Carcinoma, Non-Small-Cell Lung
Conditions
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
Interventions
DRUGXentuzumab
Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib film-coated tablet.
DRUGAfatinib
Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib film-coated tablet.
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Dose Limiting Toxicities (DLT) - Part A | During the first treatment course, up to 28 days. | DLT Criteria: Common Terminology Criteria for Adverse Events(CTCAE) CTCAE Grade (G) 4 neutropenia lasting ≥7 days; Febrile neutropenia with a single/sustained temperature of ≥38.3°C for \>1 hour; Documented infection with absolute neutrophil count (ANC) \<1.0 x 109/L; G 3/4 thrombocytopenia associated with bleeding requiring platelet transfusion; G 2/higher decrease in cardiac left ventricular function; G 2 diarrhea lasting for ≥7 days; G ≥3 diarrhea; G≥3 nausea/vomiting; G≥3 skin rash; aspartate aminotransferase (AST)/alanine aminotransferase (ALT) \>5 x Upper limit of normal (ULN)/\>baseline value +4 x ULN; G≥3 fatigue/asthenia lasting for \>7 days; G≥3 hyperglycemia lasting \>48 hours; All other non-hematologic adverse events(AEs) of G≥3 (except alopecia, infusion reaction, and allergic reaction) that led to an interruption of afatinib/xentuzumab for \>14 days until recovery to baseline/G 1; Any other study drug-related toxicity considered significant enough to qualify as DLT. |
| Maximum Tolerated Dose (MTD) - Part A | During the first treatment course, up to 28 days. | Maximum tolerated dose (MTD) of Xentuzumab in combination with Afatinib, in patients with non-small cell lung cancer with progression following prior treatment, based on the occurrence of dose limiting toxicity (DLT) during the first treatment course. MTD was defined as the highest dose level examined of trial medication, at which no more than 1 out of 6 patients experienced a DLT during the MTD evaluation period. |
| Number of Participants With Objective Response (OR) - Part B | Tumour assessment was performed every 4 weeks after the start of treatment for first 8 weeks, in 8-week intervals thereafter and in 12-week interval after Course 16 until disease progression or the start of further anti-cancer treatment, up to 1200 days. | OR was defined as best overall response of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, where best overall response was defined according to RECIST v1.1 from first administration of trial medication until the earliest of disease progression, death or last evaluable tumour assessment before start of subsequent anti-cancer therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Disease Control (DC) - Part B | Tumour assessment was performed every 4 weeks after the start of treatment for first 8 weeks, in 8-week intervals thereafter and in 12-week interval after Course 16 until disease progression or the start of further anti-cancer treatment, up to 1200 days. | DC was defined as best overall response of complete response (CR) or partial response (PR) or stable disease (SD) according to RECIST v1.1, where best overall response was defined according to RECIST v1.1 from first administration of trial medication until the earliest of disease progression, death or last evaluable tumour assessment before start of subsequent anti-cancer therapy. |
| Time to OR - Part B | Tumour assessment was performed every 4 weeks after the start of treatment for first 8 weeks, in 8-week intervals thereafter and in 12-week interval after Course 16 until disease progression or the start of further anti-cancer treatment, up to 1200 days. | Time to OR, defined as the time from first treatment administration until first documented CR or PR. For patients with OR, time to OR was summarised on a patient level. |
| Duration of OR - Part B | Tumour assessment was performed every 4 weeks after the start of treatment for first 8 weeks, in 8-week intervals thereafter and in 12-week interval after Course 16 until disease progression or the start of further anti-cancer treatment, up to 1200 days. | Duration of OR, defined as the time from first documented CR or PR until the earliest of disease progression or death among patients with OR - Part B. For patients with OR, duration of OR was summarised on a patient level. |
Countries
Japan, Singapore, South Korea, Taiwan
Participant flow
Recruitment details
Patients with epidermal growth factor receptor (EGFR) mutant lung cancer were recruited in this multi-centre, open-label, phase Ib clinical trial. The trial consisted of a dose confirmation part (Part A) and an expansion cohort (Part B), where Part A and Part B were conducted sequentially.
Pre-assignment details
All patients were screened for eligibility to participate in the trial. Patients attended specialist sites which would then ensure that they (all patients) met all inclusion/exclusion criteria. Patients were not to be entered to trial treatment if any one of the specific entry criteria were not met.
Participants by arm
| Arm | Count |
|---|---|
| Xentuzumab + Afatinib 30 Milligram (mg) - Part A Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 30 mg film-coated tablet. Dose confirmation part (Part A). | 4 |
| Xentuzumab + Afatinib 40 mg - Part A Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 40 mg film-coated tablet. Dose confirmation part (Part A). | 12 |
| Xentuzumab + Afatinib 20 mg - Part B Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 20 mg film-coated tablet. Expansion part (Part B). | 4 |
| Xentuzumab + Afatinib 30 mg - Part B Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 30 mg film-coated tablet. Expansion part (Part B). | 2 |
| Xentuzumab + Afatinib 40 mg - Part B Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 40 mg film-coated tablet. Expansion part (Part B). | 10 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 | 2 |
| Overall Study | Disease Progression | 4 | 10 | 4 | 2 | 7 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Xentuzumab + Afatinib 30 Milligram (mg) - Part A | Xentuzumab + Afatinib 40 mg - Part A | Xentuzumab + Afatinib 20 mg - Part B | Xentuzumab + Afatinib 30 mg - Part B | Xentuzumab + Afatinib 40 mg - Part B |
|---|---|---|---|---|---|---|
| Age, Continuous | 59.03 Years STANDARD_DEVIATION 9.52 | 61.75 Years STANDARD_DEVIATION 9.11 | 59.08 Years STANDARD_DEVIATION 10.16 | 57.75 Years STANDARD_DEVIATION 9.5 | 68.00 Years STANDARD_DEVIATION 2.83 | 56.60 Years STANDARD_DEVIATION 9.94 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants | 4 Participants | 12 Participants | 4 Participants | 2 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 32 Participants | 4 Participants | 12 Participants | 4 Participants | 2 Participants | 10 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 17 Participants | 2 Participants | 5 Participants | 2 Participants | 0 Participants | 8 Participants |
| Sex: Female, Male Male | 15 Participants | 2 Participants | 7 Participants | 2 Participants | 2 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 1 / 6 | 2 / 22 |
| other Total, other adverse events | 4 / 4 | 6 / 6 | 20 / 22 |
| serious Total, serious adverse events | 0 / 4 | 2 / 6 | 8 / 22 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) - Part A
Maximum tolerated dose (MTD) of Xentuzumab in combination with Afatinib, in patients with non-small cell lung cancer with progression following prior treatment, based on the occurrence of dose limiting toxicity (DLT) during the first treatment course. MTD was defined as the highest dose level examined of trial medication, at which no more than 1 out of 6 patients experienced a DLT during the MTD evaluation period.
Time frame: During the first treatment course, up to 28 days.
Population: Maximum Tolerated Dose (MTD) Set (MS): this patient set defined the set of patients in Part A who were fully evaluable for determination of the MTD in the first treatment course.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Xentuzumab + Afatinib 30 Milligram (mg) - Part A | Maximum Tolerated Dose (MTD) - Part A | 40 Milligrams (mg) |
Primary
Number of Participants With Objective Response (OR) - Part B
OR was defined as best overall response of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, where best overall response was defined according to RECIST v1.1 from first administration of trial medication until the earliest of disease progression, death or last evaluable tumour assessment before start of subsequent anti-cancer therapy.
Time frame: Tumour assessment was performed every 4 weeks after the start of treatment for first 8 weeks, in 8-week intervals thereafter and in 12-week interval after Course 16 until disease progression or the start of further anti-cancer treatment, up to 1200 days.
Population: Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Xentuzumab + Afatinib 30 Milligram (mg) - Part A | Number of Participants With Objective Response (OR) - Part B | 0 Participants |
| Xentuzumab + Afatinib 40 mg - Part A | Number of Participants With Objective Response (OR) - Part B | 0 Participants |
| Xentuzumab + Afatinib 40 mg - Part B | Number of Participants With Objective Response (OR) - Part B | 0 Participants |
Primary
Number of Patients With Dose Limiting Toxicities (DLT) - Part A
DLT Criteria: Common Terminology Criteria for Adverse Events(CTCAE) CTCAE Grade (G) 4 neutropenia lasting ≥7 days; Febrile neutropenia with a single/sustained temperature of ≥38.3°C for \>1 hour; Documented infection with absolute neutrophil count (ANC) \<1.0 x 109/L; G 3/4 thrombocytopenia associated with bleeding requiring platelet transfusion; G 2/higher decrease in cardiac left ventricular function; G 2 diarrhea lasting for ≥7 days; G ≥3 diarrhea; G≥3 nausea/vomiting; G≥3 skin rash; aspartate aminotransferase (AST)/alanine aminotransferase (ALT) \>5 x Upper limit of normal (ULN)/\>baseline value +4 x ULN; G≥3 fatigue/asthenia lasting for \>7 days; G≥3 hyperglycemia lasting \>48 hours; All other non-hematologic adverse events(AEs) of G≥3 (except alopecia, infusion reaction, and allergic reaction) that led to an interruption of afatinib/xentuzumab for \>14 days until recovery to baseline/G 1; Any other study drug-related toxicity considered significant enough to qualify as DLT.
Time frame: During the first treatment course, up to 28 days.
Population: Maximum Tolerated Dose (MTD) Set (MS): this patient set defined the set of patients in Part A who were fully evaluable for determination of the MTD in the first treatment course.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Xentuzumab + Afatinib 30 Milligram (mg) - Part A | Number of Patients With Dose Limiting Toxicities (DLT) - Part A | 0 Participants |
| Xentuzumab + Afatinib 40 mg - Part A | Number of Patients With Dose Limiting Toxicities (DLT) - Part A | 0 Participants |
Secondary
Duration of OR - Part B
Duration of OR, defined as the time from first documented CR or PR until the earliest of disease progression or death among patients with OR - Part B. For patients with OR, duration of OR was summarised on a patient level.
Time frame: Tumour assessment was performed every 4 weeks after the start of treatment for first 8 weeks, in 8-week intervals thereafter and in 12-week interval after Course 16 until disease progression or the start of further anti-cancer treatment, up to 1200 days.
Population: TS - Patients with objective response (There were no patients with objective response in the expansion cohort)
Secondary
Number of Participants With Disease Control (DC) - Part B
DC was defined as best overall response of complete response (CR) or partial response (PR) or stable disease (SD) according to RECIST v1.1, where best overall response was defined according to RECIST v1.1 from first administration of trial medication until the earliest of disease progression, death or last evaluable tumour assessment before start of subsequent anti-cancer therapy.
Time frame: Tumour assessment was performed every 4 weeks after the start of treatment for first 8 weeks, in 8-week intervals thereafter and in 12-week interval after Course 16 until disease progression or the start of further anti-cancer treatment, up to 1200 days.
Population: Treated set (TS): This patient set included all patients who were documented to have received and taken at least 1 dose of any study drug during the treatment courses (from Day 1).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Xentuzumab + Afatinib 30 Milligram (mg) - Part A | Number of Participants With Disease Control (DC) - Part B | 2 Participants |
| Xentuzumab + Afatinib 40 mg - Part A | Number of Participants With Disease Control (DC) - Part B | 2 Participants |
| Xentuzumab + Afatinib 40 mg - Part B | Number of Participants With Disease Control (DC) - Part B | 6 Participants |
Secondary
Time to OR - Part B
Time to OR, defined as the time from first treatment administration until first documented CR or PR. For patients with OR, time to OR was summarised on a patient level.
Time frame: Tumour assessment was performed every 4 weeks after the start of treatment for first 8 weeks, in 8-week intervals thereafter and in 12-week interval after Course 16 until disease progression or the start of further anti-cancer treatment, up to 1200 days.
Population: TS - Patients with objective response (There were no patients with objective response in the expansion cohort)