Clinical trial NCT02191891: Xentuzumab (BI 836845) Plus Afatinib in Patients With Epidermal Growth Factor Receptor (EGFR) Mutant Non-small Cell Lung Cancer (NSCLC)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Carcinoma, Non-Small-Cell Lung
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2014-07-16
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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


Eligibility criteria: 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)

Primary outcomes:
measure: Maximum tolerated dose (MTD) of BI 836845 in combination with afatinib - part A
timeFrame: up to 12 months
measure: Dose limiting toxicity (DLT) during the first treatment course - part A
timeFrame: up to 28 days
measure: Objective response (OR), defined as complete response (CR) or partial response (PR)
timeFrame: up to 12 months
Secondary outcomes:
measure: Disease control (DC), defined as complete response (CR), partial response (PR) or stable disease (SD)
timeFrame: up to 12 months
measure: Time to objective response, defined as the duration of time from the date of first treatment administration until objective response
timeFrame: up to 12 months
measure: 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
timeFrame: up to 12 months
Other outcomes:
Locations:
city: Fukuoka, Fukuoka
country: Japan
facility: National Hospital Organization Kyushu Cancer Center
city: Cheongju
country: Korea, Republic of
facility: Chungbuk National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Singapore
country: Singapore
facility: National Cancer Centre
city: Chiayi
country: Taiwan
facility: Chang Gung Memorial Hospital Chiayi
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Chang Gung Memorial Hospital
city: Tainan
country: Taiwan
facility: NCKUH
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References: