Carcinoma, Non-Small-Cell Lung
Conditions
Brief summary
The primary objective of this randomized, open-label, active-controlled, multi-center trial is to determine the efficacy of BIBW 2992 given as an add-on to chemotherapy in patients with NSCLC Stage IIIb or IV progressing after BIBW 2992 monotherapy compared to chemotherapy alone in this patient population. Patients on both treatment arms will receive best supportive care in addition to study treatment. Patients enrolled into the trial will be treated and followed until death or lost to follow-up. Additional information on the health-related quality of life (HRQOL) will be collected.
Interventions
DRUGInvestigator´s choice of chemotherapy
BIBW 2992 in a medium dose in combination with Paclitaxel to explore safety and efficacy versus investigator´s choice of chemotherapy
DRUGBIBW 2992
BIBW 2992 will be given in a medium dose in combination with Paclitaxel to explore safety and efficacy versus investigator´s choice of chemotherapy
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Part A 1. Patients with pathologically confirmed diagnosis of NSCLC Stage IIIB (with cytologically proven pleural effusion or pericardial effusion) or Stage IV who have failed treatment with erlotinib (Tarceva) or gefitinib (Iressa). 2. Patients should have received and failed at least one line of cytotoxic chemotherapy including a platinum-based regimen in patients eligible for platinum-based therapy and pemetrexed in pemetrexed eligible patients (unless pemetrexed is not considered a regulatory or clinical standard of care e.g. no label indication, no availability or no coverage by 3rd party payer(s)) for advanced or metastatic disease and have progressive disease following at least 12 weeks of treatment with erlotinib or gefitinib 3. Patients pretreated with taxane-based chemotherapy for advanced or metastatic disease must have experienced stable disease, partial or complete response as best response 4. Eastern Cooperative Oncology Group performance Score 0 or 1. 5. Patients with at least one tumor lesion that can accurately be measured by magnetic resonance imaging (MRI), or computed tomography (CT) in at least one dimension with longest diameter to be recorded as 10 mm but no less than double the slice thickness according to RESIST 1.1. 6. Male and female patients no less than 18 years of age. 7. Life expectancy of at least three (3) months. 8. Written informed consent that is consistent with ICH-GCP guidelines. Part B 1) Clinical benefit (disease stabilization or antitumor response) of 12 weeks duration in Part A of the trial determined on the second tumour assessment. 2.) Patients should have progressed in Part A according to RECIST 1.1 3.) New informed consent, including consent to biomarker sampling, must be signed before patients enter Part B of the trial
Exclusion criteria
1. Previous treatment with BIBW 2992 2. Chemo-, hormone- (other than megestrol acetate, steroids required for maintenance non-cancer therapy or as premedication before chemotherapy) or immunotherapy within the past 4 weeks; except for TKI pretreatment (2 weeks only) 3. Active/symptomatic brain metastases including leptomeningeal disease. Patients with a history of treated brain metastasis must have a stable or normal brain MRT/CT scan at screening and be at least 4 weeks post-radiation or surgery for brain metastasis. Dexamethasone therapy will be allowed if administered as a stable dose for at least one month before randomization. 4. Significant or recent acute gastrointestinal disorders with diarrhea as a major symptom e.g., Crohn's disease, mal-absorption, or CTCAE Grade \>2 diarrhea of any etiology at baseline 5. Patients who have any other life-threatening illness or organ system dysfunction, which in the opinion of the Investigator, would either compromise patient safety or interfere with the evaluation of the safety of the test drug 6. Other malignancies diagnosed within the past five (5) years (other than non-melanomatous skin cancer and in situ cervical cancer) 7. Radiotherapy within the past 2 weeks prior to treatment with the trial drug 8. History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New york Heart Association (NYHA) functional classification of 3, unstable angina, or poorly controlled arrhythmia. Myocardial infarction within 6 months prior to entering the trial. 9. Cardiac left ventricular function with resting ejection fraction of less than 50% measured by multigated blood pool imaging of the heart (MUGA scan) or echocardiogram . 10. Prior treatment with anthracyclines with a cumulative dose of doxorubicin (or equivalent) at or greater than 400 mg/m2 11. Absolute neutrophil count (ANC) at or less than 1500 / mm3 12. Platelet count at or less than 100,000 / mm3 13. Bilirubin at or greater than 1.5 mg / dL (\>26 mol / L, SI unit equivalent) 14. Aspartate amino transferase (AST) or alanine amino transferase (ALT) at or greater than three times the upper limit of normal (if related to liver metastases at or greater than five times the upper limit of normal) 15. Serum creatinine at or greater 1.5 times the upper normal limit or calculated/measured creatinine clearance at or less than 45 mL/min 16. Women of child-bearing potential or men who are able to father a child unwilling to use a medically acceptable method of contraception during the trial 17. Pregnancy or breast feeding 18. Patients unable to comply with the protocol 19. Patients with any serious active infection including known human immunodeficiency virus (HIV), active hepatitis B or active hepatitis C 20. Known or suspected active drug or alcohol abuse 21. Pre-existing or current Interstitial lung disease (ILD) 22.) 22. Peripheral polyneuropathy of \> Grade 2 23. Requirement for treatment with any of the pohibited concomitant medication listed in section 4.2.2.1.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (Part B) | From randomization until disease progression or death; Up to 32 months | Progression free survival (PFS) time as determined by Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 from day of randomization until disease progression or death for patients randomised to combination therapy with afatinib plus paclitaxel or to investigator's choice of chemotherapy. Median was calculated from the Kaplan-Meier curve. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (Part A) | From first dose administration until disease progression or death; Up to 51 months | Progression free survival (PFS) as determined by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 for Part A. Median was calculated from the Kaplan-Meier curve. |
| Overall Survival (Part B) | From randomization until death; Up to 32 months | Overall survival (OS) as determined by the time from randomization to death in part B. Median was calculated from the Kaplan-Meier curve. |
| Objective Response (Part A) | Post baseline tumour-imaging was performed at every 6 weeks thereafter until disease progression; upto 51 months | Objective response defined as the best overall response of complete response \[CR\]: disappearance of all target lesion & partial response \[PR\]: ≥30% decrease in the sum of the longest diameter of target lesions , taking as reference the baseline sum longest diameter of Afatinib monotherapy according to RECIST 1.1 for Part A. |
| Objective Response (Part B) | Post baseline tumour-imaging was performed at every 8 weeks thereafter until disease progression; up to 32 Months | Objective response (CR, PR) of Afatinib/paclitaxel combination therapy and comparator chemotherapy in Part B after progression in Part A according to RECIST 1.1 . |
| Intensity and Incidence of Adverse Events (AEs) for Part A & Part B. | From first administration of treatment until 28 days after last drug administration, up to 51 Months (Part A) and from randomization until 28 days after last drug administration of Trial medication, up to 32 Months (Part B) | Safety of Afatinib as indicated by intensity and incidence of adverse events, graded according to United States National Cancer Institute Common terminology Criteria for Adverse Events (US NCI CTCAE) Version 3.0 both for Part A and Part B. The CTCAE grades are: 1 (mild AE), 2 (moderate AE), 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related to AE). |
Countries
Argentina, Australia, Austria, Belgium, Brazil, China, Finland, France, Germany, Hungary, India, Israel, Italy, Mexico, Netherlands, Peru, Poland, Russia, South Korea, Spain, Taiwan, Ukraine, United Kingdom
Participant flow
Pre-assignment details
PD = Progression Disease
Participants by arm
| Arm | Count |
|---|---|
| Afatinib Monotherapy (Part A) Afatinib 50 mg film-coated tablet was orally administered once daily of each 28-day treatment course, with dose reductions to 40 mg/day and 30 mg/day (following the protocol-defined dose reduction scheme). | 1,154 |
| Total | 1,154 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Part A | Lost to Follow-up | 3 | 0 | 0 |
| Part A | Other Adverse event | 223 | 0 | 0 |
| Part A | Other reason not defined above | 30 | 0 | 0 |
| Part A | Protocol Violation | 3 | 0 | 0 |
| Part A | Refusal to continue trial medication | 64 | 0 | 0 |
| Part B | Not treated | 0 | 4 | 8 |
| Part B | Other AE | 0 | 29 | 8 |
| Part B | Other reason not defined above | 0 | 6 | 3 |
| Part B | Refusal to continue trial medication | 0 | 12 | 7 |
Baseline characteristics
| Characteristic | Afatinib Monotherapy (Part A) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 413 Participants |
| Age, Categorical Between 18 and 65 years | 741 Participants |
| Age, Continuous | 60.1 years STANDARD_DEVIATION 10.9 |
| Baseline Eastern Cooperative Oncology Group (ECOG) performance score 0 | 341 Participants |
| Baseline Eastern Cooperative Oncology Group (ECOG) performance score 1 | 691 Participants |
| Baseline Eastern Cooperative Oncology Group (ECOG) performance score 2 | 122 Participants |
| Histologic classification Adenocarcinoma | 985 Participants |
| Histologic classification Missing | 1 Participants |
| Histologic classification Other | 78 Participants |
| Histologic classification Squamous | 90 Participants |
| Race/Ethnicity, Customized Caucasian | 459 Participants |
| Race/Ethnicity, Customized Eastern Asian | 491 Participants |
| Race/Ethnicity, Customized Other | 29 Participants |
| Race/Ethnicity, Customized Unknown | 175 Participants |
| Sex: Female, Male Female | 654 Participants |
| Sex: Female, Male Male | 500 Participants |
| Smoking history <15 pack years & stopped >1 year before diagnosis | 132 Participants |
| Smoking history Never smoked | 615 Participants |
| Smoking history Other current or ex-smoker | 407 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 1,129 / 1,154 | 128 / 134 | 50 / 60 |
| serious Total, serious adverse events | 471 / 1,154 | 54 / 134 | 19 / 60 |
Outcome results
Primary
Progression Free Survival (Part B)
Progression free survival (PFS) time as determined by Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 from day of randomization until disease progression or death for patients randomised to combination therapy with afatinib plus paclitaxel or to investigator's choice of chemotherapy. Median was calculated from the Kaplan-Meier curve.
Time frame: From randomization until disease progression or death; Up to 32 months
Population: Randomised Set: This analysis set consist of all randomised patients irrespective of whether treated or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib Plus Paclitaxel (Part B) | Progression Free Survival (Part B) | 5.55 Months |
| Investigators Choice of Chemotherapy (Part B) | Progression Free Survival (Part B) | 2.89 Months |
Comparison: Hazard ratio is calculated from Cox proportional hazard model with treatment as the only factor, stratified by gender and maximum duration of erlotinib or gefitinib (\<6 months vs \>=6 months).p-value: 0.00395% CI: [0.44, 0.85]stratified log-rank test
Secondary
Intensity and Incidence of Adverse Events (AEs) for Part A & Part B.
Safety of Afatinib as indicated by intensity and incidence of adverse events, graded according to United States National Cancer Institute Common terminology Criteria for Adverse Events (US NCI CTCAE) Version 3.0 both for Part A and Part B. The CTCAE grades are: 1 (mild AE), 2 (moderate AE), 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related to AE).
Time frame: From first administration of treatment until 28 days after last drug administration, up to 51 Months (Part A) and from randomization until 28 days after last drug administration of Trial medication, up to 32 Months (Part B)
Population: Treated Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib Plus Paclitaxel (Part B) | Intensity and Incidence of Adverse Events (AEs) for Part A & Part B. | Grade 4 | 4.9 Percentage of participants |
| Afatinib Plus Paclitaxel (Part B) | Intensity and Incidence of Adverse Events (AEs) for Part A & Part B. | Grade 3 | 41.1 Percentage of participants |
| Afatinib Plus Paclitaxel (Part B) | Intensity and Incidence of Adverse Events (AEs) for Part A & Part B. | Grade 2 | 28.0 Percentage of participants |
| Afatinib Plus Paclitaxel (Part B) | Intensity and Incidence of Adverse Events (AEs) for Part A & Part B. | Grade 1 | 8.6 Percentage of participants |
| Afatinib Plus Paclitaxel (Part B) | Intensity and Incidence of Adverse Events (AEs) for Part A & Part B. | Grade 5 | 16.6 Percentage of participants |
| Investigators Choice of Chemotherapy (Part B) | Intensity and Incidence of Adverse Events (AEs) for Part A & Part B. | Grade 3 | 44.0 Percentage of participants |
| Investigators Choice of Chemotherapy (Part B) | Intensity and Incidence of Adverse Events (AEs) for Part A & Part B. | Grade 2 | 26.1 Percentage of participants |
| Investigators Choice of Chemotherapy (Part B) | Intensity and Incidence of Adverse Events (AEs) for Part A & Part B. | Grade 1 | 4.5 Percentage of participants |
| Investigators Choice of Chemotherapy (Part B) | Intensity and Incidence of Adverse Events (AEs) for Part A & Part B. | Grade 4 | 9.7 Percentage of participants |
| Investigators Choice of Chemotherapy (Part B) | Intensity and Incidence of Adverse Events (AEs) for Part A & Part B. | Grade 5 | 12.7 Percentage of participants |
| Investigators Choice of Chemotherapy (Part B) | Intensity and Incidence of Adverse Events (AEs) for Part A & Part B. | Grade 5 | 6.7 Percentage of participants |
| Investigators Choice of Chemotherapy (Part B) | Intensity and Incidence of Adverse Events (AEs) for Part A & Part B. | Grade 4 | 6.7 Percentage of participants |
| Investigators Choice of Chemotherapy (Part B) | Intensity and Incidence of Adverse Events (AEs) for Part A & Part B. | Grade 1 | 8.3 Percentage of participants |
| Investigators Choice of Chemotherapy (Part B) | Intensity and Incidence of Adverse Events (AEs) for Part A & Part B. | Grade 3 | 38.3 Percentage of participants |
| Investigators Choice of Chemotherapy (Part B) | Intensity and Incidence of Adverse Events (AEs) for Part A & Part B. | Grade 2 | 26.7 Percentage of participants |
Secondary
Objective Response (Part A)
Objective response defined as the best overall response of complete response \[CR\]: disappearance of all target lesion & partial response \[PR\]: ≥30% decrease in the sum of the longest diameter of target lesions , taking as reference the baseline sum longest diameter of Afatinib monotherapy according to RECIST 1.1 for Part A.
Time frame: Post baseline tumour-imaging was performed at every 6 weeks thereafter until disease progression; upto 51 months
Population: Treated set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib Plus Paclitaxel (Part B) | Objective Response (Part A) | 8.5 Percentage of participants |
Secondary
Objective Response (Part B)
Objective response (CR, PR) of Afatinib/paclitaxel combination therapy and comparator chemotherapy in Part B after progression in Part A according to RECIST 1.1 .
Time frame: Post baseline tumour-imaging was performed at every 8 weeks thereafter until disease progression; up to 32 Months
Population: Randomized Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib Plus Paclitaxel (Part B) | Objective Response (Part B) | 31.2 Percentage of participants |
| Investigators Choice of Chemotherapy (Part B) | Objective Response (Part B) | 13.2 Percentage of participants |
Comparison: Odds ratio, 95% Confidence Interval (CI) and p-value (two-sided) from logistic regression stratified for maximum treatment duration of prior erlotinib or gefitinib (\>=6 months vs \<6 months) and gender.p-value: 0.006595% CI: [1.357, 6.543]Regression, Logistic
Secondary
Overall Survival (Part B)
Overall survival (OS) as determined by the time from randomization to death in part B. Median was calculated from the Kaplan-Meier curve.
Time frame: From randomization until death; Up to 32 months
Population: Randomised Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib Plus Paclitaxel (Part B) | Overall Survival (Part B) | 12.25 Months |
| Investigators Choice of Chemotherapy (Part B) | Overall Survival (Part B) | 13.08 Months |
Comparison: Hazard ratio was calculated from Cox proportional hazard model with treatment as the only factor, stratified by gender and maximum duration of erlotinib or gefitinib (\<6 months vs \>=6 months).p-value: 0.790595% CI: [0.76, 1.44]Stratified log-rank test.
Secondary
Progression Free Survival (Part A)
Progression free survival (PFS) as determined by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 for Part A. Median was calculated from the Kaplan-Meier curve.
Time frame: From first dose administration until disease progression or death; Up to 51 months
Population: Treated set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib Plus Paclitaxel (Part B) | Progression Free Survival (Part A) | 3.15 Months |