Combination of BI6727 (Volasertib) and BIBF1120 in Solid Tumors

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

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.

Study Overview

• Status: Completed
• Conditions: Neoplasms
• Intervention / Treatment: Drug: BI 6727; Drug: BIBF 1120

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• Italy
  • Ancona, Italy
    • 1230.7.39002 Boehringer Ingelheim Investigational Site
  • Milano, Italy
    • 1230.7.39001 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. 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
2. Age > or = 18 years
3. European Cooperative Oncology Group performance status < or = 2
4. Written informed consent in accordance with International Conference on Harmonization -Good Clinical Practice (ICH-GCP) and local legislation
5. 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:

1. Serious illness or concomitant non-oncological disease considered by the investigator to be incompatible with the trial
2. Known hypersensitivity to the trial drugs or their excipients
3. 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
4. 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
5. Active infectious disease infection or HIV I/II
6. Other malignancy currently requiring another anti-cancer therapy
7. Clinical evidence of symptomatic progressive brain or leptomeningeal disease during the past 6 months
8. Known inherited predisposition to bleeding or thrombosis
9. Radiographic evidence of cavitary or necrotic tumours
10. History of clinically significant haemoptysis within the past 3 months
11. Centrally located tumours with radiographic evidence (Computed Tomography or Magnetic Resonance Imaging) of local invasion of major blood vessels
12. Absolute Neutrophil Count (ANC) less than 1.5 x 1000000000/L
13. Platelets Count (PLT) less than 100 x 1000000000/L
14. Total bilirubin > upper limit of normal (ULN)
15. Alaninaminotransferase (ALT) and/or Aspartateaminotransferase (AST) >= 1.5 x ULN (in case of liver metastases: ALT and AST >= 2.5 x ULN)
16. Serum creatinine > 1.5 mg/dl
17. 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
18. Known history of clinically relevant QT prolongation (e.g. long QT syndrome)
19. History of severe haemorrhagic or thromboembolic event in the past 6 months (excluding central venous catheter thrombosis and peripheral deep vein thrombosis)
20. 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)
21. Active alcohol or drug abuse
22. Women and men who are sexually active and unwilling to use a medically acceptable method of contraception during the trial
23. Pregnancy or breast-feeding
24. Patients unable to comply with the protocol
25. Uncontrolled hypertension

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info
• Related Info

Study record dates

Study Major Dates

• Study Start: December 1, 2009
• Primary Completion (Actual): February 1, 2013
• Study Completion (Actual): February 1, 2013

Study Registration Dates

• First Submitted: November 26, 2009
• First Submitted That Met QC Criteria: November 26, 2009
• First Posted (Estimate): December 1, 2009

Study Record Updates

• Last Update Posted (Actual): July 30, 2018
• Last Update Submitted That Met QC Criteria: October 23, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Nintedanib
• Other Study ID Numbers: 1230.7; 2008-008304-41 (EudraCT Number: EudraCT)