An Open Label Phase I Dose Escalation Trial of Intravenous BI 6727 (Volasertib)in Combination With Oral BIBW 2992 (Afatinib) in Patients With Advanced Solid Tumours

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 the combination of BI 6727 with BIBW 2992, in patients with advanced or metastatic solid tumours. Dosages of both BI 6727 and BIBW 2992 will be varied to establish the MTD of the combination. Two combination treatment schedules will be tested, the MTD of each combination will be determined. Secondary objectives are the exploration of pharmacokinetics, overall safety and preliminary efficacy.

Official Title
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An Open Label Phase I Dose Escalation Trial of Intravenous BI 6727 in Combination With Oral BIBW 2992 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 + BIBW 2992


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patients with histologically or cytologically confirmed diagnosis of advanced, non resectable and/or metastatic, relapsed or refractory solid tumours not amenable to standard therapy and for whom no therapy of proven efficacy exists Eastern Cooperative Oncology Group performance score 0 - 2 Recovery from clinically significant toxicities from previous systemic anti-cancer therapies or radiotherapy Exclusion criteria: Serious illness, concomitant non-oncological disease or mental problem considered by the investigator to be incompatible with participation to the trial Known hypersensitivity to the trial drugs or their excipients Treatment with any other investigational drug or active participation in any other interventional trial within 28 days before first administration of trial drug(s) or concomitantly with this trial Major surgery or radiotherapy within 28 days before start of therapy or concomitantly with this trial Systemic anti-cancer therapy within 28 days before start of therapy or concomitantly with this trial Requirements for treatment with any of the prohibited concomitant medications Active infectious disease or known HIV I/II infection Gastrointestinal disorders that may interfere with the absorption of the study drug or chronic diarrhoea Active brain metastases History or presence of cardiovascular abnormalities deemed clinically relevant by the investigator Cardial left ventricular function with resting ejection fraction < 50% Inadequate hepatic, renal and haematologic organ function QT prolongation deemed clinically relevant by the investigator Active alcohol or drug abuse Women of childbearing potential and men who are able to father a child unwilling to use a medically acceptable method of contraception during the trial and 28 days thereafter Pregnancy or breast-feeding Patients unable to comply with the protocol Patients with known pre-existing interstitial lung disease

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: two experimental arms<br>patients receive increasing doses of BI 6727 in combination with increasing doses of BIBW 2992 | Drug: BI 6727 + BIBW 2992<br>* BI 6727 administered i.v. every 21 days + BIBW 2992 given orally once a day<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 (DLT) | MTD was defined on the basis of DLTs occuring during Cycle 1 of the dose escalation part in each of the 2 treatment schedules. DLTs were defined as drug related based on Common Terminology Criteria for AE's (CTCAE) Grade(G) :1) G4 neutropenia (ANC, including bands, <500/mm³) for more than 7 days, 2) G3 or 4 neutropenia associated with fever >38.5° C (febrile neutropenia),3) Neutropenic infection G ≥3, 4) G4 thrombocytopenia or G3 thrombocytopenia associated with bleeding requiring whole blood transfusion.5) Non-haematological G ≥3 toxicity excluding: (a) untreated G3 diarrhoea, (b) untreated G3 nausea and/or vomiting, (c) untreated G3 rash. 6) G2 increase in AST and/or ALT in conjunction with an elevated bilirubin level of G ≥2, 7) G2 nausea and/or vomiting despite optimal supportive/antiemetic treatment for at least 7consecutive days. 8) G2 diarrhoea for 2 or more consecutive days despite antidiarrhoeal medication/hydration, 9) Decrease in left ventricular function G ≥2. | 22 Days | 
| Maximum Tolerable Dose (MTD) of Two Combination Therapy of Volasertib and Afatinib. | Maximum Tolerable Dose (MTD) was determined by dose escalation for volasertib and afatinib. The 3 + 3 design with de-escalation for both the Schedules A and B. Patients were sequentially allocated to the dose cohorts. Apart from allocation to the treatment schedules, escalation and/or de-escalation to determine the MTD occurred independently within the 2 dose schedules. Cohorts of 3 patients were to be treated at the starting dose levels according to the treatment schedule. Before entering patients at a higher dose level, all patients at the previous dose level combination had to complete at least the initial cycle of 21 days. | MTD was assessed during the first cycle of combination of Volasertib and Afatinib therapy (22 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Drug-related Adverse Events According to Common Terminology Criteria for Adverse Events (CTCAE) Criteria v 3.0 | Number of patients with investigator defined drug-related adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) criteria v 3.0 | After the first drug administration until 28 days after the last drug administration, up to 413 days. | 
| 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 Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by using appropriate radiology techniques: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions. | Tumor assessment was performed at screening and at the end of every 3 treatment cycle (ie every 9 weeks of treatment). | 
| 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 complete response, partial response, stable disease, progressive disease or not evaluable. As Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by using appropriate radiology techniques: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; progression, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression. | Tumor assessment was performed at screening and at the end of every 3 treatment cycle (ie every 9 weeks of treatment). | 
| Number of Patients With 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. As Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by using appropriate radiology techniques: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression. | Tumor assessment was performed at screening and at the end of every 3 treatment cycle (ie every 9 weeks of treatment). |