Combination of BI6727 (Volasertib) and BIBF1120 in Solid Tumors

Study Overview
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Brief Summary
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The primary objective of the current study is to investigate the Maximum Tolerated Dose (MTD) in terms of safety and tolerability of BI 6727 in combination with fixed dose BIBF 1120, in patients with advanced or metastatic solid tumours.

Official Title
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An Open Label Phase I Dose Escalation Trial of Intravenous BI 6727 in Combination With Oral BIBF 1120 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
* Drug: BIBF 1120


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, and for whom no therapy of proven efficacy exists, or who are not amenable to established forms of treatment Age > or = 18 years European Cooperative Oncology Group performance status < or = 2 Written informed consent in accordance with International Conference on Harmonization -Good Clinical Practice (ICH-GCP) and local legislation Recovery from Common Terminology Criteria for Adverse Events grade 2-4 therapy-related toxicities from previous systemic anti-cancer therapies or radiotherapy (except alopecia) Exclusion criteria: Serious illness or concomitant non-oncological disease considered by the investigator to be incompatible with the trial Known hypersensitivity to the trial drugs or their excipients Treatment with any other investigational drug or participation in any other interventional trial within 28 days before first administration of trial drug (BIBF 1120) or concomitantly with this trial Systemic anti-cancer therapy or radiotherapy within 28 days before start of therapy or concomitantly with this trial. The restriction does not apply to steroids and bisphosphonates Active infectious disease infection or HIV I/II Other malignancy currently requiring another anti-cancer therapy Clinical evidence of symptomatic progressive brain or leptomeningeal disease during the past 6 months Known inherited predisposition to bleeding or thrombosis Radiographic evidence of cavitary or necrotic tumours History of clinically significant haemoptysis within the past 3 months Centrally located tumours with radiographic evidence (Computed Tomography or Magnetic Resonance Imaging) of local invasion of major blood vessels Absolute Neutrophil Count (ANC) less than 1.5 x 1000000000/L Platelets Count (PLT) less than 100 x 1000000000/L Total bilirubin > upper limit of normal (ULN) Alaninaminotransferase (ALT) and/or Aspartateaminotransferase (AST) >= 1.5 x ULN (in case of liver metastases: ALT and AST >= 2.5 x ULN) Serum creatinine > 1.5 mg/dl Major injuries and/or surgery or bone fracture within 28 days before first administration of trial drug (BIBF 1120), or planned surgical procedures during the trial period Known history of clinically relevant QT prolongation (e.g. long QT syndrome) History of severe haemorrhagic or thromboembolic event in the past 6 months (excluding central venous catheter thrombosis and peripheral deep vein thrombosis) Therapeutic anticoagulation (except low dose heparin and/or heparin flush as needed for maintenance of an indwelling intravenous device) or antiplatelet therapy (except for chronic low-dose therapy with acetylsalicylic acid < or = 325mg per day) Active alcohol or drug abuse Women and men who are sexually active and unwilling to use a medically acceptable method of contraception during the trial Pregnancy or breast-feeding Patients unable to comply with the protocol Uncontrolled hypertension

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BIBF 1120 and BI 6727<br>Finding Maximum Tolerated Dose of BI 6727 in combination with BIBF 1120 | Drug: BI 6727<br>* intravenous each 21 days<br>Drug: BIBF 1120<br>* oral continuously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD). | DLT was defined as: Drug-related CTCAE (Common Terminology Criteria for Adverse Events) grade 3 or 4 non-haematological toxicity (except untreated vomiting, untreated nausea, or untreated diarrhoea) or Drug-related CTCAE grade 4 neutropenia for 7 or more days and/or complicated by infection or CTCAE grade 4 thrombocytopenia | 28 days | 
| Maximum Tolerated Dose (MTD) of Volasertib in Combination With Nintedanib | The MTD was determined using a 3+3 design with de-escalation. The MTD was defined as the highest dose level at which maximal 1 out of 6 patients experienced DLT in the first course of the escalation nd de-escalation phase. However, all DLT's occurring in the trial were considered for selection of the recommended dose for further development. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Drug Related Adverse Events | Number of participants with investigator-defined drug related adverse events. | From first study drug administration until 28 days after the last administration of any study medication, up to 485 days | 
| Number of Participants With Dose Limiting Toxicities | Number of participants with dose limiting toxicities (DLTs). DLT was defined as: Drug-related CTCAE grade 3 or 4 non-haematological toxicity (except untreated vomiting, untreated nausea, or untreated diarrhoea) or Drug-related CTCAE grade 4 neutropenia for 7 or more days and/or complicated by infection or CTCAE grade 4 thrombocytopenia | From first study drug administration until 28 days after the last administration of any study medication, up to 485 days | 
| Cmax of Volasertib | Maximum measured concentration (Cmax) in plasma of Volasertib in Cycle 1. | 0:05 h before start of Volasertib infusion and 1:00, 2:00, 3:00, 4:00, 8:00 and 24 h after start of Volasertib infusion | 
| CL of Volasertib | Total plasma Clearance (CL) of Volasertib in Cycle 1. | 0:05 h before start of Volasertib infusion and 1:00, 2:00, 3:00, 4:00, 8:00 and 24 h after start of Volasertib infusion | 
| Vss of Volasertib | Volume of distribution at steady state (Vss) of Volasertib in Cycle 1. | 0:05 h before start of Volasertib infusion and 1:00, 2:00, 3:00, 4:00, 8:00 and 24 h after start of Volasertib infusion | 
| Cmax of Nintedanib | Maximum measured concentration (Cmax) of Nintedanib in Cycle 1. 400 mg Volasertib + 200 mg Nintedanib group is not displayed due to data only being available for one patient. | 5 min before Nintedanib administration in the morning and 1:00, 2:00, 3:00, 4:00, 6:00 h after administration on Day 9 | 
| AUC(0-6h) of Nintedanib | Area under the concentration-time curve (AUC) of Nintedanib over the time interval 0 to 6 hours in Cycle 1. 400 mg Volasertib + 200 mg Nintedanib group is not displayed due to data only being available for one patient. | 5 min before Nintedanib administration in the morning and 1:00, 2:00, 3:00, 4:00, 6:00 h after administration on Day 9 | 
| Tmax of Nintedanib | Time from dosing to the maximum measured concentration, Cmax, of Nintedanib (tmax) in Cycle 1. 400 mg Volasertib + 200 mg Nintedanib group is not displayed due to data only being available for one patient. | 5 min before Nintedanib administration in the morning and 1:00, 2:00, 3:00, 4:00, 6:00 h after administration on Day 9 | 
| Number of Patients With Best Overall Response | Best overall response based on response evaluation criteria in solid tumors (RECIST) version 1.1. Best overall response is defined as the best overall response (complete response, partial response, stable disease, progressive disease or not evaluable) since the start of treatment. | Tumor assessment was performed at screening and every 2nd course until earliest time of progression, death or end of treatment. | 
| Number of Patients With Objective Response (OR) | Objective tumor response based on response evaluation criteria in solid tumors (RECIST) version 1.1. OR is defined as complete response (CR) or partial response (PR) as best response throughout the study. | Tumor assessment was performed at screening and every 2nd course until earliest time of progression, death or end of treatment. | 
| Number of Patients With Disease Control | Disease control based on response evaluation criteria in solid tumors (RECIST) version 1.1. Disease control is defined as complete response (CR), partial response (PR) or stable disease (SD) as best response throughout the study. | Tumor assessment was performed at screening and every 2nd course until earliest time of progression, death or end of treatment. | 
| Duration of Disease Control | Disease control based on response evaluation criteria in solid tumors (RECIST) version 1.1. Patients who had a best overall tumour response of complete response (CR), partial response (PR) or stable disease (SD) were assessed to show disease control. | Tumor assessment was performed at screening and every 2nd course until earliest time of progression, death or end of treatment. | 
| Progression Free Survival (PFS) | PFS is defined as the time from start of treatment with study medication to tumour progression or death whichever occurs first. Tumour response was to be documented using appropriate techniques such as magnetic resonance imaging (MRI) or computer tomography (CT). | Tumor assessment was performed at screening and every 2nd course until earliest time of progression, death or end of treatment. |