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

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.

Time frame: From the first administration of study drug up to 3 weeks

Population: The treated set.

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.

Time frame: From first administration of study drug up to 3 weeks

Population: The treated set consisted of all patients whe received at least one dose of volasertib.

This endpoint will be presented as a change from baseline to last value on treatment in neutrophils.

Time frame: Baseline (Visit 1, prior to first administration of volasertib) and up to 21 days after last observation on treatment (up to 548 days)

Population: Treated Set

This endpoint will be presented as a change from baseline to last value on treatment in platelets.

Time frame: Baseline (Visit 1, prior to first administration of volasertib) and up to 21 days after last observation on treatment (up to 548 days)

Population: Treated Set

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.

Time frame: At screening and at the end of every other treatment course up to 527 days (= longest treatment exposure)

Population: The treated set

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.

Time frame: Baseline, 2 hours (before the end of infusion of volasertib) and 24 hours after first infusion in Cycle 1

Population: Treated Set, only the patients in the Maximum Tolerated Dose (MTD) groups are evaluated for this endpoint.

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.

Time frame: At screening and at the end of every other treatment course up to 527 days (= longest treatment exposure)

Population: The treated set

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.

Time frame: From first administration of volasertib to the last dose, up to 527 days

Population: Treated Set

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.

Time frame: From first administration of volasertib to 21 days after the last dose, up to 548 days

Population: Treated Set

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.

Time frame: 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

Population: Treated Set. All evaluable patients were included in the PK analyses.

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.

Time frame: 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

Population: Treated Set. All evaluable patients were included in the PK analyses. Patients who were considered not evaluable were not included. A patient was considered to be not evaluable if they had an important protocol violation relevant to the evaluation of PK, or they had insufficient data.

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.

Time frame: 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

Population: Treated Set. All evaluable patients were included in the PK analyses. Patients who were considered not evaluable were not included. A patient was considered to be not evaluable if they had an important protocol violation relevant to the evaluation of PK, or they had insufficient data. D1 Schedule, no administration of trial drug on Day 8.

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.

Time frame: At screening and at the end of every other treatment course up to 527 days (= longest treatment exposure)

Population: The treated set

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.

Time frame: 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

Population: The reason not to analyze the duration of objective response is that only 2 patients in different arms achieved an objective response and the analysis would reduce to a single patient case report.

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.

Time frame: At screening and at the end of every other treatment course up to 527 days (= longest treatment exposure)

Population: No descriptive statistics were calculated, but the time profile of sum of largest diameter was plotted for each patient.

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.

Time frame: Baseline (Visit 1, prior to the first administration of volasertib), up to 21 days after last observation on treatment (up to 548 days)

Population: Treated Set

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.

Time frame: Baseline (Visit 1, prior to the first administration of volasertib), up to 21 days after last observation on treatment (up to 548 days)

Population: Treated Set