Carcinoma, Non-Small-Cell Lung
Conditions
Brief summary
This is a non-randomized, open label, two-cohort, multi-institutional study to evaluate the use of diarrheal management tools intended to facilitate timely intervention and treatment modifications due to afatinib treatment-related diarrhea in patients with EGFR mutations-positive adenocarcinoma of the lung. Patients in Cohort 1 will follow diarrhea management. Patients in Cohort 2 will receive prophylactic loperamide starting the fist day of afatinib treatment.
Interventions
DRUGafatinib
Daily treatment starting 40 mg per day
DRUGloperamide
Follow cohort assignment and diarrhea management guidelines
Sponsors
Boehringer Ingelheim
Study design
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Pathologically confirmed diagnosis of Stage IIIB or Stage IV adenocarcinoma of the lung, with EGFR mutations-positive status, who are not eligible to receive surgery or chemoradiotherapy. Patients with mixed histology are eligible if adenocarcinoma is the predominant histology, and is a suitable candidate for EGFR-TKI monotherapy, in the opinion of the investigator. 2. Patients must have Epidermal Growth Factor Receptor (EGFR) mutation-positive status according to the institutional standard of care. 3. Patient received no more than one (1) prior chemotherapy for locally advanced or metastatic adenocarcinoma of the lung. 4. Male or female patients Age 18 years and older. 5. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 6. Adequate organ function, defined as all of the following: * Left Ventricular Ejection Fraction (LVEF) of above 50% or within institution normal values * Absolute neutrophil count (ANC) above 1500 / mm3. * Platelet count above 75,000 / mm3. * Estimated creatinine clearance more than 45ml / min. * Total Bilirubin less than 1.5 times upper limit of (institutional/central) normal * Aspartate amino transferase (AST) or alanine amino transferase (ALT) less than three times the upper limit of (institutional/central) normal (ULN) (if related to liver metastases less than five times ULN). 7. Recovered from any previous therapy related toxicity to Grade 0 or 1 at study entry 8. Able and willing to follow diarrhea management guidelines provided under this study and to complete Diarrhea Management Worksheet as instructed.
Exclusion criteria
1. Chemotherapy, biological therapy or investigational agents within four weeks prior to the start of study treatment. 2. Prior treatment with EGFR directed small molecules or antibodies. 3. Hormonal treatment within 2 weeks prior to start of study treatment (continued use of anti-androgens and/or gonadorelin analogues for treatment of prostate cancer permitted). 4. Major surgery within 4 weeks before starting study treatment or scheduled for surgery during the projected course of the study. 5. Known hypersensitivity to afatinib or the excipients of any of the trial drugs. 6. History or presence of clinically relevant cardiovascular abnormalities. 7. Any history of or concomitant condition that, in the opinion of the Investigator, would compromise the patient¿s ability to comply with the study or interfere with the evaluation of the efficacy and safety of the test drug. 8. Previous or concomitant invasive malignancies at other sites. 9. Known pre-existing interstitial lung disease (ILD). 10. Any history or presence of poorly controlled gastrointestinal disorders that could affect the absorption of the study drug. 14\. Active hepatitis B infection, active hepatitis C infection and/or known HIV carrier, who are determined by the investigator as not a suitable candidate to receive EGFR-TKI treatment. 15\. Patients with meningeal carcinomatosis. 16. Patients with brain or subdural metastases.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurence of CTCAE Grade >= 2 Diarrhea | From first drug administration until 28 days after the end of third treatment course, up to 84 days. | Overall incidence of patients who experienced diarrhea during the first three courses of afatinib treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Initial Onset of Diarrhea Grade 2 or Higher | From first drug administration until end of third treatment course, up to 84 days. | Time to initial onset of diarrhea grade 2 or higher |
| Duration of First Episode of Diarrhea Grade 2 or Higher | From first drug administration until end of third treatment course, up to 84 days. | Duration of first episode of diarrhea grade 2 or higher. Please note that the nine patients experienced diarrhea episodes that were not managed according to the protocol specified afatinib treatment interruptions and dose reductions. No patients were excluded from the primary analysis. |
| Changes in Intensity of Diarrhea Over Time | Up to 12 weeks (equivalent to 3 courses) | Percentage of participants with grade 2 or higher diarrhea each week for the first 3 cycles of afatinib treatment |
| PFS | Every 08 weeks during the first 6 months of treatment, and every 12 weeks thereafter until the end of treatment. | Progression-free survival (PFS). PFS was defined as the time from the start of treatment to an event occurred. In the analyses for the PFS endpoint, an event was defined as disease progression or death, whichever occurred earlier. Data for patients who did not die or progress during the trial were censored at the time of afatinib discontinuation or transition to commercially available afatinib. Median PFS is estimated using Kaplan-Meier method. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1). |
Countries
United States
Participant flow
Pre-assignment details
PD: Progressive Disease (PD)
Participants by arm
| Arm | Count |
|---|---|
| Afatinib 40 mg + Loperamide (Cohort 1) Subjects were orally administered with the starting dose of Afatinib Film-coated tablets 40 mg once daily - with possible dose reductions to 30 mg and 20 mg and if any diarrhea was experienced Common Terminology Criteria for Adverse Events (CTCAE Grade 1), 2 tablets of loperamide 2 mg were to be taken immediately, followed by 1 tablet of loperamide 2 mg with every subsequent loose bowel movement until bowel movements ceased for 12 hours. | 18 |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) Subjects were orally administered with the starting dose of Afatinib Film-coated tablets 40 mg once daily - with possible dose reductions to 30 mg and 20 mg and 2 tablets of loperamide 2 mg daily (i.e., 4 mg daily) starting on Course 1 Day 1. If any diarrhea was experienced (CTCAE Grade 1) by subjects, 2 tablets of loperamide 2 mg were to be taken immediately, followed by 1 tablet of loperamide 2mg with every subsequent loose bowel movement until bowel movements ceased for 12 hours. Subjects who experienced no diarrhea during Course 1 were allowed to reduce the loperamide dose to 2 mg daily and subjects who experienced no diarrhea during the first two courses discontinued daily prophylactic loperamide at the end of Course 2. | 22 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Other Adverse Event | 4 | 5 |
| Overall Study | Other than stated | 7 | 8 |
| Overall Study | PD per clinical progression | 6 | 8 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Afatinib 40 mg + Loperamide (Cohort 1) | Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Total |
|---|---|---|---|
| Age, Continuous | 69.70 Years STANDARD_DEVIATION 10.8 | 68.00 Years STANDARD_DEVIATION 6.5 | 68.80 Years STANDARD_DEVIATION 8.62 |
| Sex: Female, Male Female | 12 Participants | 12 Participants | 24 Participants |
| Sex: Female, Male Male | 6 Participants | 10 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 18 / 18 | 22 / 22 |
| serious Total, serious adverse events | 10 / 18 | 5 / 22 |
Outcome results
Primary
Occurence of CTCAE Grade >= 2 Diarrhea
Overall incidence of patients who experienced diarrhea during the first three courses of afatinib treatment.
Time frame: From first drug administration until 28 days after the end of third treatment course, up to 84 days.
Population: Treated set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib 40 mg + Loperamide (Cohort 1) | Occurence of CTCAE Grade >= 2 Diarrhea | 72.20 Percentage of participants |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Occurence of CTCAE Grade >= 2 Diarrhea | 31.80 Percentage of participants |
Secondary
Changes in Intensity of Diarrhea Over Time
Percentage of participants with grade 2 or higher diarrhea each week for the first 3 cycles of afatinib treatment
Time frame: Up to 12 weeks (equivalent to 3 courses)
Population: Treated set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib 40 mg + Loperamide (Cohort 1) | Changes in Intensity of Diarrhea Over Time | Grade >=3: Week 1 (N=1, 1) | 5.60 Percentage of participants |
| Afatinib 40 mg + Loperamide (Cohort 1) | Changes in Intensity of Diarrhea Over Time | Grade 2: Week 12 (N=1, 1) | 5.90 Percentage of participants |
| Afatinib 40 mg + Loperamide (Cohort 1) | Changes in Intensity of Diarrhea Over Time | Grade 2: Week 6 (N=0, 1) | 0.00 Percentage of participants |
| Afatinib 40 mg + Loperamide (Cohort 1) | Changes in Intensity of Diarrhea Over Time | Grade 2: Week 2 (N=4, 3) | 22.20 Percentage of participants |
| Afatinib 40 mg + Loperamide (Cohort 1) | Changes in Intensity of Diarrhea Over Time | Grade >=3: Week 3 (N=3, 1) | 16.70 Percentage of participants |
| Afatinib 40 mg + Loperamide (Cohort 1) | Changes in Intensity of Diarrhea Over Time | Grade 2: Week 7 (N=2, 1) | 11.80 Percentage of participants |
| Afatinib 40 mg + Loperamide (Cohort 1) | Changes in Intensity of Diarrhea Over Time | Grade >=3: Week 4 (N=0, 1) | 0.00 Percentage of participants |
| Afatinib 40 mg + Loperamide (Cohort 1) | Changes in Intensity of Diarrhea Over Time | Grade >=3: Week 2 (N=2, 2) | 11.10 Percentage of participants |
| Afatinib 40 mg + Loperamide (Cohort 1) | Changes in Intensity of Diarrhea Over Time | Grade >=3: Week 5 (N=0, 0) | 0.00 Percentage of participants |
| Afatinib 40 mg + Loperamide (Cohort 1) | Changes in Intensity of Diarrhea Over Time | Grade 2: Week 8 (N=3, 0) | 17.60 Percentage of participants |
| Afatinib 40 mg + Loperamide (Cohort 1) | Changes in Intensity of Diarrhea Over Time | Grade >=3: Week 6 (N=0, 0) | 0.00 Percentage of participants |
| Afatinib 40 mg + Loperamide (Cohort 1) | Changes in Intensity of Diarrhea Over Time | Grade 2: Week 3 (N=3, 3) | 16.70 Percentage of participants |
| Afatinib 40 mg + Loperamide (Cohort 1) | Changes in Intensity of Diarrhea Over Time | Grade >=3: Week 7 (N=1, 0) | 5.90 Percentage of participants |
| Afatinib 40 mg + Loperamide (Cohort 1) | Changes in Intensity of Diarrhea Over Time | Grade 2: Week 9 (N=2, 0) | 11.80 Percentage of participants |
| Afatinib 40 mg + Loperamide (Cohort 1) | Changes in Intensity of Diarrhea Over Time | Grade >=3: Week 8 (N=0, 0) | 0.00 Percentage of participants |
| Afatinib 40 mg + Loperamide (Cohort 1) | Changes in Intensity of Diarrhea Over Time | Grade 2: Week 1 (N=2, 1) | 11.10 Percentage of participants |
| Afatinib 40 mg + Loperamide (Cohort 1) | Changes in Intensity of Diarrhea Over Time | Grade >=3: Week 9 (N=0, 0) | 0.00 Percentage of participants |
| Afatinib 40 mg + Loperamide (Cohort 1) | Changes in Intensity of Diarrhea Over Time | Grade 2: Week 10 (N=0, 0) | 0.00 Percentage of participants |
| Afatinib 40 mg + Loperamide (Cohort 1) | Changes in Intensity of Diarrhea Over Time | Grade >=3: Week 10 (N=1, 0) | 5.90 Percentage of participants |
| Afatinib 40 mg + Loperamide (Cohort 1) | Changes in Intensity of Diarrhea Over Time | Grade 2: Week 5 (N=2, 0) | 11.10 Percentage of participants |
| Afatinib 40 mg + Loperamide (Cohort 1) | Changes in Intensity of Diarrhea Over Time | Grade >=3: Week 11 (N=0, 0) | 0.00 Percentage of participants |
| Afatinib 40 mg + Loperamide (Cohort 1) | Changes in Intensity of Diarrhea Over Time | Grade 2: Week 11 (N=2, 0) | 11.80 Percentage of participants |
| Afatinib 40 mg + Loperamide (Cohort 1) | Changes in Intensity of Diarrhea Over Time | Grade >=3: Week 12 (N=0, 0) | 0.00 Percentage of participants |
| Afatinib 40 mg + Loperamide (Cohort 1) | Changes in Intensity of Diarrhea Over Time | Grade 2: Week 4 (N=6, 2) | 33.30 Percentage of participants |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Changes in Intensity of Diarrhea Over Time | Grade >=3: Week 12 (N=0, 0) | 0.00 Percentage of participants |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Changes in Intensity of Diarrhea Over Time | Grade 2: Week 4 (N=6, 2) | 9.10 Percentage of participants |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Changes in Intensity of Diarrhea Over Time | Grade >=3: Week 1 (N=1, 1) | 4.50 Percentage of participants |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Changes in Intensity of Diarrhea Over Time | Grade 2: Week 1 (N=2, 1) | 4.50 Percentage of participants |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Changes in Intensity of Diarrhea Over Time | Grade 2: Week 2 (N=4, 3) | 13.60 Percentage of participants |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Changes in Intensity of Diarrhea Over Time | Grade 2: Week 3 (N=3, 3) | 13.60 Percentage of participants |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Changes in Intensity of Diarrhea Over Time | Grade 2: Week 5 (N=2, 0) | 0.00 Percentage of participants |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Changes in Intensity of Diarrhea Over Time | Grade 2: Week 6 (N=0, 1) | 4.80 Percentage of participants |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Changes in Intensity of Diarrhea Over Time | Grade 2: Week 7 (N=2, 1) | 5.00 Percentage of participants |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Changes in Intensity of Diarrhea Over Time | Grade 2: Week 8 (N=3, 0) | 0.00 Percentage of participants |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Changes in Intensity of Diarrhea Over Time | Grade 2: Week 9 (N=2, 0) | 0.00 Percentage of participants |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Changes in Intensity of Diarrhea Over Time | Grade 2: Week 10 (N=0, 0) | 0.00 Percentage of participants |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Changes in Intensity of Diarrhea Over Time | Grade 2: Week 11 (N=2, 0) | 0.00 Percentage of participants |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Changes in Intensity of Diarrhea Over Time | Grade 2: Week 12 (N=1, 1) | 6.30 Percentage of participants |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Changes in Intensity of Diarrhea Over Time | Grade >=3: Week 2 (N=2, 2) | 9.10 Percentage of participants |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Changes in Intensity of Diarrhea Over Time | Grade >=3: Week 3 (N=3, 1) | 4.50 Percentage of participants |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Changes in Intensity of Diarrhea Over Time | Grade >=3: Week 4 (N=0, 1) | 4.50 Percentage of participants |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Changes in Intensity of Diarrhea Over Time | Grade >=3: Week 5 (N=0, 0) | 0.00 Percentage of participants |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Changes in Intensity of Diarrhea Over Time | Grade >=3: Week 6 (N=0, 0) | 0.00 Percentage of participants |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Changes in Intensity of Diarrhea Over Time | Grade >=3: Week 7 (N=1, 0) | 0.00 Percentage of participants |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Changes in Intensity of Diarrhea Over Time | Grade >=3: Week 8 (N=0, 0) | 0.00 Percentage of participants |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Changes in Intensity of Diarrhea Over Time | Grade >=3: Week 9 (N=0, 0) | 0.00 Percentage of participants |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Changes in Intensity of Diarrhea Over Time | Grade >=3: Week 10 (N=1, 0) | 0.00 Percentage of participants |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Changes in Intensity of Diarrhea Over Time | Grade >=3: Week 11 (N=0, 0) | 0.00 Percentage of participants |
Secondary
Duration of First Episode of Diarrhea Grade 2 or Higher
Duration of first episode of diarrhea grade 2 or higher. Please note that the nine patients experienced diarrhea episodes that were not managed according to the protocol specified afatinib treatment interruptions and dose reductions. No patients were excluded from the primary analysis.
Time frame: From first drug administration until end of third treatment course, up to 84 days.
Population: Treated set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 40 mg + Loperamide (Cohort 1) | Duration of First Episode of Diarrhea Grade 2 or Higher | 3.10 days | Standard Deviation 4.09 |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Duration of First Episode of Diarrhea Grade 2 or Higher | 7.60 days | Standard Deviation 5.19 |
Secondary
PFS
Progression-free survival (PFS). PFS was defined as the time from the start of treatment to an event occurred. In the analyses for the PFS endpoint, an event was defined as disease progression or death, whichever occurred earlier. Data for patients who did not die or progress during the trial were censored at the time of afatinib discontinuation or transition to commercially available afatinib. Median PFS is estimated using Kaplan-Meier method. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1).
Time frame: Every 08 weeks during the first 6 months of treatment, and every 12 weeks thereafter until the end of treatment.
Population: Treated Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 40 mg + Loperamide (Cohort 1) | PFS | 15.40 Months |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | PFS | 9.90 Months |
Secondary
Time to Initial Onset of Diarrhea Grade 2 or Higher
Time to initial onset of diarrhea grade 2 or higher
Time frame: From first drug administration until end of third treatment course, up to 84 days.
Population: Treated set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 40 mg + Loperamide (Cohort 1) | Time to Initial Onset of Diarrhea Grade 2 or Higher | 23.50 days | Standard Deviation 22.64 |
| Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) | Time to Initial Onset of Diarrhea Grade 2 or Higher | 15.40 days | Standard Deviation 14.97 |