Colorectal Neoplasms
Conditions
Brief summary
The objective of this Phase III study is to evaluate the efficacy of nintedanib in patients with metastatic colorectal cancer (mCRC) after failure of previous treatment with standard chemotherapy and biological agents.
Interventions
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
* Age \>= 18 years * Signed informed consent * Histologically or cytologically confirmed colorectal adenocarcinoma * Metastatic or locally advanced disease not amenable to curative surgery and/or radiotherapy * Eastern Cooperative Oncology Group (ECOG) performance status = 1 * At least one measurable lesion according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 * Progression on standard therapies or withdrawn from standard treatment due to unacceptable toxicity. Previous standard treatment must include all of the following: * \- fluoropyrimidine * \- oxaliplatin: Patients treated with oxaliplatin in adjuvant setting should have progressed within 6 months of completion of adjuvant therapy or they must have been treated with oxaliplatin for metastatic disease * \- irinotecan * \- bevacizumab or aflibercept * \- cetuximab or panitumumab for patients with K-Ras wt or Ras wt tumours * \- The remaining standard available therapy as recommended by investigator is best supportive care (note: previous treatment with regorafenib and TAS 102 are allowed and these agents should be administered before study if available to patient according to local standards) * \- Life expectancy of at least 12 weeks * \- Hepatic function: aspartate aminotransferase (AST)/ Alanine Amino Transferase (ALT) = 1.5 X Upper Limit of Normal (ULN) and bilirubin = ULN for patients without liver metastases. AST/ALT = 2.5 X ULN and bilirubin = ULN for patients with liver metastases. Patients with Gilbert syndrome and bilirubin \< 2 X ULN and normal AST/ALT are eligible * Coagulation parameters: International normalised ratio (INR) \< 2 and partial prothrombin Time (PTT) = 2xULN
Exclusion criteria
* Previous treatment with nintedanib * toxicity attributed to previous anticancer therapy that did not resolve to Common Terminology Criteria for Adverse Events (CTCAE) grade =1 * History of other malignancies in the last 5 years, in particular those that could interfere with interpretation of results. * Serious concomitant disease or medical condition affecting compliance with trial requirements or which are considered relevant for the evaluation of the efficacy or safety of the trial drug, * Significant cardiovascular diseases * History of severe haemorrhagic or thromboembolic event in the past 12 months * Bleeding or thrombotic disorders requiring anticoagulant therapy such as warfarin, or similar agents requiring therapeutic INR monitoring * Gastrointestinal disorders or abnormalities that would interfere with absorption of study drug * Patient with brain metastases that are symptomatic and/or require therapy. * Patients of childbearing potential who are sexually active and unwilling to use a highly effective method of contraception * Pregnancy or breast-feeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) by Central Review Assessment | From randomisation until cut-off date 14JUN2016. | PFS by central review assessment was defined as the time from the date of randomisation to the date of disease progression according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 or death from any cause, whichever occurred first. Median, 95% Confidence Interval were calculated from an unadjusted Kaplan-Meier curve for each treatment arm. |
| Overall Survival (OS) | From randomisation until cut-off date 14JUN2016. | OS was defined as the time from randomisation to the time of death from any cause. Median, 95% Confidence Interval were calculated from an unadjusted Kaplan-Meier curve for each treatment arm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Tumour Response (Complete Response (CR)) + Partial Response (PR) by Central Review Assessment | From randomisation until cut-off date 14JUN2016. | Objective tumour response was defined as best overall response of CR or PR determined by central review assessment. |
| Disease Control (Complete Response + Partial Response + Stable Disease) by Central Review Assessment | From randomisation until cut-off date 14JUN2016. | Disease control was defined as best overall response of CR, PR, or Stable Disease (SD). |
Countries
Argentina, Australia, Austria, Belgium, Canada, Czechia, Denmark, France, Germany, Hong Kong, Israel, Italy, Japan, Mexico, Netherlands, Poland, Portugal, Russia, South Korea, Spain, Sweden, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
The completed patients were on treatment (2 patients on Placebo, 3 patients on Nintedanib) at the data cut-off date 14JUN2016. The NOT Completed patients were off-treatment (380 patients on Placebo, 383 patients on Nintedanib) at the data cut-off date 14JUN2016.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo soft gelatin capsule matching that of Nintedanib twice daily (b.i.d.) administered orally of 21-day treatment course. 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. | 382 |
| Nintedanib Nintedanib 200 mg twice daily (b.i.d.) administered orally in the form of a soft gelatin capsule of 21-day treatment course. 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. | 386 |
| Total | 768 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Not treated | 1 | 2 |
| Overall Study | Other Adverse Event (AE) | 8 | 18 |
| Overall Study | Other not defined above | 0 | 2 |
| Overall Study | Progressive Disease (PD) | 324 | 318 |
| Overall Study | Refusal to continue trial medication | 15 | 11 |
| Overall Study | Worsening/adverse event cancer disease | 31 | 32 |
Baseline characteristics
| Characteristic | Placebo | Nintedanib | Total |
|---|---|---|---|
| Age, Continuous | 61.1 Years STANDARD_DEVIATION 10.8 | 61.0 Years STANDARD_DEVIATION 11.3 | 61.1 Years STANDARD_DEVIATION 11 |
| Sex: Female, Male Female | 164 Participants | 150 Participants | 314 Participants |
| Sex: Female, Male Male | 218 Participants | 236 Participants | 454 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 309 / 381 | 351 / 384 |
| serious Total, serious adverse events | 133 / 381 | 149 / 384 |
Outcome results
Primary
Overall Survival (OS)
OS was defined as the time from randomisation to the time of death from any cause. Median, 95% Confidence Interval were calculated from an unadjusted Kaplan-Meier curve for each treatment arm.
Time frame: From randomisation until cut-off date 14JUN2016.
Population: Randomised Set: This patient set included all patients who were randomised to receive treatment, whether treated or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Overall Survival (OS) | 6.05 Months |
| Nintedanib | Overall Survival (OS) | 6.44 Months |
p-value: 0.865995% CI: [0.86, 1.19]Log Rank
Primary
Progression-Free Survival (PFS) by Central Review Assessment
PFS by central review assessment was defined as the time from the date of randomisation to the date of disease progression according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 or death from any cause, whichever occurred first. Median, 95% Confidence Interval were calculated from an unadjusted Kaplan-Meier curve for each treatment arm.
Time frame: From randomisation until cut-off date 14JUN2016.
Population: Randomised Set: This patient set included all patients who were randomised to receive treatment, whether treated or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Progression-Free Survival (PFS) by Central Review Assessment | 1.38 Months |
| Nintedanib | Progression-Free Survival (PFS) by Central Review Assessment | 1.51 Months |
p-value: <0.000195% CI: [0.49, 0.69]Log Rank
Secondary
Disease Control (Complete Response + Partial Response + Stable Disease) by Central Review Assessment
Disease control was defined as best overall response of CR, PR, or Stable Disease (SD).
Time frame: From randomisation until cut-off date 14JUN2016.
Population: Randomised Set: This patient set included all patients who were randomised to receive treatment, whether treated or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Disease Control (Complete Response + Partial Response + Stable Disease) by Central Review Assessment | 10.5 Percentage of participants |
| Nintedanib | Disease Control (Complete Response + Partial Response + Stable Disease) by Central Review Assessment | 25.6 Percentage of participants |
p-value: <0.000195% CI: [2, 4.47]Regression, Logistic
Secondary
Objective Tumour Response (Complete Response (CR)) + Partial Response (PR) by Central Review Assessment
Objective tumour response was defined as best overall response of CR or PR determined by central review assessment.
Time frame: From randomisation until cut-off date 14JUN2016.
Population: Randomised Set: This patient set included all patients who were randomised to receive treatment, whether treated or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Objective Tumour Response (Complete Response (CR)) + Partial Response (PR) by Central Review Assessment | 0 Percentage of participants |
| Nintedanib | Objective Tumour Response (Complete Response (CR)) + Partial Response (PR) by Central Review Assessment | 0 Percentage of participants |