Xentuzumab (BI 836845) Plus Afatinib in Patients With Epidermal Growth Factor Receptor (EGFR) Mutant Non-small Cell Lung Cancer (NSCLC)

Study Overview
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Brief Summary
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Part A: To determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of Xentuzumab (BI 836845) in combination with afatinib in patients with non-small cell lung cancer with progression following prior treatment (EGFR TKI or platinum-based chemotherapy). Part B: To evaluate the early anti-tumour activity of Xentuzumab (BI 836845) in combination with afatinib in patients with EGFR mutant non-small cell lung cancer with progression following prior irreversible EGFR TKIs. Part A and B: To evaluate the safety and pharmacokinetics of BI 836845 in combination with afatinib in patients with non-small cell lung cancer

Official Title
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A Phase Ib Open-label Clinical Trial of Once Daily Oral Treatment of Afatinib Plus Weekly Intravenous Infusion of Xentuzumab (BI 836845) in Patients With EGFR Mutant Non-small Cell Lung Cancer With Progression Following Prior EGFR Tyrosine Kinase Inhibitors

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: BI 836845
* Drug: afatinib


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Aged 18 years or older Pathologically confirmed of advanced and/or metastatic stage IIIb/IV non-small cell carcinoma of lung Activating EGFR mutation (exon 19 deletion, L858R, G719X, L861X) Presence of EGFR activating mutation and absence of EGFR T790M in the tumour associated with the latest disease progression. Only applicable in Part B Must have adequate fresh or archival tumour tissue at the late disease progression immediately prior to the study entry Part A: Progression of disease (RECIST 1.1) while on continuous treatment with single EGFR TKI or for histology other than adenocarcinoma and without prior EGFR TKI treatment: progression of disease (RECIST v1.1) on platinum-based chemotherapy. Part B: Progression of disease (RECIST v1.1) while on continuous treatment with single agent of the second generation irreversible EGFR TKI (e.g. afatinib or dacomitinib) No intervening systemic therapy between cessation of EGFR TKI and study treatment Patient must have measurable disease per RECIST 1.1 presented after tumour biopsy for the late disease progression Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1 Life expectancy of >= 3 months Fasting plasma glucose < 8.9 mmol/L (< 160mg/dL) and HbA1C < 8% Adequate organ function Recovered from any previous therapy related toxicity to <= Grade 1 at study entry (except for stable sensory neuropathy <= Grade 2 and alopecia) Written informed consent that is consistent with ICH-GCP guidelines and local regulations No known potentially targetable mutation other than IGF signaling pathway or EGFR or no available treatment for potentially targetable mutation Exclusion criteria: Part A only: For patient who has been treated with afatinib: last treatment at reduced dose below the assigned dose level Patient whose disease progressed on insufficient dose of EGFR TKI immediately prior to study in the opinion of the investigator More than 2 prior EGFR TKI treatment regimens for Part B Chemotherapy, biological therapy or investigational agents (except EGFR TKIs) within 4 weeks Use of previous EGFR TKIs except afatinib within 3 days Radiotherapy within 4 weeks prior to the start of study treatment Active brain or subdural metastases Meningeal carcinomatosis. Major surgery (as judged by the investigator) within 4 weeks Known hypersensitivity to afatinib, monoclonal antibody Prior severe infusion-related reaction to a monoclonal antibody History or presence of clinically relevant cardiovascular abnormalities Female patients of childbearing potential (see Section 4.2.2.3) and male who are able to father a child Any history of or concomitant condition that, in the opinion of the investigator not to comply with the study or interfere with the evaluation of the efficacy and safety of the test drug Previous or concomitant malignancies at other sites, except effectively treated non-melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ or effectively treated malignancy that has been in remission for more than 3 years and is considered to be cured. Disease that is considered by the investigator to be rapidly progressing or life threatening such as extensive symptomatic visceral disease including hepatic involvement and pulmonary lymphangitic spread of tumour (subjects who are intended for urgent chemotherapy) Requiring treatment with any of the prohibited concomitant medications Known pre-existing interstitial lung disease (ILD) Any history or presence of poorly controlled gastrointestinal disorders that could affect the absorption of the study drug Active hepatitis B infection active hepatitis C infection and/or known HIV carrier. Previous treatment with agents targeting the insulin like growth factor (IGF) signalling pathway. Previous treatment with EGFR TKI which cannot be documented as either reversible or irreversible (Part B only) Part B only: Prior treatment with third generation irreversible EGFR TKI (e.g. AZD9291 or CO-1686)

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: BI 836845 + afatinib<br>BI 836845 low or high dose (weekly IV infusion), afatinib 30mg or 40mg (once daily oral dosing) | Drug: BI 836845<br>* Human monoclonal antibody. Two dose levels (high or low) depending on the dose cohort explored<br>* Other names: Xentuzumab;Drug: afatinib<br>* Irreversible EGFR tyrosine kinase inhibitor. Two dose levels (30 mg, 40 mg) depending on the dose cohort explored or determined dose at part A<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) of BI 836845 in combination with afatinib - part A |  | up to 12 months | 
| Dose limiting toxicity (DLT) during the first treatment course - part A |  | up to 28 days | 
| Objective response (OR), defined as complete response (CR) or partial response (PR) |  | up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease control (DC), defined as complete response (CR), partial response (PR) or stable disease (SD) |  | up to 12 months | 
| Time to objective response, defined as the duration of time from the date of first treatment administration until objective response |  | up to 12 months | 
| Duration of objective response, defined as the duration of time from first objective response to the date of first objective tumour progression or death due to any cause |  | up to 12 months |