Infusion over 1 hour (1h) in course 1 and over 2 hours (2h) in course 2.

Infusion over 2 hours (2h) in course 1 and over 1 hours (1h) in course 2.

BI 6727

Boehringer Ingelheim

The primary objective of this trial is to identify the maximum tolerated dose (MTD) of BI 6727 therapy in terms of drug-related adverse events. Secondary objectives are the collection of overall safety and antitumour efficacy data and the determination of the pharmacokinetic profile of BI 6727.

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

An Open Phase I Single Dose Escalation Study of BI 6727 Administered Intravenously in Patients With Advanced Solid Tumours With Repeated Administration in Patients With Clinical Benefit

Clinical studies sponsored by Boehringer Ingelheim, phases I to IV, interventional and non-interventional, are in scope for sharing of the raw clinical study data and clinical study documents, except for the following exclusions:

1. studies in products where Boehringer Ingelheim is not the license holder;
2. studies regarding pharmaceutical formulations and associated analytical methods, and studies pertinent to pharmacokinetics using human biomaterials;
3. studies conducted in a single center or targeting rare diseases (because of limitations with anonymization).

For more details refer to: https://www.mystudywindow.com/msw/datasharing

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.

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 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).

Treated Set (TS): ALL patients who received at least one dose of BI 6727.

12 milligram (mg) solution for injection of BI 6727 was administered as intravenous infusion over 60 minutes once every 21 days (as long as there was clinical benefit for the patients).

12 mg BI 6727

24 mg solution for injection of BI 6727 was administered as intravenous infusion over 60 minutes once every 21 days (as long as there was clinical benefit for the patients).

24 mg BI 6727

48 mg solution for injection of BI 6727 was administered as intravenous infusion over 60 minutes once every 21 days (as long as there was clinical benefit for the patients).

48 mg BI 6727

75 mg solution for injection of BI 6727 was administered as intravenous infusion over 60 minutes once every 21 days (as long as there was clinical benefit for the patients).

75 mg BI 6727

125 mg solution for injection of BI 6727 was administered as intravenous infusion over 60 minutes once every 21 days (as long as there was clinical benefit for the patients).

125 mg BI 6727

200 mg solution for injection of BI 6727 was administered as intravenous infusion over 60 minutes once every 21 days (as long as there was clinical benefit for the patients).

200 mg BI 6727

300 mg solution for injection of BI 6727 was administered as intravenous infusion over 60 minutes once every 21 days (as long as there was clinical benefit for the patients).

300 mg BI 6727

300 mg solution for injection of BI 6727 was administered as intravenous infusion over 1 hour (1h) in course 1 and over 2 hours (2h) in course 2 once every 21 days (as long as there was clinical benefit for the patients). QT extension cohort.

300 mg BI 6727 1h2h

300 mg solution for injection of BI 6727 was administered as intravenous infusion over 2 hour (2h) in course 1 and over 1 hour (1h) in course 2 once every 21 days (as long as there was clinical benefit for the patients). QT extension cohort.

300 mg BI 6727 2h1h

350 mg solution for injection of BI 6727 was administered as intravenous infusion over 60 minutes once every 21 days (as long as there was clinical benefit for the patients).

350 mg BI 6727

400 mg solution for injection of BI 6727 was administered as intravenous infusion over 60 minutes once every 21 days (as long as there was clinical benefit for the patients).

400 mg BI 6727

450 mg solution for injection of BI 6727 was administered as intravenous infusion over 60 minutes once every 21 days (as long as there was clinical benefit for the patients).

450 mg BI 6727

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Treated Set (TS): The treated set consists of all patients who received at least one dose of BI 6727.

Boehringer Ingelheim, Call Center

Comprises all dose groups during the dose escalation phase. 12/24/48/75/125/200/300/350/400 and 450 milligram (mg) solution for injection of BI 6727 was administered as intravenous infusion over 60 minutes once every 21 days (as long as there was clinical benefit for the patients). 300 mg 1h2h solution for injection of BI 6727 was administered as intravenous infusion over 1 hour (1h) in course 1 and over 2 hours (2h) in course 2 once every 21 days (as long as there was clinical benefit for the patients). 300 mg 2h1h solution for infusion of BI 6727 was administered as intravenous infusion over 2 hour (2h) in course 1 and over 1 hour (1h) in course 2 once every 21 days (as long as there was clinical benefit for the patients).

Treated Set (TS): All patients who received at least one dose of BI 6727.

Maximum Tolerated Dose (MTD)

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Number of Participants With Adverse Events (AEs)

Haematocrit

Haemoglobin

Mean corpuscular volume (MCV)

Platelets

Red blood cell count (RBC)

White blood cell count (WBC)

Neutrophils

Sodium

Alkaline phosphatase

Lactate dehydrogenase (LDH)

Albumin

Creatinine

Glucose

Number of Participants With Clinically Relevant Abnormalities

Improved

Unchanged

Deteriorated

Unknown

Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Patient Performance Score

Change from baseline to 5 minutes before infusion end. Linear mixed model with sequence, course, treatment (both infusion types i.e. 1 hour duration and 2 hour duration) and time as fixed effects and treatment\*time as interaction effect, as well as the continuous , fixed covariate of baseline value.

Change from baseline to 1 hour after infusion end. Linear mixed model with sequence, course, treatment (both infusion types i.e. 1 hour duration and 2 hour duration) and time as fixed effects and treatment\*time as interaction effect, as well as the continuous , fixed covariate of baseline value.

Change from baseline to 4 hours after infusion start. Linear mixed model with sequence, course, treatment (both infusion types i.e. 1 hour duration and 2 hour duration) and time as fixed effects and treatment\*time as interaction effect, as well as the continuous , fixed covariate of baseline value.

Change from baseline to 24 hours after infusion start. Linear mixed model with sequence, course, treatment (both infusion types i.e. 1 hour duration and 2 hour duration) and time as fixed effects and treatment\*time as interaction effect, as well as the continuous , fixed covariate of baseline value.

CfB to 5 minutes before infusion end

CfB to 1 hours after infusion end

CfB to 4 hours after infusion start

CfB to 24 hours after infusion start

300 mg solution for injection of BI 6727 was administered as intravenous infusion over 1 hour (1h). QT extension cohort.

300 mg BI 6727 1h

300 mg solution for injection of BI 6727 was administered as intravenous infusion over 2 hours (2h). QT extension cohort.

300 mg BI 6727 2h

QT extension cohort: Patients treated with 300 mg BI6727 to investigate QTc changes, according to two different treatment schedules in course 1 and course 2, (300 mg BI 6727 1h2h and 300 mg BI 6727 2h1h). Results are reported for 300 mg over 1 hour infusion vs. 300 mg over 2 hours infusion. Only participants with non-missing data were included in the analysis.

Electrocardiogram (ECG) - QTcF Change From Baseline

Systolic blood pressure

Diastolic blood pressure

Vital Signs - Blood Pressure

Vital Signs - Pulse Rate

Complete response

Partial Response

Stable disease

Non-evaluable, clinically non-progressive disease (NEVCNPD)

Progressive Disease (PD) or NEVCPD

Number of Participants With Unconfirmed Best Overall Response

Number of Participants With Progression

Treated Set (TS): All patients who received at least one dose of BI 6727. Only patients with non-missing values were included in the analysis.

Maximum Concentration of BI 6727 in Plasma (Cmax)

Time From Dosing to Maximum Concentration (Tmax)

Only patients in the treated set who had non-missing values were included in the analysis. For arms with 0 patients analysed: No sufficient data had been collected to determine the terminal half-life T1/2, which is needed to analyse the PK data.

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)

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)

Only patients in the treated set (TS) who had non-missing values were included in the analysis. Descriptive statistics for the 200 mg group could not be evaluated, since plasma concentrations of BI 6727 was only quantifiable in less than two-thirds of the patients. Descriptive statistics is calculated in case that 2/3 patients of total could be evaluated, as defined in the trial statistical analysis plan (TSAP).

Amount of BI 6727 That is Eliminated in Urine From the Time Point 0 to Time Point 24 Hours (Ae0-24)

Only patients in the treated set (TS) who had non-missing values were included in the analysis. Descriptive statistics for 200mg and 350mg group could not be evaluated, since plasma concentrations of BI 6727 was only quantifiable in less than two-thirds of the patients, respectively. Descriptive statistics is calculated in case that 2/3 patients of total could be evaluated, as defined in the trial statistical analysis plan (TSAP).

Amount of BI 6727 That is Eliminated in Urine From the Time Point 0 to Time Point 48 Hours (Ae0-48)

Only patients in the treated set (TS) who had non-missing values were included in the analysis. Descriptive statistics for 200 mg group could not be evaluated, since plasma concentrations of BI 6727 was only quantifiable in less than two-thirds of the patients. Descriptive statistics is calculated in case that 2/3 patients of total could be evaluated, as defined in the trial statistical analysis plan (TSAP).

Fraction of BI 6727 Eliminated in Urine From Time Point 0 to Time Point 24 Hours (Fe0-24)

Fraction of BI 6727 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)

Only patients in the treated set with non-missing values. For arms with 0 patients analysed: No sufficient data had been collected to determine the terminal half-life T1/2, which is needed to analyse the PK data. Descriptive statistics for 200 and 350 mg group could not be evaluated, since plasma concentrations of BI 6727 was only quantifiable in less than 2/3 of patients, respectively. Descriptive statistics is calculated in case that 2/3 patients of total could be evaluated as defined in TSAP.

Spots Global Cancer Trial Database for BI 6727 Administered Intravenously Every 3 Weeks in Patients With Solid Tumours

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