BI 6727 (Volasertib) in Combination With Cisplatin or Carboplatin in Patients With Advanced or Metastatic Solid Tumour

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 when combined with a platinum therapy (cisplatin or carboplatin). Secondary objectives are the collection of overall safety and antitumour efficacy data and the determination of the pharmacokinetic profile of BI 6727 combination treatment with cisplatin and carboplatin.

Official Title
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A Phase I Dose Escalation Trial of BI 6727 in Combination With Cisplatin or Carboplatin in Patients With Advanced or Metastatic Solid Tumors

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: BI-6727
* 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 Indication for a treatment with platinum therapy as judged by the investigator Age 18 years or older Written informed consent consistent with ICH-GCP and local legislation ECOG performance score lower or equal 2 Recovery from CTCAE Grade 2 - 4 therapy-related toxicities from previous systemic anti-cancer therapies or radiotherapies (except alopecia grade 2) 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 and HIV I/II Clinical evidence of symptomatic progressive brain or leptomeningeal disease during the past 6 months Second malignancy currently requiring another anti-cancer therapy ANC less than 1500 / mm3 Platelet count less than 100 000 / mm3 Bilirubin greater than 1.5 mg / dl (> 26 micromol / L, SI unit equivalent) (except Gilbert's syndrome) 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 micromol / L, SI unit equivalent) or creatinine clearance <70ml/min (as calculated according to Cockcroft-Gault formula for GFR estimate) Known history of relevant QT-prolongation, e.g. long QT-syndrome Pre-existing clinically relevant hearing loss 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 interventional trial within the past four weeks before start of therapy or concomitantly with this trial Systemic anti-cancer therapy or radiotherapy 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A. BI 6727-cisplatin<br>patient to receive 3-weekly infusion escalating dose of BI 6727 combined to cisplatin | Drug: BI 6727<br>* low to high dose<br>|
| Experimental: B. BI 6727-carboplatin<br>patient to receive 3-weekly infusion escalating dose of BI 6727 combined to carboplatin | Drug: BI-6727<br>* Low to high dose (administered every 3 weeks). Depending on the toxicities observed, intermediary dose levels may be added<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose | The maximum tolerated dose (MTD) was defined as the highest dose studied for which the incidence of DLT was less than 33% (i.e. 1/6 patients) during the first cycle, for Volasertib in combination with cisplatin or carboplatin. 0=not maximum tolerated dose, 1=was maximum tolerated dose. | 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Dose Limiting Toxicities | Percentage of participants with dose limiting toxicities (DLTs) during the first treatment cycle. | 3 weeks | 
| Objective Response Rate | Objective response was defined as the proportion of participants having at least a best response of complete response (CR) or partial response (PR) determined based on RECIST criteria, version 1.0 (V1.0). Tumour response was documented using appropriate techniques | From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days | 
| Duration of Objective Response | Duration of objective response was defined as the time from first documented confirmed complete response (CR) or partial response (PR) to first evidence of progressive disease (PD) or death from any cause, whichever occurred first, determined based on RECIST V1.0 criteria. Tumour response was documented using appropriate techniques | From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days | 
| Best Overall Response | Best overall response was defined as the best response obtained since the start of study treatment until disease progression, determined based on RECIST V1.0 criteria. | From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days | 
| Disease Control Rate | Percentage of participants with confirmed disease control, defined as the proportion of patients with a best overall response of at least stable disease (SD), determined based on RECIST V1.0 criteria. | From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days | 
| Duration of Disease Control | Duration of Disease control was defined as the time from the start of study treatment to the time of disease progression or death, whichever occurred first. | From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days | 
| Progression-free Survival | Progression-free survival based on RECIST V1.0 criteria was defined as the time from start of treatment to the date of evidence of progressive disease (PD) or death from any cause, whichever occurred first. | From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days | 
| Incidence and Intensity of Adverse Events According to CTCAE Version 3.0 | Incidence and intensity of adverse events according to common terminology criteria for adverse events (CTCAE) version 3.0 | From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days | 
| Percentage of Participants With Serious Adverse Events | Percentage of participants with serious adverse events (AEs) | From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days | 
| Percentage of Participants With Significant Adverse Events | Percentage of participants with significant adverse events (AEs): dose limiting toxicity (DLT) was defined as significant AE. DLTs (i.e. significant AEs) per protocol were: drug related CTCAE grade 3 or 4 non haematological toxicity (except vomiting or diarrhoea responding to supportive treatment and ototoxicity) drug related CTCAE grade 4 neutropenia for seven or more days and / or complicated by infection drug related CTCAE Grade 4 thrombocytopenia drug related febrile neutropenia grade 3 (ANC<1000/mm³ and fever≥ 38.5°C) | From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days | 
| Total Plasma Clearance After Intravascular Administration (CL) | Total plasma clearance after intravascular administration (CL) of Volasertib in combination with cisplatin or carboplatin during treatment cycle 1. | 1 hour (h) 35 minutes (min) before start of volasertib infusion and 1h, 2h, 8h, 24h, 48h, 168h and 336h after start of volasertib infusion | 
| Apparent Volume of Distribution at Steady State Following Intravascular Administration (Vss) | Apparent volume of distribution at steady state following intravascular administration (Vss) of Volasertib in combination with cisplatin or carboplatin during treatment cycle 1. | 1 hour (h) 35 minutes (min) before start of volasertib infusion and 1h, 2h, 8h, 24h, 48h, 168h and 336h after start of volasertib infusion | 
| Change From Baseline in Pulse Rate | Change from baseline in pulse rate at last value on treatment | Baseline and from first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days | 
| Change From Baseline in Neutrophils | Change from baseline in neutrophils with the maximum value on treatment | Baseline and from first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days | 
| Change From Baseline in Platelets | Change from baseline in platelets with the maximum value on treatment | Baseline and from first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days | 
| Frequency of Participants (%) With Possible Clinically Significant Abnormalities for Neutrophils | Frequency of participants (%) with possible clinically significant abnormalities for neutrophils: : defined as neutrophils >=CTCAE grade 2 (CTCAE v3.0), with worsening from baseline. The CTCAE scale measures the severity of adverse events which goes from 1 (mild AE) to 5 (death related AE). | From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days | 
| Frequency of Participants (%) With Possible Clinically Significant Abnormalities for Platelets | Frequency of participants (%) with possible clinically significant abnormalities for platelets : defined as platelets >=CTCAE grade 2 (based on CTCAE v3.0), with worsening from baseline. The CTCAE scale measures the severity of adverse events which goes from 1 (mild AE) to 5 (death related AE). | From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days | 
| Frequency of Participants With Transitions Relative to the Baseline CTC Grade for Platelets Based on Last Value on Treatment | Percentage of participants with transitions relative to the baseline CTC grade (version 3) for platelets based on last value on treatment. Common terminology criteria for adverse events (CTCAE) grade on treatment for platelets (CTC version 3). The CTCAE scale measures the severity of adverse events which goes from 1 (mild AE) to 5 (death related AE). | From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days | 
| Frequency of Participants With Transitions Relative to the Baseline CTC Grade for Neutrophils Based on Last Value on Treatment | Percentage of participants with transitions relative to the baseline CTC grade (version 3) for neutrophils based on last value on treatment. Common terminology criteria for adverse events (CTCAE) grade on treatment for neutrophils (CTC version 3). The CTCAE scale measures the severity of adverse events which goes from 1 (mild AE) to 5 (death related AE) | From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days | 
| Frequency of Participants With Transitions Relative to the Baseline CTC Grade for Platelets Based on Worst Value on Treatment | Percentage of participants with transitions relative to the baseline CTC grade (version 3) for platelets based on worst value on treatment. Worst Common terminology criteria for adverse events (CTCAE) grade on treatment for platelets (CTC version 3). The CTCAE scale measures the severity of adverse events which goes from 1 (mild AE) to 5 (death related AE). | From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days | 
| Frequency of Participants With Transitions Relative to the Baseline CTC Grade for Neutrophils Based on Worst Value on Treatment | Percentage of participants with transitions relative to the baseline CTC grade (version 3) for neutrophils based on worst value on treatment. Worst Common terminology criteria for adverse events (CTCAE) grade on treatment for neutrophils (CTC version 3). The CTCAE scale measures the severity of adverse events which goes from 1 (mild AE) to 5 (death related AE) | From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days | 
| Worst CTCAE Grade on Treatment for Platelets | Worst Common terminology criteria for adverse events (CTCAE) grade on treatment for platelets (CTC version 3). The CTCAE scale measures the severity of adverse events which goes from 1 (mild AE) to 5 (death related AE). | From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days | 
| Worst CTCAE Grade on Treatment for Neutrophils | Worst Common terminology criteria for adverse events (CTCAE) grade on treatment for neutrophils (CTC version 3). The CTCAE scale measures the severity of adverse events which goes from 1 (mild AE) to 5 (death related AE). | From first intake of trial drug to last intake of trial drug plus 21 days, up to 441 days |