Carcinoma, Non-Small-Cell Lung
Conditions
Brief summary
The LUME-Lung3 study is in 2 parts: Run-in Phase I - Open label study to identify the Maximum Tolerated Dose of BIBF 1120 that can be added to standard first-line treatment with 3 weekly schedules of gemcitabine and cisplatin. Phase II - Placebo controlled efficacy study of BIBF 1120 added to standard 3 weekly cycles of gemcitabine and cisplatin therapy in patients with at least Stable Disease after 2 previous courses of the chemotherapy
Interventions
DRUGBIBF 1120
VEGF inhibitor
DRUGPlacebo
BIBF 1120 placebo
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Run-in Phase I 1. Histologically or cytologically confirmed diagnosis of stage IIIB/IV or recurrent Non Small Cell Lung Cancer (NSCLC) with squamous cell histology. 2. Measurable disease according to Response Evaluation Criteria in Solid Tumours ( RECIST 1.1). 3. Patient Eastern Cooperative Oncology Group (ECOG) score of 0-1. 4. Male or female patients age = 18 years. 5. Life expectancy of at least three (3) months. 6. Written informed consent in accordance with International Conference on Harmonisation - Good Clinical Practice (ICH-GCP) guidelines. Phase II - in addition to the above criteria: 7. Radiologically-confirmed at least stable disease after 2 prior cycles of cisplatin / gemcitabine chemotherapy.
Exclusion criteria
1. Prior therapy for advanced or metastatic or recurrent Non Small Cell Lung Cancer (NSCLC). One prior adjuvant, neoadjuvant or adjuvant + neoadjuvant treatment is allowed if at least 12 months have elapsed between the end of the treatment and randomization 2. Prior treatment with other Vascular Endothelial Growth Factor Receptor (VEGFR) inhibitors (other than bevacizumab) 3. Any contraindications for treatment with gemcitabine and/or cisplatin. 4. Use of any investigational drug within 4 weeks of entering the 1199.82 study. 5. History of major thrombotic or clinically relevant bleeding event in the past 6 months. 6. Significant cardiovascular diseases (i.e. hypertension not controlled by medication. 7. Surgery within 4 weeks (except tumour biopsy) prior randomisation and incomplete wound healing. 8. Active brain metastases 9. Radiotherapy (except extremities) within 3 months prior to baseline imaging and radiotherapy for brain metastasis \< 4 weeks prior baseline imaging. 10. Any other current malignancy or malignancy diagnosed within the past five (5) years.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLTs) During First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | Up to 21 days from first drug administration | The following drug-related adverse events (AEs) qualified as a DLT: Non-hematological toxicity - Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥3 events excluding transient electrolyte abnormality, hyperuricemia and isolated elevation of gamma-glutamyl trans-peptidase. Gastrointestinal AEs (nausea, vomiting, diarrhoea, abdominal pain) or hypertension of CTCAE Grade ≥3 despite optimal supportive care/intervention. Alanine aminotransferase and or Aspartate aminotransferase elevation of CTCAE Grade ≥3. Haematological toxicity - Uncomplicated CTCAE Grade 4 neutropenia (that was not associated with fever of ≥38.5° Celsius) for \>7 days (except during Cycle 1). CTCAE Grade 4 febrile neutropenia associated with fever ≥38.5º Celsius. A decrease in platelet levels to CTCAE Grade 4 or CTCAE Grade 3 associated with bleeding or requiring transfusion. The inability to resume nintedanib dosing within 14 days of stopping due to a drug-related AE was also considered a DLT. |
| Maximum Tolerated Dose (MTD) of Nintedanib Added to Cisplatin/Gemcitabine Based on the Occurrence of DLTs During Treatment Cycle 1. | Up to 21 days from first drug administration | The MTD was defined as the dose of nintedanib administered with gemcitabine/cisplatin at which no more than 1 of 6 patients experienced DLT (or one dose tier below that dose at which 2 or more of 6 patients experienced DLT) during the first 21-day treatment cycle. Any DLTs experienced after the start of the second treatment period were considered separately. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events (AEs) According to the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.00 | From the first drug administration until 28 days after last study drug administration, up to 804 days | Incidence of adverse events (AEs) according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.00 with grade 1-5. |
Countries
Italy, Netherlands, Spain, United Kingdom
Participant flow
Pre-assignment details
Phase I was open-label, 3+3 dose-confirmation part of the trial aimed to confirm safety of nintedanib to a maximum dose of 200 milligram twice daily given in combination with the standard regimen of gemcitabine and cisplatin. Phase II was to be double-blind, randomised, placebo-controlled part, but this part of the trial was not conducted.
Participants by arm
| Arm | Count |
|---|---|
| Nintedanib 150 Milligram Patient received 150 milligram (mg) Nintedanib (BIBF 1120) soft gelatin capsules, administered orally twice daily until withdrawal criteria were fulfilled along with standard therapy of Gemcitabine and Cisplatin. Gemcitabine was administered as an intravenous infused dose of 1250 milligram per meter squared (mg/m2) on days 1 and 8 of each 21-day treatment cycle. Cisplatin was administered as an intravenous infused dose of 75 mg/m2 given on day 1 of each 21-day treatment cycle. | 4 |
| Nintedanib 200 Milligram Patient received 200 milligram (mg) Nintedanib (BIBF 1120) soft gelatin capsules, administered orally twice daily until withdrawal criteria were fulfilled along with standard therapy of Gemcitabine and Cisplatin. Gemcitabine was administered as an intravenous infused dose of 1250 milligram per meter squared (mg/m2) on days 1 and 8 of each 21-day treatment cycle. Cisplatin was administered as an intravenous infused dose of 75 mg/m2 given on day 1 of each 21-day treatment cycle. | 12 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 4 |
| Overall Study | Progressive disease-RECIST 1.1 criteria | 3 | 8 |
Baseline characteristics
| Characteristic | Nintedanib 150 Milligram | Nintedanib 200 Milligram | Total |
|---|---|---|---|
| Age, Continuous | 64.5 Years STANDARD_DEVIATION 10.9 | 65.7 Years STANDARD_DEVIATION 5 | 65.4 Years STANDARD_DEVIATION 6.5 |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 4 Participants | 11 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 4 | 12 / 12 |
| serious Total, serious adverse events | 2 / 4 | 5 / 12 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of Nintedanib Added to Cisplatin/Gemcitabine Based on the Occurrence of DLTs During Treatment Cycle 1.
The MTD was defined as the dose of nintedanib administered with gemcitabine/cisplatin at which no more than 1 of 6 patients experienced DLT (or one dose tier below that dose at which 2 or more of 6 patients experienced DLT) during the first 21-day treatment cycle. Any DLTs experienced after the start of the second treatment period were considered separately.
Time frame: Up to 21 days from first drug administration
Population: All patients who received at least one dose of nintedanib were included in the Safety Set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nintedanib 150 Milligram | Maximum Tolerated Dose (MTD) of Nintedanib Added to Cisplatin/Gemcitabine Based on the Occurrence of DLTs During Treatment Cycle 1. | 200 Milligram |
Primary
Number of Participants With Dose Limiting Toxicities (DLTs) During First Cycle for the Determination of the Maximum Tolerated Dose (MTD)
The following drug-related adverse events (AEs) qualified as a DLT: Non-hematological toxicity - Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥3 events excluding transient electrolyte abnormality, hyperuricemia and isolated elevation of gamma-glutamyl trans-peptidase. Gastrointestinal AEs (nausea, vomiting, diarrhoea, abdominal pain) or hypertension of CTCAE Grade ≥3 despite optimal supportive care/intervention. Alanine aminotransferase and or Aspartate aminotransferase elevation of CTCAE Grade ≥3. Haematological toxicity - Uncomplicated CTCAE Grade 4 neutropenia (that was not associated with fever of ≥38.5° Celsius) for \>7 days (except during Cycle 1). CTCAE Grade 4 febrile neutropenia associated with fever ≥38.5º Celsius. A decrease in platelet levels to CTCAE Grade 4 or CTCAE Grade 3 associated with bleeding or requiring transfusion. The inability to resume nintedanib dosing within 14 days of stopping due to a drug-related AE was also considered a DLT.
Time frame: Up to 21 days from first drug administration
Population: All patients who received at least one dose of nintedanib were included in the Safety Set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nintedanib 150 Milligram | Number of Participants With Dose Limiting Toxicities (DLTs) During First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 0 Participants |
| Nintedanib 200 Milligram | Number of Participants With Dose Limiting Toxicities (DLTs) During First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | 0 Participants |
Secondary
Incidence of Adverse Events (AEs) According to the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.00
Incidence of adverse events (AEs) according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.00 with grade 1-5.
Time frame: From the first drug administration until 28 days after last study drug administration, up to 804 days
Population: Treated Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nintedanib 150 Milligram | Incidence of Adverse Events (AEs) According to the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.00 | Grade 1 | 0 Participants |
| Nintedanib 150 Milligram | Incidence of Adverse Events (AEs) According to the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.00 | Grade 4 | 3 Participants |
| Nintedanib 150 Milligram | Incidence of Adverse Events (AEs) According to the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.00 | Grade 3 | 1 Participants |
| Nintedanib 150 Milligram | Incidence of Adverse Events (AEs) According to the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.00 | Grade 5 | 0 Participants |
| Nintedanib 150 Milligram | Incidence of Adverse Events (AEs) According to the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.00 | Grade 2 | 0 Participants |
| Nintedanib 200 Milligram | Incidence of Adverse Events (AEs) According to the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.00 | Grade 5 | 2 Participants |
| Nintedanib 200 Milligram | Incidence of Adverse Events (AEs) According to the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.00 | Grade 2 | 0 Participants |
| Nintedanib 200 Milligram | Incidence of Adverse Events (AEs) According to the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.00 | Grade 1 | 0 Participants |
| Nintedanib 200 Milligram | Incidence of Adverse Events (AEs) According to the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.00 | Grade 3 | 8 Participants |
| Nintedanib 200 Milligram | Incidence of Adverse Events (AEs) According to the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.00 | Grade 4 | 2 Participants |