Mesothelioma
Conditions
Brief summary
This is a phase II/III confirmatory study designed to evaluate the safety and efficacy of nintedanib (BIBF 1120) in combination + (pemetrexed / cisplatin) followed by nintedanib (BIBF 1120) versus placebo + pemetrexed / cisplatin followed by placebo for the treatment of patients with unresectable malignant pleural mesothelioma.
Interventions
DRUGNintedanib
triple kinase inhibitor; 200mg starting dose
DRUGPemetrexed
backbone chemo
DRUGCisplatin
backbone chemo
DRUGPlacebo
Nintedanib matching 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
* Histologically confirmed malignant pleural mesothelioma (MPM) (Epithelioid or biphasic subtype for Phase II patients; epithelioid subtype only for Phase III patients) * Life expectancy of at least 3 months in the opinion of the investigator * Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 * Measurable disease according to modified RECIST (Response Evaluation Criteria In Solid Tumours) criteria
Exclusion criteria
* Previous systemic chemotherapy for MPM * Prior treatment with nintedanib or any other prior line of therapy * Phase II patients with sarcomatoid subtype MPM or Phase III patients with biphasic or sarcomatoid subtype MPM * Patients with symptomatic neuropathy * Radiotherapy (except extremities) within 3 months prior to baseline imaging * Active brain metastases (e.g. stable for \< 4 weeks) * Radiographic evidence of cavitary or necrotic tumours or local invasion of major blood vessels by MPM * Significant cardiovascular diseases * Inadequate hematologic, renal, or hepatic function
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | From randomization until the earliest of disease progression, death or (Phase II: cut-off date of 4-March-2016; up to 889 days) (Phase III: cut-off date of 16-March-2018; up to 31 months) | This outcome measure presents progression-free survival. Disease progression was defined according to the modified Response Evaluation Criteria in Solid Tumours (RECIST) criteria. Progression-free survival time was calculated as the duration from the date of randomization to the date of disease progression or death, whichever occurred first. For patients with known date of progression (or death): PFS (days) = min (date of progression, date of death) - date of randomization + 1 day. For patients without progression or death, PFS was censored at the last imaging date that showed no disease progression: PFS (days, censored) = date of last imaging showing no progression - date randomization + 1 day. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomization until the earliest of disease progression, death or (Phase II: cut-off date of 4-March-2016; up to 889 days) (Phase III: cut-off date of 16-March-2018; up to 31 months) | Overall survival was defined as the duration of time from randomization to time of death. This is the key secondary endpoint of the trial. |
| Objective Response According to Modified RECIST- Investigator Assessment | Tumour imaging was to be performed every 6 weeks until disease progression, death or start of subsequent anti-cancer therapy, whichever occurred earlier; up to 54 months | Objective response (best overall tumour response of confirmed complete response \[CR\] or confirmed partial response \[PR\]). Complete Response: disappearance of all target lesions Partial Response: at least a 30 % decrease in the total tumour measurement of target lesions, taking as reference the baseline total tumour measurement. Percentage of Patients with confirmed objective response is presented. This endpoint was only evaluated for Phase III part. |
| Disease Control According to Modified RECIST- Investigator Assessment | Tumour imaging was to be performed every 6 weeks until disease progression, death or start of subsequent anti-cancer therapy, whichever occurred earlier; up to 54 months | Disease control (best overall response of confirmed CR or PR, or Stable Disease (SD) that lasted ≥36 days) according to modified RECIST. Percentage of Patients with Disease control is presented. This endpoint was only evaluated for Phase III part. |
Countries
Argentina, Australia, Austria, Belgium, Canada, Chile, Croatia, Czechia, Denmark, Egypt, France, Germany, Israel, Italy, Japan, Mexico, Netherlands, Norway, Poland, Portugal, Russia, South Africa, Spain, Sweden, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Patients were initially treated with combination therapy consisting of nintedanib or placebo plus standard chemotherapy (pemetrexed/cisplatin), for a maximum of 6 cycles of 21 days duration. After completion of combination therapy, patients who had not progressed continued with nintedanib or placebo monotherapy.
Pre-assignment details
All participants were screened for eligibility to participate in trial. Subjects attended specialist sites to ensure that they (the participants) met all implemented inclusion/exclusion criteria. Participants were not to be entered to trial if any of the specific entry criteria was violated. PD: Progressive Disease
Participants by arm
| Arm | Count |
|---|---|
| Placebo_Phase II Phase II part: Nintedanib matching placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. | 43 |
| Nintedanib_Phase II Phase II part: Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. | 44 |
| Placebo_Phase III Phase III part: Nintedanib matching Placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. | 229 |
| Nintedanib_Phase III Phase III part: Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. | 229 |
| Total | 545 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse event (AE) | 6 | 3 | 22 | 23 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 |
| Overall Study | Not treated | 2 | 0 | 1 | 2 |
| Overall Study | Other than reasons specified | 1 | 0 | 10 | 6 |
| Overall Study | PD based on modified RECIST criteria | 31 | 32 | 95 | 92 |
| Overall Study | Protocol Violation | 0 | 0 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 5 | 10 | 13 |
| Overall Study | Worsening/AE underlying cancer disease | 0 | 0 | 8 | 8 |
Baseline characteristics
| Characteristic | Nintedanib_Phase III | Total | Nintedanib_Phase II | Placebo_Phase II | Placebo_Phase III |
|---|---|---|---|---|---|
| Age, Continuous | 63.6 Years STANDARD_DEVIATION 9.5 | 64.3 Years STANDARD_DEVIATION 9.1 | 66.4 Years STANDARD_DEVIATION 8.6 | 65.9 Years STANDARD_DEVIATION 7.6 | 64.3 Years STANDARD_DEVIATION 8.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | — | 0 Participants | — | — | — |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | — | 0 Participants | — | — | — |
| Ethnicity (NIH/OMB) Unknown or Not Reported | — | 0 Participants | — | — | — |
| Race (NIH/OMB) American Indian or Alaska Native | 12 Participants | 26 Participants | 0 Participants | 0 Participants | 14 Participants |
| Race (NIH/OMB) Asian | 14 Participants | 30 Participants | 0 Participants | 0 Participants | 16 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 16 Participants | 46 Participants | 6 Participants | 5 Participants | 19 Participants |
| Race (NIH/OMB) White | 185 Participants | 441 Participants | 38 Participants | 38 Participants | 180 Participants |
| Sex: Female, Male Female | 64 Participants | 142 Participants | 10 Participants | 8 Participants | 60 Participants |
| Sex: Female, Male Male | 165 Participants | 403 Participants | 34 Participants | 35 Participants | 169 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 25 / 43 | 22 / 44 | 63 / 229 | 64 / 229 |
| other Total, other adverse events | 41 / 41 | 44 / 44 | 219 / 228 | 218 / 227 |
| serious Total, serious adverse events | 17 / 41 | 16 / 44 | 89 / 228 | 99 / 227 |
Outcome results
Primary
Progression-Free Survival (PFS)
This outcome measure presents progression-free survival. Disease progression was defined according to the modified Response Evaluation Criteria in Solid Tumours (RECIST) criteria. Progression-free survival time was calculated as the duration from the date of randomization to the date of disease progression or death, whichever occurred first. For patients with known date of progression (or death): PFS (days) = min (date of progression, date of death) - date of randomization + 1 day. For patients without progression or death, PFS was censored at the last imaging date that showed no disease progression: PFS (days, censored) = date of last imaging showing no progression - date randomization + 1 day.
Time frame: From randomization until the earliest of disease progression, death or (Phase II: cut-off date of 4-March-2016; up to 889 days) (Phase III: cut-off date of 16-March-2018; up to 31 months)
Population: Randomised Set: This patient set included all randomized patients.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Progression-Free Survival (PFS) | Phase II | 5.72 Months |
| Placebo | Progression-Free Survival (PFS) | Phase III | 6.97 Months |
| Nintedanib | Progression-Free Survival (PFS) | Phase II | 9.36 Months |
| Nintedanib | Progression-Free Survival (PFS) | Phase III | 6.77 Months |
Comparison: Phase II Partp-value: 0.017495% CI: [0.34, 0.907]Proportional hazards mode
Comparison: Phase III part:~A Cox proportional hazards model was fitted to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the comparison of treatment arms (Nintedanib vs Placebo).~If the hazard ratio is below 1 then it favours nintedanib.p-value: 0.54395% CI: [0.79, 1.3]Proportional hazards model
Secondary
Disease Control According to Modified RECIST- Investigator Assessment
Disease control (best overall response of confirmed CR or PR, or Stable Disease (SD) that lasted ≥36 days) according to modified RECIST. Percentage of Patients with Disease control is presented. This endpoint was only evaluated for Phase III part.
Time frame: Tumour imaging was to be performed every 6 weeks until disease progression, death or start of subsequent anti-cancer therapy, whichever occurred earlier; up to 54 months
Population: Randomised Set: This patient set included all randomized patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Disease Control According to Modified RECIST- Investigator Assessment | 92.6 Percentage of participants |
| Nintedanib | Disease Control According to Modified RECIST- Investigator Assessment | 90.8 Percentage of participants |
p-value: 0.751295% CI: [0.4, 1.55]Regression, Logistic
Secondary
Objective Response According to Modified RECIST- Investigator Assessment
Objective response (best overall tumour response of confirmed complete response \[CR\] or confirmed partial response \[PR\]). Complete Response: disappearance of all target lesions Partial Response: at least a 30 % decrease in the total tumour measurement of target lesions, taking as reference the baseline total tumour measurement. Percentage of Patients with confirmed objective response is presented. This endpoint was only evaluated for Phase III part.
Time frame: Tumour imaging was to be performed every 6 weeks until disease progression, death or start of subsequent anti-cancer therapy, whichever occurred earlier; up to 54 months
Population: Randomised Set: This patient set included all randomized patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Objective Response According to Modified RECIST- Investigator Assessment | 42.8 Percentage of participants |
| Nintedanib | Objective Response According to Modified RECIST- Investigator Assessment | 45.0 Percentage of participants |
p-value: 0.318995% CI: [0.76, 1.58]Regression, Logistic
Secondary
Overall Survival (OS)
Overall survival was defined as the duration of time from randomization to time of death. This is the key secondary endpoint of the trial.
Time frame: From randomization until the earliest of disease progression, death or (Phase II: cut-off date of 4-March-2016; up to 889 days) (Phase III: cut-off date of 16-March-2018; up to 31 months)
Population: Randomised Set: This patient set included all randomized patients.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Overall Survival (OS) | Phase II | 14.46 Months |
| Placebo | Overall Survival (OS) | Phase III | 16.07 Months |
| Nintedanib | Overall Survival (OS) | Phase II | 18.30 Months |
| Nintedanib | Overall Survival (OS) | Phase III | 14.36 Months |
Comparison: Phase IIp-value: 0.413295% CI: [0.433, 1.412]Proportional hazards mode
Comparison: Phase III:~A Cox proportional hazards model was fitted to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the comparison of treatment arms (Nintedanib vs Placebo).~If the hazard ratio is below 1 then it favours nintedanib.p-value: 0.730695% CI: [0.79, 1.58]Proportional hazards model