BI 6727 Administered Intravenously Every 3 Weeks in Patients With Solid Tumours

MTD is defined as: the dose of BI 6727 which is one dose tier below that dose at which two or more out of a maximum of six patients experienced dose-limiting toxicity (DLT). At the maximum tolerated dose, no more than one patient out of six patients may experience DLT, i.e. MTD is defined as the highest dose studied for which the incidence of dose-limiting toxicity is no more than 17% (i.e. 1/6 patients) during the first course.

DLT is defined as drug related common terminology criteria for adverse events (CTCAE) grade 3 or 4 non haematological toxicity (except emesis or diarrhoea responding to supportive treatment), or drug related CTCAE grade 4 neutropenia for seven or more days and / or complicated by infection, or CTCAE Grade 4 thrombocytopenia .

Number of participants with adverse events. The events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v.3.0.

Grade refers to the severity of adverse event. Grade 1: Mild AE; Grade 2: Moderate AE; Grade 3: Severe AE; Grade 4: Life-threatening or disabling AE; Grade 5: Death related to AE.

Number of participants with clinically relevant abnormalities, occurring in >5% of the total number of participants, is reported.

Clinically relevant post baseline values with Common Terminology Criteria for Adverse Events (CTCAE) grades:

• CTCAE grade ≥4 for White blood cell count (WBC) , Neutrophils (NEUT), NEUABS Lymphocytes (LMPH) if baseline CTCAE grade is not 4
• CTCAE grade ≥3 for Haemoglobin (HGB), Platelets count (PLTCT), Alkaline phosphatase (ALKP), serum glutamic-oxaloacetic-transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), total bilirubin (TBILI), if baseline CTCAE grade is ≥3 increases of one grade
• CTCAE grade ≥2 for other parameters, if baseline CTCAE grade is ≥2 increases of at least one grade

ECOG score: The scale of ECOG score is defined as a six point categorical scale as described ranging from 0 (asymptomatic) to 5 (death). ECOG score change from baseline to end of treatment is calculated, and defined as

= ECOG score at end of treatment - ECOG score at baseline.

Scale of ECOG score change:

The ECOG score changes from baseline score are categorized on a three point categorical scale: Improved, unchanged, and deteriorated. Improvement or deterioration of performance status required a decrease or an increase from baseline, respectively, of at least one point on the ECOG scale. The number of patients per category ("improved", "unchanged", "deteriorated" "unknown") is reported.

Electrocardiogram (ECG) - QTcF change from baseline. QTcF intervals form the ECGs were analysed for changes during and after intravenous infusion of BI 300 mg dose over 1 hours and over 2 hours. For baseline ECG, the combined baseline, defined as the mean of the 2 triplicates at the time-point closest to but prior to the start of the infusion of both treatment courses, i.e. a common baseline is used for both treatment courses, was used. Mean is adjusted mean.

Abbreviations:

QTcF: QT interval, corrected for heart rate according to Fridericia's formula (seconds) = measured QT / (cube root of preceding RR interval) QT: Interval from the beginning of the Q wave to the end of the T wave on an ECG (seconds).

CfB: Change from baseline.

Systolic blood pressure and diastolic blood pressure are reported.

Pulse rate is reported.

For solid tumours, evaluation of tumour response was assessed according to the Response Evaluation Criteria in Solid Tumours (RECIST) definition. The overall response of target and non-target lesions together with or without the appearance of new lesions as reported by the investigator was assessed on a four point categorical scale as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) according to the RECIST criteria. In order to best handle measurements that were non-evaluable (NEV) a modified version of the RECIST criteria was used. If a RECIST overall response was deemed NEV, it could be further classified into non-evaluable clinically progressive disease (NEVCPD ) or non-evaluable clinically non-progressive disease (NEVCNPD), depending on the subjective assessment of the investigator.

Number of participants with progression of disease.

Progressive disease is defined according to the Response Evaluation Criteria in Solid Tumours (RECIST) as: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeter.

Maximum concentration of BI 6727 in plasma (Cmax).

Different time frame for dose groups 300 mg BI 6727 1h2h and 300 mg BI 6727 2h1h:

For 300mg BI 6727 1h2h: At course 1: 0.083 hours before drug administration and at 1*, 2, 4, 8, 24 hours after start of infusion (*immediately prior to end of infusion of BI 6727).

For 300mg BI 6727 2h1h: At course 1: 0.083 hours before drug administration and at 1*, 2, 3, 4 and 24 hours after start of infusion (*immediately prior to end of infusion of BI 6727).

Time from dosing to maximum concentration (tmax).

Different time frame for dose groups 300 mg BI 6727 1h2h and 300 mg BI 6727 2h1h:

For 300mg BI 6727 1h2h: At course 1: 0.083 hours before drug administration and at 1*, 2, 4, 8, 24 hours after start of infusion (*immediately prior to end of infusion of BI 6727).

For 300mg BI 6727 2h1h: At course 1: 0.083 hours before drug administration and at 1*, 2, 3, 4 and 24 hours after start of infusion (*immediately prior to end of infusion of BI 6727).

Area under the concentration-time curve of BI 6727 in plasma over the time interval from 0 extrapolated to infinity (AUC0-inf).

Area under the concentration-time curve of BI 6727 in plasma over the time interval from 0 to the last quantifiable time point tz (AUC0-tz).

Different time frame for dose groups 300 mg BI 6727 1h2h and 300 mg BI 6727 2h1h:

For 300mg BI 6727 1h2h: At course 1: 0.083 hours before drug administration and at 1*, 2, 4, 8, 24 hours after start of infusion (*immediately prior to end of infusion of BI 6727).

For 300mg BI 6727 2h1h: At course 1: 0.083 hours before drug administration and at 1*, 2, 3, 4 and 24 hours after start of infusion (*immediately prior to end of infusion of BI 6727).

Terminal rate constant in plasma (λz).

Terminal half-life of the analyte in plasma (t1/2).

Mean residence time of BI 6727 in the body after intravenous administration (MRT).

Total clearance of BI 6727 in the plasma after intravascular adminstration (CL).

Apparent volume of distribution at steady state following intravascular administration (Vss).

Apparent volume of distribution during the terminal phase λz following an intravascular dose (Vz).

Amount of BI 6727 that is eliminated in urine from the time point 0 to time point 24 hours (Ae0-24).

Amount of BI 6727 that is eliminated in urine from the time point 0 to time point 48 hours (Ae0-48).

Fraction of BI 6727 (percentage of dose) eliminated in urine from time point 0 to time point 24 hours (Fe0-24).

Fraction of BI 6727 (percentage of dose) eliminated in urine from time point 0 to time point 48 hours (Fe0-48).

Renal clearance of BI 6727 from the time point 0 to time point 24 hours (CLr,0-24).

Renal clearance of BI 6727 from the time point 0 to time point 48 hours (CLr,0-48).