseline to Last Value on Treatment in Platelets | This endpoint will be presented as a change from baseline to last value on treatment in platelets. | Baseline (Visit 1, prior to first administration of volasertib) and up to 21 days after last observation on treatment (up to 548 days) | 
| Change From Baseline to Last Value on Treatment in Neutrophils | This endpoint will be presented as a change from baseline to last value on treatment in neutrophils. | Baseline (Visit 1, prior to first administration of volasertib) and up to 21 days after last observation on treatment (up to 548 days) | 
| Patient Performance | This endpoint will present the best clinical assessment. The investigator will perform a clinical assessment. An evaluation will be done whether the patient appears to be clinically improved, unchanged, or deteriorated. The presented numbers show the percentage of patients. | From first administration of volasertib to the last dose, up to 527 days | 
| Vital Signs (Blood Pressure) | This endpoint will be presented as a change from baseline at last observation of systolic blood pressure (SBP), diastolic blood pressure (DBP) in millimeter of mercury (mmHg) and pulse rate (PR) in beats per minute (bpm). In this outcome measure SBP and DBP are presented. | Baseline (Visit 1, prior to the first administration of volasertib), up to 21 days after last observation on treatment (up to 548 days) | 
| Vital Signs (Pulse Rate) | This endpoint will be presented as a change from baseline at last observation of systolic blood pressure (SBP), diastolic blood pressure (DBP) in millimeter of mercury (mmHg) and pulse rate (PR) in beats per minute (bpm). In this outcome measure the pulse rate is presented. | Baseline (Visit 1, prior to the first administration of volasertib), up to 21 days after last observation on treatment (up to 548 days) | 
| ECG | This endpoint will be presented as a change from individual baseline in QT interval, corrected according to Fridericias formula (QTcF) to end of infusion (2 hours) and 24 hours after first infusion in Cycle 1. | Baseline, 2 hours (before the end of infusion of volasertib) and 24 hours after first infusion in Cycle 1 | 
| Objective Response | The objective response (OR) was defined as complete response (CR; disappearance of all target lesions) or partial response (PR; at least a 30 percent decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest) assessed by tumour measurement and evaluated according to the Response Evaluation Criteria in solid tumours (RECIST), version 1.0. The data represents the percentage of patients. | At screening and at the end of every other treatment course up to 527 days (= longest treatment exposure) | 
| Progression-free Survival | Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of progression or death. PFS was assessed by tumour measurement and evaluated according to RECIST, version 1.0. | At screening and at the end of every other treatment course up to 527 days (= longest treatment exposure) | 
| Response Duration | The duration of overall response was measured from the time measurement criteria were met for complete response (CR) or partial response (PR), whichever was recorded first, until the first date that recurrent or progressive disease was objectively documented. The duration of overall CR was measured from the time measurement criteria were first met for CR until the first date that recurrent disease was objectively documented. | From first drug administration up to at 3 month interval after final End of treatment visit until disease progression, death, or lost to follow-up, up to 548 days | 
| Disease Control | The disease control (DC) presented are the percentage of patients with CR, PR or stable disease as best response throughout the study assessed by tumour measurement and evaluated according to RECIST, version 1.0. | At screening and at the end of every other treatment course up to 527 days (= longest treatment exposure) | 
| Sum of the Largest Diameters of Target Lesions | The individual time profile of the sum of the largest diameters of target lesions (LD) is presented graphically for each patient in the Clinical Trial Report (CTR) only. No descriptive statistics were planned. | At screening and at the end of every other treatment course up to 527 days (= longest treatment exposure) | 
| Pharmacokinetics (PK) AUC0-∞ of Volasertib | The PK of volasertib will be presented for the area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) for the population attending the D1 schedule, the area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to 168 hours (AUC0-168) for the population attending the D1+ D8 schedule and the maximum measured concentration of volasertib in plasma (Cmax). In this outcome measure AUC0-∞ is presented. | Both schedules: 10 minutes prior to first drug administration and 1 hour (h), 2, 2:30, 3, 4, 8, 24, 336h thereafter; additional planned times in schedule D1+D8: 167:50, 169, 170, 170:30, 171, 172, 176, 192h; additional planned time in D1 schedule: 168h | 
| Pharmacokinetics (PK) AUC0-168 of Volasertib | The PK of volasertib will be presented for the area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) for the population attending the D1 schedule, the area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to 168 hours (AUC0-168) for the population attending the D1+ D8 schedule and the maximum measured concentration of volasertib in plasma (Cmax). In this outcome measure AUC0-168 is presented. | Both schedules: 10 minutes prior to first drug administration and 1 hour (h), 2, 2:30, 3, 4, 8, 24, 336h thereafter; additional planned times in schedule D1+D8: 167:50, 169, 170, 170:30, 171, 172, 176, 192h; additional planned time in D1 schedule: 168h | 
| Pharmacokinetics (PK) Cmax of Volasertib | The PK of volasertib will be presented for the area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) for the population attending the D1 schedule, the area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to 168 hours (AUC0-168) for the population attending the D1+ D8 schedule and the maximum measured concentration of volasertib in plasma (Cmax). In this outcome measure Cmax is presented. | Both schedules: 10 minutes prior to first drug administration and 1 hour (h), 2, 2:30, 3, 4, 8, 24, 336h thereafter; additional planned times in schedule D1+D8: 167:50, 169, 170, 170:30, 171, 172, 176, 192h; additional planned time in D1 schedule: 168h |