Carcinoma, Non-Small-Cell Lung
Conditions
Brief summary
This trial is divided into Part A and Part B. The primary objective of Part A is to establish the Maximal Tolerated Dose of intermittent high dose afatinib. The primary objective of Part B is to assess the response rate of patients with non-small cell lung cancer with EGFR T790M mutations to a dose of intermittent afatinib established in Part A. The secondary objective is to explore tumor response and tumor-derived biological markers of response to afatinib, as well as pharmacokinetic parameters of afatinib.
Interventions
DRUGDose escalation followed by treatment with MTD
Fixed 3+3 dose escalation; expansion of MTD cohort
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Part A only: 1. Patients with histologically confirmed advanced solid tumours that are metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective. Patients who refuse standard therapy are also eligible. Part B only: 2. Pathologically confirmed diagnosis of Stage IV (M1a or b) non-small cell lung cancer 3. Documented Epidermal Growth Factor Receptor (EGFR) T790M mutation 4. Progression of disease on a reversible tyrosine kinase inhibitor within 30 days of starting study drug. Loss of exposure to prior EGFR TKI should not be \>30 days; any procedural delay in confirmation of progression is to be discussed with the BI Clinical Monitor. Parts A and B: 5. Evaluable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 6. Age \>/= to 18 years 7. Eastern Cooperative Group (ECOG) performance status 0-1 8. Adequate organ function 9. Recovered from any previous therapy-related toxicity to \</= to Grade 1 at study entry (except for stable sensory neuropathy \</= Grade 2 and alopecia) 10. Written informed consent 11. Ability to take oral medication
Exclusion criteria
Parts A and B: 1. Chemotherapy, biological therapy, or investigational agents (except erlotinib or gefitinib) within 4 weeks prior to the start of study treatment 2. Hormonal treatment within 2 weeks prior to the start of study treatment (continued use of anti-androgens and/or gonadorelin analogues for treatment of prostate cancer is permitted) 3. Radiotherapy within two weeks prior to the start of study treatment (except palliative radiotherapy given for symptom control) 4. Less than 3 days from prior treatment with gefitinib or erlotinib. Patients with adverse events related to gefitinib or erlotinib must recover to Grade 1 or less to be eligible. 5. Major surgery within 4 weeks before starting study treatment or scheduled for surgery during the projected course of the study 6. Known hypersensitivity to afatinib or the excipients of any of the trial drugs 7. History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association classification of 3, unstable angina or poorly controlled arrhythmia as determined by the investigator. Myocardial infarction within 6 months prior to starting study treatment 8. Women of childbearing potential and men who are able to father a child, unwilling to be abstinent or use adequate contraception prior to study entry, for the duration of study participation and for at least 2 months after treatment has ended. 9. Female patients of childbearing potential who are nursing; are pregnant; are not using an acceptable method of birth control, or do not plan to continue using this method throughout the study; and do not agree to submit to pregnancy testing required by this protocol 10. 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 11. 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 12. Required treatment with any of the prohibited medications listed in this protocol that cannot be stopped for the duration of trial participation 13. Known pre-existing Interstitial Lung Disease 14. Any history or presence of poorly controlled gastrointestinal disorders that could affect the absorption of the study drug (for example, Crohn's disease, ulcerative colitis, chronic diarrhea, malabsorption) in the opinion of the investigator 15. Active hepatitis B infection (defined as the presence of Hepatitis B DNA), active hepatitis C infection (defined as the presence of Hepatitis C RNA) and/or known Human Immunodeficiency Virus carrier 16. Prior participation in a blinded afatinib clinical study, unless permission to unblind was granted in consultation with the Clinical Monitor of the blinded study 17. Meningeal carcinomatosis 18. Patients with brain or subdural metastases are not eligible, unless they have completed local therapy and have discontinued use of corticosteroids or have been on stable doses of corticosteroids for at least 4 weeks before starting study treatment. Any symptoms attributed to brain metastases must be stable for at least 4 weeks before starting study treatment 19. QTc interval \> 0.47 seconds as measured during screening procedures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Dose Limiting Toxicities | 28 days | Percentage of participants with Dose Limiting Toxicities (DLTs), based on investigator assessment, for determination of Maximum Tolerated Dose (MTD). MTD was defined as the dose in which less than 2 of up to 6 patients developed a DLT. |
| Maximum Tolerated Dose | 28 days | Maximum Tolerated Dose (MTD) was defined as the dose in which less than 2 of up to 6 patients developed a Dose Limiting Toxicity (DLT). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate for Patients With EGFR T790M Mutations | From first drug administration until last drug administration, up to 420 days | Objective response rate for patients with Epidermal Growth Factor Receptor (EGFR) T790M mutations. Objective response was defined as Complete Response (CR): Disappearance of all target lesion or Partial Response and (PR): \>=30% decrease in the sum of the longest diameter of target lesions, according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. This endpoint was originally planned to be analysed in part B of the study, however as no participants were treated in part B the analysis was performed on the part A participants. |
| Cmax of Afatinib on Day 3 of Course 1 | 47 hours (h) 55 minutes (min), 49h, 50h, 51h, 52h, 53h, 54h, 55h after first dose administration (on day 3 of course 1) | Maximum measured concentration (Cmax) of afatinib as determined on day 3 of course 1 for patients in Part A |
| Determination of Dosage for Expansion Cohort in Part B | 28 days | Determination of dosage for expansion cohort in Part B. Dosage was the MTD or less depending on tolerability. |
Countries
United States
Participant flow
Pre-assignment details
Afatinib was administered until disease progression, however patients experiencing clinical benefit were allowed to continue treatment for as long as judged beneficial by the investigator.
Participants by arm
| Arm | Count |
|---|---|
| Afatinib 90mg Patients received oral administration of afatinib 90mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle. | 6 |
| Afatinib 120mg Patients received oral administration of afatinib 120mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle. | 3 |
| Afatinib 150mg Patients received oral administration of afatinib 150mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle. | 9 |
| Afatinib 160mg Patients received oral administration of afatinib 160mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle. | 11 |
| Afatinib 200mg Patients received oral administration of afatinib 200mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle. | 6 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Other adverse event | 0 | 0 | 2 | 0 | 2 |
| Overall Study | Other reason not defined | 0 | 1 | 1 | 1 | 0 |
| Overall Study | Progressive disease | 6 | 2 | 6 | 8 | 2 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Refused to continue taking medication | 0 | 0 | 0 | 2 | 1 |
Baseline characteristics
| Characteristic | Afatinib 90mg | Afatinib 120mg | Afatinib 150mg | Afatinib 160mg | Afatinib 200mg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 65.0 Years | 58.0 Years | 65.0 Years | 61.0 Years | 62.5 Years | 64.0 Years |
| Gender Female | 2 Participants | 1 Participants | 6 Participants | 10 Participants | 5 Participants | 24 Participants |
| Gender Male | 4 Participants | 2 Participants | 3 Participants | 1 Participants | 1 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 3 / 3 | 9 / 9 | 11 / 11 | 6 / 6 | 35 / 35 |
| serious Total, serious adverse events | 1 / 6 | 1 / 3 | 7 / 9 | 4 / 11 | 1 / 6 | 14 / 35 |
Outcome results
Primary
Maximum Tolerated Dose
Maximum Tolerated Dose (MTD) was defined as the dose in which less than 2 of up to 6 patients developed a Dose Limiting Toxicity (DLT).
Time frame: 28 days
Population: Treated set including patients eligible for MTD determination
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib 90mg | Maximum Tolerated Dose | 160 mg |
Primary
Percentage of Participants With Dose Limiting Toxicities
Percentage of participants with Dose Limiting Toxicities (DLTs), based on investigator assessment, for determination of Maximum Tolerated Dose (MTD). MTD was defined as the dose in which less than 2 of up to 6 patients developed a DLT.
Time frame: 28 days
Population: Treated set including patients eligible for MTD determination
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib 90mg | Percentage of Participants With Dose Limiting Toxicities | 16.7 Percentage of participants |
| Afatinib 120mg | Percentage of Participants With Dose Limiting Toxicities | 0.0 Percentage of participants |
| Afatinib 150mg | Percentage of Participants With Dose Limiting Toxicities | 0.0 Percentage of participants |
| Afatinib 160mg | Percentage of Participants With Dose Limiting Toxicities | 0.0 Percentage of participants |
| Afatinib 200mg | Percentage of Participants With Dose Limiting Toxicities | 40.0 Percentage of participants |
Secondary
Cmax of Afatinib on Day 3 of Course 1
Maximum measured concentration (Cmax) of afatinib as determined on day 3 of course 1 for patients in Part A
Time frame: 47 hours (h) 55 minutes (min), 49h, 50h, 51h, 52h, 53h, 54h, 55h after first dose administration (on day 3 of course 1)
Population: Pharmacokinetic set which included all patients treated in part A who were documented to have taken at least one dose of afatinib and who had in addition at least one valid afatinib concentration available.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 90mg | Cmax of Afatinib on Day 3 of Course 1 | 129 ng/mL | Geometric Coefficient of Variation 46.2 |
| Afatinib 120mg | Cmax of Afatinib on Day 3 of Course 1 | 155 ng/mL | Geometric Coefficient of Variation 86.9 |
| Afatinib 150mg | Cmax of Afatinib on Day 3 of Course 1 | 311 ng/mL | Geometric Coefficient of Variation 58.8 |
| Afatinib 160mg | Cmax of Afatinib on Day 3 of Course 1 | 313 ng/mL | Geometric Coefficient of Variation 35.6 |
| Afatinib 200mg | Cmax of Afatinib on Day 3 of Course 1 | 461 ng/mL | Geometric Coefficient of Variation 50.3 |
Secondary
Determination of Dosage for Expansion Cohort in Part B
Determination of dosage for expansion cohort in Part B. Dosage was the MTD or less depending on tolerability.
Time frame: 28 days
Population: Treated set including patients eligible for MTD determination
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib 90mg | Determination of Dosage for Expansion Cohort in Part B | 150 mg |
Secondary
Objective Response Rate for Patients With EGFR T790M Mutations
Objective response rate for patients with Epidermal Growth Factor Receptor (EGFR) T790M mutations. Objective response was defined as Complete Response (CR): Disappearance of all target lesion or Partial Response and (PR): \>=30% decrease in the sum of the longest diameter of target lesions, according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. This endpoint was originally planned to be analysed in part B of the study, however as no participants were treated in part B the analysis was performed on the part A participants.
Time frame: From first drug administration until last drug administration, up to 420 days
Population: Treated set including participants with EGFR T790M positive mutations
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib 90mg | Objective Response Rate for Patients With EGFR T790M Mutations | 0.0 Percentage of participants |
| Afatinib 150mg | Objective Response Rate for Patients With EGFR T790M Mutations | 14.3 Percentage of participants |
| Afatinib 160mg | Objective Response Rate for Patients With EGFR T790M Mutations | 0.0 Percentage of participants |
| Afatinib 200mg | Objective Response Rate for Patients With EGFR T790M Mutations | 0.0 Percentage of participants |