Carcinoma, Non-Small-Cell Lung
Conditions
Brief summary
The primary objective of this open-label, single arm Phase II trial is to explore the efficacy of BIBW 2992 defined by the objective response rate (CR, PR) as determined by RECIST criteria in patients with advanced NSCLC Stage IIIB or IV whose tumors harbor activating mutations within exon 18 to exon 21 of the EGFR receptor. Patients progressing or relapsing after one prior cytotoxic chemotherapy regimen as well as chemotherapy naïve patients (only in stage 2) will be allowed to enter into the trial.
Interventions
DRUGBIBW 2992
This is an open label study. Patients are treated with BIBW 2992 until disease progression or undue AEs
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
1. Patients with pathologically confirmed diagnosis of NSCLC Stage IIIB (with pleural effusion) adenocarcinoma or Stage IV adenocarcinoma. 2. Presence of activating mutation(s) in exon 18 to exon 21 of the EGFR-receptor confirmed by direct DNA sequencing of NSCLC tumor tissue. 3. Progressive disease following a first line cytotoxic chemotherapy regimen or have recurrent disease after prior neoadjuvant or adjuvant chemotherapy. Patients who have not received first-line cytotoxic chemotherapy can be enrolled in stage 2 of the trial, if the criteria for entering stage 2 are met. 4. Patients with at least one tumor lesion that can accurately be measured by computed tomography (CT) or magnetic resonance imaging (MRI) in at least one dimension with longest diameter to be recorded as 20 mm using conventional techniques or 10 mm with spiral CT scan. 5. Male or female patient aged 18 years. 6. Life expectancy of at least three (3) months. 7. Written informed consents that is consistent with ICH-GCP guidelines. 8. Eastern Cooperative Oncology Group (ECOG) performance score 0, 1 or 2.
Exclusion criteria
1. More than one (1) prior cytotoxic chemotherapy treatment regimen for relapsed or metastatic NSCLC. 2. Chemo-, hormone- (other than Megace®) or immunotherapy within the past 4 weeks or within less than four half-lives of the previous drug prior to treatment with the trial drug and/or persistence of toxicities of prior anticancer therapies which are deemed to be clinically relevant. 3. Previous treatment with erlotinib (Tarceva®), gefitinib (Iressa®) or any other EGFR inhibiting small molecule or antibody. 4. Brain metastases, which are symptomatic; patients with treated, asymptomatic brain metastases are eligible with stable brain disease for at least four (4) weeks without the requirement for steroids or anti-epileptic therapy. 5. Significant or recent acute gastrointestinal disorders with diarrhea as a major symptom e.g., Crohns disease, malabsorption, or CTCAE Grade \>2 diarrhea of any etiology at baseline. 6. 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. 7. Other malignancies diagnosed within the past five (5) years (other than non-melanomatous skin cancer and in situ cervical cancer). 8. Radiotherapy within the past 2 weeks prior to treatment with the trial drug. 9. Patients with any serious active infection (i.e., requiring an IV antibiotic, antifungal, or antiviral agents). 10. Patients with known HIV, active hepatitis B or active hepatitis C. 11. Known or suspected active drug or alcohol abuse. 12. 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. 13. Pregnancy or breast feeding. 14. Patient unable to comply with the protocol. 15. History of clinically significant or uncontrolled cardiac disease, including congestive heart failure, angina, myocardial infarction, arrhythmia, including New York Heart Association (NYHA) functional classification of 3. 16. 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. 17. QTc interval greater than 0.47 second. 18. Prior treatment with anthracyclines with a cumulative dose of doxorubicin (or equivalent) greater than 400 mg/m2. 19. Absolute neutrophil count (ANC) less than 1500/mm3. 20. Platelet count less than 100 000 /mm3. 21. Bilirubin greater than 1.5 mg / dl (greater than 26 micromol / L, SI unit equivalent). 22. Aspartate amino transferase (AST) or alanine amino transferase (ALT) greater than three times the upper limit of normal (if related to liver metastases greater than five times the upper limit of normal). 23. Serum creatinine greater than 1.5 times of the upper normal limit or calculated/measured creatinine clearance equal or less than 45 ml / min. 24. Patients with known pre-existing interstitial lung disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response (OR) as Determined by RECIST 1.0 | Response assessment is done at end of Week 4 (after Course 1), Week 8 (after Course 2), Week 12 (after Course 3) and at 8-week intervals thereafter, up to 93 months. | Objective response (OR) was assessed for all treated patients by independent review as determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0. OR included complete response (CR) and partial response (PR), where CR or PR must have been confirmed by a subsequent response in ≥28 days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Clinical Benefit | Response assessment is done at end of Week 4 (after Course 1), Week 8 (after Course 2), Week 12 (after Course 3) and at 8-week intervals thereafter, up to 93 months. | Duration of clinical benefit (disease control) as per independent review was defined as the time from the start of treatment to the time of progression or death (whichever occurred first), among patients with evidence of SD, PR or CR. |
| Duration of Objective Response | Response assessment is done at end of Week 4 (after Course 1), Week 8 (after Course 2), Week 12 (after Course 3) and at 8-week intervals thereafter, up to 93 months. | Duration of objective response (OR) was measured from the time the criteria for CR or PR (whichever was documented first) were first met until the first date that progressive disease or death (or date of censoring for PFS) was objectively documented as per independent review. |
| Time to Objective Response | Response assessment is done at end of Week 4 (after Course 1), Week 8 (after Course 2), Week 12 (after Course 3) and at 8-week intervals thereafter, up to 93 months. | Time to objective response was defined as the number of days from the start of treatment to the first recorded objective response. Patients who did not experience objective response during the study were censored at the time of treatment discontinuation. The results are provided as the percentage of participants for this Outcome Measure. |
| Progression-free Survival | Response assessment is done at end of Week 4 (after Course 1), Week 8 (after Course 2), Week 12 (after Course 3) and at 8-week intervals thereafter, up to 93 months. | Progression-free survival (PFS) as per independent review was defined as the duration of time from the start of treatment until the day of objective tumor progression was confirmed by tumor imaging (Progressive Disease according to RECIST 1.0) or death, whichever came first. Patients with unknown progression status or unknown date of progression were reviewed on a case-by-case basis. Patients known to be alive without progression at the end of the trial or the last follow-up visit were censored at the date of the last imaging when the patient was known to be alive and progression-free. Medians are calculated from the Kaplan-Meier estimates and 95% confidence intervals, using Greenwood's standard error estimate. |
| Clinical Benefit as Determined by RECIST 1.0 | Response assessment is done at end of Week 4 (after Course 1), Week 8 (after Course 2), Week 12 (after Course 3) and at 8-week intervals thereafter, up to 93 months. | Clinical benefit was evaluated according to RECIST 1.0 by independent review assessment. Patients whose best RECIST 1.0 assessment was stable disease (SD), partial response (PR), or complete response (CR) were considered to have derived a clinical benefit from treatment. |
| Cpre,ss,29 | -0:05h (pre-dose) on Day 29 | Predose concentration of the analyte in plasma at steady state immediately before administration of the 29th dose (Cpre,ss,29). |
| Safety of BIBW 2992 as Indicated by Incidence of Specified Adverse Events. | First administration of trial medication until 28 days after last administration of trial medication, up to 93 months. | Safety of afatinib as indicated by incidence of specified adverse events: skin reactions (a preferred term of the system organ class: Skin and subcutaneous tissue disorders) and gastrointestinal (GI) (a system organ class). |
| Safety of BIBW 2992 as Indicated by Intensity and Incidence of Worst Adverse Events Graded According to NCI CTCAE Version 3.0 | First administration of trial medication until 28 days after last administration of trial medication, up to 93 months. | Safety of afatinib as indicated by intensity and incidence of worst adverse events graded according to National Cancer Institute (NCI) Common terminology criteria for adverse events (CTCAE) Version 3.0 (R04-0474). |
| Overall Survival Time | Start of treatment to time to all death, up to 93 months | Overall survival time (OS) was also evaluated and was defined as the duration of time from start of treatment to time of death up to 93 months, regardless of the cause of death. Medians are calculated from the Kaplan-Meier estimates and 95% confidence intervals, using Greenwood's standard error estimate. |
Countries
Taiwan, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| First-line Afatinib 40 mg First-line patients were enrolled after Amendment 1 with a starting oral dose of Afatinib 40 mg daily after Amendment 2. Dose reduction scheme was defined for patients unable to tolerate this dose. | 23 |
| First-line Afatinib 50 mg First-line patients were enrolled after Amendment 1 with a starting oral dose of Afatinib 50 mg daily. Dose reduction scheme was defined for patients unable to tolerate this dose. | 38 |
| Second-line Afatinib 40 mg Second-line patients received a starting oral dose of Afatinib 40 mg daily only after Amendment 2. Dose reduction scheme was defined for patients unable to tolerate this dose. | 7 |
| Second-line Afatinib 50 mg Second-line patients received a starting oral dose of Afatinib 50 mg daily. Dose reduction scheme was defined for patients unable to tolerate this dose. | 61 |
| Total | 129 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Other Adverse Event | 3 | 5 | 1 | 8 |
| Overall Study | Other than stated | 2 | 1 | 0 | 3 |
| Overall Study | Progressive disease | 18 | 30 | 6 | 49 |
| Overall Study | Refused continuation of study medication | 0 | 2 | 0 | 1 |
Baseline characteristics
| Characteristic | First-line Afatinib 40 mg | First-line Afatinib 50 mg | Second-line Afatinib 40 mg | Second-line Afatinib 50 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 64 years STANDARD_DEVIATION 11 | 62 years STANDARD_DEVIATION 9.6 | 57 years STANDARD_DEVIATION 14.5 | 61 years STANDARD_DEVIATION 11.5 | 62 years STANDARD_DEVIATION 11.1 |
| Sex: Female, Male Female | 13 Participants | 27 Participants | 3 Participants | 32 Participants | 75 Participants |
| Sex: Female, Male Male | 10 Participants | 11 Participants | 4 Participants | 29 Participants | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 30 / 30 | 98 / 99 |
| serious Total, serious adverse events | 9 / 30 | 44 / 99 |
Outcome results
Primary
Objective Response (OR) as Determined by RECIST 1.0
Objective response (OR) was assessed for all treated patients by independent review as determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0. OR included complete response (CR) and partial response (PR), where CR or PR must have been confirmed by a subsequent response in ≥28 days.
Time frame: Response assessment is done at end of Week 4 (after Course 1), Week 8 (after Course 2), Week 12 (after Course 3) and at 8-week intervals thereafter, up to 93 months.
Population: Treated set: The patients who had taken at least one dose of afatinib were included in the treated set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib | Objective Response (OR) as Determined by RECIST 1.0 | 62.0 percentage of participants |
Secondary
Clinical Benefit as Determined by RECIST 1.0
Clinical benefit was evaluated according to RECIST 1.0 by independent review assessment. Patients whose best RECIST 1.0 assessment was stable disease (SD), partial response (PR), or complete response (CR) were considered to have derived a clinical benefit from treatment.
Time frame: Response assessment is done at end of Week 4 (after Course 1), Week 8 (after Course 2), Week 12 (after Course 3) and at 8-week intervals thereafter, up to 93 months.
Population: Treated set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib | Clinical Benefit as Determined by RECIST 1.0 | 82.2 Percentage of participants |
Secondary
Cpre,ss,29
Predose concentration of the analyte in plasma at steady state immediately before administration of the 29th dose (Cpre,ss,29).
Time frame: -0:05h (pre-dose) on Day 29
Population: Treated Set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib | Cpre,ss,29 | 54.1 ng/mL | Geometric Coefficient of Variation 78.5 |
| Afatinib 40 mg | Cpre,ss,29 | 27.9 ng/mL | Geometric Coefficient of Variation 63.1 |
| Afatinib 50 mg | Cpre,ss,29 | 33.7 ng/mL | Geometric Coefficient of Variation 64.1 |
Secondary
Duration of Clinical Benefit
Duration of clinical benefit (disease control) as per independent review was defined as the time from the start of treatment to the time of progression or death (whichever occurred first), among patients with evidence of SD, PR or CR.
Time frame: Response assessment is done at end of Week 4 (after Course 1), Week 8 (after Course 2), Week 12 (after Course 3) and at 8-week intervals thereafter, up to 93 months.
Population: Treated Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Afatinib | Duration of Clinical Benefit | 81.6 weeks | Standard Deviation 80.5 |
Secondary
Duration of Objective Response
Duration of objective response (OR) was measured from the time the criteria for CR or PR (whichever was documented first) were first met until the first date that progressive disease or death (or date of censoring for PFS) was objectively documented as per independent review.
Time frame: Response assessment is done at end of Week 4 (after Course 1), Week 8 (after Course 2), Week 12 (after Course 3) and at 8-week intervals thereafter, up to 93 months.
Population: Treated set including only patients with objective response.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Afatinib | Duration of Objective Response | 76.5 Weeks | Standard Deviation 77.2 |
Secondary
Overall Survival Time
Overall survival time (OS) was also evaluated and was defined as the duration of time from start of treatment to time of death up to 93 months, regardless of the cause of death. Medians are calculated from the Kaplan-Meier estimates and 95% confidence intervals, using Greenwood's standard error estimate.
Time frame: Start of treatment to time to all death, up to 93 months
Population: Treated set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib | Overall Survival Time | 26.8 Months |
Secondary
Progression-free Survival
Progression-free survival (PFS) as per independent review was defined as the duration of time from the start of treatment until the day of objective tumor progression was confirmed by tumor imaging (Progressive Disease according to RECIST 1.0) or death, whichever came first. Patients with unknown progression status or unknown date of progression were reviewed on a case-by-case basis. Patients known to be alive without progression at the end of the trial or the last follow-up visit were censored at the date of the last imaging when the patient was known to be alive and progression-free. Medians are calculated from the Kaplan-Meier estimates and 95% confidence intervals, using Greenwood's standard error estimate.
Time frame: Response assessment is done at end of Week 4 (after Course 1), Week 8 (after Course 2), Week 12 (after Course 3) and at 8-week intervals thereafter, up to 93 months.
Population: Treated Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib | Progression-free Survival | 10.2 Months |
Secondary
Safety of BIBW 2992 as Indicated by Incidence of Specified Adverse Events.
Safety of afatinib as indicated by incidence of specified adverse events: skin reactions (a preferred term of the system organ class: Skin and subcutaneous tissue disorders) and gastrointestinal (GI) (a system organ class).
Time frame: First administration of trial medication until 28 days after last administration of trial medication, up to 93 months.
Population: Treated set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib | Safety of BIBW 2992 as Indicated by Incidence of Specified Adverse Events. | skin reactions | 16.7 Percentage of participants |
| Afatinib | Safety of BIBW 2992 as Indicated by Incidence of Specified Adverse Events. | gastrointestinal (GI) | 100.0 Percentage of participants |
| Afatinib 40 mg | Safety of BIBW 2992 as Indicated by Incidence of Specified Adverse Events. | skin reactions | 27.3 Percentage of participants |
| Afatinib 40 mg | Safety of BIBW 2992 as Indicated by Incidence of Specified Adverse Events. | gastrointestinal (GI) | 97.0 Percentage of participants |
Secondary
Safety of BIBW 2992 as Indicated by Intensity and Incidence of Worst Adverse Events Graded According to NCI CTCAE Version 3.0
Safety of afatinib as indicated by intensity and incidence of worst adverse events graded according to National Cancer Institute (NCI) Common terminology criteria for adverse events (CTCAE) Version 3.0 (R04-0474).
Time frame: First administration of trial medication until 28 days after last administration of trial medication, up to 93 months.
Population: Treated set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib | Safety of BIBW 2992 as Indicated by Intensity and Incidence of Worst Adverse Events Graded According to NCI CTCAE Version 3.0 | Grade 5 | 6.7 Percentage of participants |
| Afatinib | Safety of BIBW 2992 as Indicated by Intensity and Incidence of Worst Adverse Events Graded According to NCI CTCAE Version 3.0 | Grade 1 | 3.3 Percentage of participants |
| Afatinib | Safety of BIBW 2992 as Indicated by Intensity and Incidence of Worst Adverse Events Graded According to NCI CTCAE Version 3.0 | Grade 2 | 36.7 Percentage of participants |
| Afatinib | Safety of BIBW 2992 as Indicated by Intensity and Incidence of Worst Adverse Events Graded According to NCI CTCAE Version 3.0 | Grade 3 | 46.7 Percentage of participants |
| Afatinib | Safety of BIBW 2992 as Indicated by Intensity and Incidence of Worst Adverse Events Graded According to NCI CTCAE Version 3.0 | Grade 4 | 6.7 Percentage of participants |
| Afatinib 40 mg | Safety of BIBW 2992 as Indicated by Intensity and Incidence of Worst Adverse Events Graded According to NCI CTCAE Version 3.0 | Grade 4 | 3.0 Percentage of participants |
| Afatinib 40 mg | Safety of BIBW 2992 as Indicated by Intensity and Incidence of Worst Adverse Events Graded According to NCI CTCAE Version 3.0 | Grade 3 | 57.6 Percentage of participants |
| Afatinib 40 mg | Safety of BIBW 2992 as Indicated by Intensity and Incidence of Worst Adverse Events Graded According to NCI CTCAE Version 3.0 | Grade 1 | 1.0 Percentage of participants |
| Afatinib 40 mg | Safety of BIBW 2992 as Indicated by Intensity and Incidence of Worst Adverse Events Graded According to NCI CTCAE Version 3.0 | Grade 5 | 12.1 Percentage of participants |
| Afatinib 40 mg | Safety of BIBW 2992 as Indicated by Intensity and Incidence of Worst Adverse Events Graded According to NCI CTCAE Version 3.0 | Grade 2 | 25.3 Percentage of participants |
Secondary
Time to Objective Response
Time to objective response was defined as the number of days from the start of treatment to the first recorded objective response. Patients who did not experience objective response during the study were censored at the time of treatment discontinuation. The results are provided as the percentage of participants for this Outcome Measure.
Time frame: Response assessment is done at end of Week 4 (after Course 1), Week 8 (after Course 2), Week 12 (after Course 3) and at 8-week intervals thereafter, up to 93 months.
Population: Treated set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib | Time to Objective Response | >= Week 52 | 2.3 Percentage of participants |
| Afatinib | Time to Objective Response | Week 4 | 38.8 Percentage of participants |
| Afatinib | Time to Objective Response | Week 8 | 12.4 Percentage of participants |
| Afatinib | Time to Objective Response | Week 12 | 1.6 Percentage of participants |
| Afatinib | Time to Objective Response | Week 20 | 5.4 Percentage of participants |
| Afatinib | Time to Objective Response | Week 28 | 0.0 Percentage of participants |
| Afatinib | Time to Objective Response | Week 36 | 1.6 Percentage of participants |
| Afatinib | Time to Objective Response | Week 44 | 0.0 Percentage of participants |
| Afatinib | Time to Objective Response | no objective response | 38.0 Percentage of participants |