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

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 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.

Official Title
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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

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 confirmed diagnosis of advanced, non resectable and / or metastatic solid tumours, who have failed conventional treatment, or for whom no therapy of proven efficacy exists, or who are not amenable to established forms of treatment Age 18 years or older Written informed consent consistent with ICH-GCP and local legislation Eastern Cooperative Oncology Group (ECOG, R01-0787) performance score ¿ 2 Recovery from CTCAE Grade 2 - 4 therapy-related toxicities from previous chemo-, hormone-, immuno-, or radiotherapies (except alopecia) The 18 additional patients recruited at the MTD must also meet the following criterion: Measurable tumour deposits (RECIST) by one or more techniques (CT, MRI) Exclusion criteria: Serious illness or concomitant non-oncological disease considered by the investigator to be incompatible with the protocol Pregnancy or breastfeeding Active infectious disease or known chronic Hepatitis B/Hepatitis C infection Clinical evidence of active brain or leptomeningeal disease during the past 12 months Second malignancy currently requiring active therapy Absolute neutrophil count less than 1500 / mm3 Platelet count less than 100 000 / mm3 Bilirubin greater than 1.5 mg / dl (> 26 ¿mol / L, SI unit equivalent) 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) Serum creatinine greater than 1.5 mg / dl (> 132 ¿mol / L, SI unit equivalent) Known history of relevant QT-prolongation, e.g. long QT-syndrome Women and men who are sexually active and unwilling to use a medically acceptable method of contraception Treatment with other investigational drugs or participation in another clinical trial within the past four weeks before start of therapy or concomitantly with this trial (except for present trial drug) Chemo-, radio or immunotherapy within the past four weeks before start of therapy or concomitantly with this trial. This restriction does not apply to steroids and bisphosphonates. Patients unable to comply with the protocol Active alcohol or drug abuse

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 12 mg BI 6727<br> | Drug: BI 6727<br>* BI 6727<br>* Other names: Volasertib;|
| Experimental: 24 mg BI 6727<br> | Drug: BI 6727<br>* BI 6727<br>* Other names: Volasertib;|
| Experimental: 48 mg BI 6727<br> | Drug: BI 6727<br>* BI 6727<br>* Other names: Volasertib;|
| Experimental: 75 mg BI 6727<br> | Drug: BI 6727<br>* BI 6727<br>* Other names: Volasertib;|
| Experimental: 125 mg BI 6727<br> | Drug: BI 6727<br>* BI 6727<br>* Other names: Volasertib;|
| Experimental: 200 mg BI 6727<br> | Drug: BI 6727<br>* BI 6727<br>* Other names: Volasertib;|
| Experimental: 300 mg BI 6727<br> | Drug: BI 6727<br>* BI 6727<br>* Other names: Volasertib;|
| Experimental: 300 mg BI 6727 1h2h<br>Infusion over 1 hour (1h) in course 1 and over 2 hours (2h) in course 2. | Drug: BI 6727<br>* BI 6727<br>* Other names: Volasertib;|
| Experimental: 300 mg BI 6727 2h1h<br>Infusion over 2 hours (2h) in course 1 and over 1 hours (1h) in course 2. | Drug: BI 6727<br>* BI 6727<br>* Other names: Volasertib;|
| Experimental: 350 mg BI 6727<br> | Drug: BI 6727<br>* BI 6727<br>* Other names: Volasertib;|
| Experimental: 400 mg BI 6727<br> | Drug: BI 6727<br>* BI 6727<br>* Other names: Volasertib;|
| Experimental: 450 mg BI 6727<br> | Drug: BI 6727<br>* BI 6727<br>* Other names: Volasertib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | 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 . | 21 days (first treatment course). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) | 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. | From first drug administration until last drug administration plus 21 days, up to 835 days. | 
| Number of Participants With Clinically Relevant Abnormalities | 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 | From baseline to the last value on treatment, up to 814 days. | 
| Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Patient Performance Score | 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. | At baseline and at end of treatment (up to 814 days). | 
| Electrocardiogram (ECG) - QTcF Change From Baseline | 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. | At baseline and 5 minutes before infusion end, 1 hour after end of infusion and at 4 and 12 hours after start of infusion, at course 1. | 
| Vital Signs - Blood Pressure | Systolic blood pressure and diastolic blood pressure are reported. | At baseline. | 
| Vital Signs - Pulse Rate | Pulse rate is reported. | At baseline. | 
| Number of Participants With Unconfirmed Best Overall Response | 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. | Up to 814 days. | 
| Number of Participants With Progression | 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. | Up to 814 days. | 
| Maximum Concentration of BI 6727 in Plasma (Cmax) | 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). | At course 1: 0.083 hours before drug administration and at 0.25, 0.5, 075, 1*, 1.5, 2, 4, 8, 24, 48, 96, 168, 336 hours after start of infusion (*immediately prior to end of infusion of BI 6727). | 
| Time From Dosing to Maximum Concentration (Tmax) | 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). | At course 1: 0.083 hours before drug administration and at 0.25, 0.5, 075, 1*, 1.5, 2, 4, 8, 24, 48, 96, 168, 336 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 extrapolated to infinity (AUC0-inf). | 0.083 hours before drug administration and at 0.25, 0.5, 075, 1*, 1.5, 2, 4, 8, 24, 48, 96, 168, 336 and 504 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 to the Last Quantifiable Time Point tz (AUC0-tz) | 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). | 0.083 hours before drug administration and at 0.25, 0.5, 075, 1*, 1.5, 2, 4, 8, 24, 48, 96, 168, 336 and 504 hours after start of infusion (*immediately prior to end of infusion of BI 6727). | 
| Terminal Rate Constant in Plasma (λz) | Terminal rate constant in plasma (λz). | At course 1: 0.083 hours before drug administration and at 0.25, 0.5, 075, 1*, 1.5, 2, 4, 8, 24, 48, 96, 168, 336 hours after start of infusion (*immediately prior to end of infusion of BI 6727). | 
| Terminal Half-life of the Analyte in Plasma (t1/2) | Terminal half-life of the analyte in plasma (t1/2). | At course 1: 0.083 hours before drug administration and at 0.25, 0.5, 075, 1*, 1.5, 2, 4, 8, 24, 48, 96, 168, 336 hours after start of infusion (*immediately prior to end of infusion of BI 6727). | 
| Mean Residence Time of BI 6727 in the Body After Intravenous Administration (MRT) | Mean residence time of BI 6727 in the body after intravenous administration (MRT). | At course 1: 0.083 hours before drug administration and at 0.25, 0.5, 075, 1*, 1.5, 2, 4, 8, 24, 48, 96, 168, 336 hours after start of infusion (*immediately prior to end of infusion of BI 6727). | 
| Total Clearance of BI 6727 in the Plasma After Intravascular Adminstration (CL) | Total clearance of BI 6727 in the plasma after intravascular adminstration (CL). | At course 1: 0.083 hours before drug administration and at 0.25, 0.5, 075, 1*, 1.5, 2, 4, 8, 24, 48, 96, 168, 336 hours after start of infusion (*immediately prior to end of infusion of BI 6727). | 
| Apparent Volume of Distribution at Steady State Following Intravascular Administration (Vss) | Apparent volume of distribution at steady state following intravascular administration (Vss). | At course 1: 0.083 hours before drug administration and at 0.25, 0.5, 075, 1*, 1.5, 2, 4, 8, 24, 48, 96, 168, 336 hours after start of infusion (*immediately prior to end of infusion of BI 6727). | 
| Apparent Volume of Distribution During the Terminal Phase λz Following an Intravascular Dose (Vz) | Apparent volume of distribution during the terminal phase λz following an intravascular dose (Vz). | At course 1: 0.083 hours before drug administration and at 0.25, 0.5, 075, 1*, 1.5, 2, 4, 8, 24, 48, 96, 168, 336 hours after start of infusion (*immediately prior to end of infusion of BI 6727). | 
| 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 24 hours (Ae0-24). | 5 minutes prior to the infusion on day 1, course 1 and up to 24 hours after the infusion. | 
| Amount of BI 6727 That is Eliminated in Urine From the Time Point 0 to Time Point 48 Hours (Ae0-48) | Amount of BI 6727 that is eliminated in urine from the time point 0 to time point 48 hours (Ae0-48). | 5 minutes prior to the infusion on day 1, course 1 and up to 48 hours after the infusion. | 
| Fraction of BI 6727 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 24 hours (Fe0-24). | 5 minutes prior to the infusion on day 1, course 1 and up to 24 hours after the infusion. | 
| Fraction of BI 6727 Eliminated in Urine From Time Point 0 to Time Point 48 Hours (Fe0-48) | Fraction of BI 6727 (percentage of dose) eliminated in urine from time point 0 to time point 48 hours (Fe0-48). | 5 minutes prior to the infusion on day 1, course 1 and up to 48 hours after the infusion. | 
| 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 24 hours (CLr,0-24). | 5 minutes prior to the infusion on day 1, course 1 and up to 24 hours after the infusion. | 
| Renal Clearance of BI 6727 From the Time Point 0 to Time Point 48 Hours (CLr,0-48) | Renal clearance of BI 6727 from the time point 0 to time point 48 hours (CLr,0-48). | 5 minutes prior to the infusion on day 1, course 1 and up to 48 hours after the infusion. |