Colorectal Neoplasms
Conditions
Brief summary
The objective of this trial is to evaluate the safety and tolerability of BI 695502 in combination with leucovorin/5-fluorouracil/oxaliplatin (mFOLFOX6) and as maintenance therapy (when applicable). As well as to evaluate the following efficacy parameters: Progression-free survival (PFS), objective response rate (proportion of patients with complete response \[CR\] plus partial response \[PR\]), overall survival (OS), duration of response (DOR), time to progression (TTP).
Interventions
DRUGBI 695502
DRUGAvastin
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
* Males and females aged \>=18 years (for Japan only: Age \>=20 years at time of signing Informed Consent Form) with histologically confirmed metastatic colorectal cancer (mCRC). * Metastatic disease not amenable to surgical curative treatment and eligible to receive therapy with mFOLFOX6 (Leucovorin/5-Fluorouracil/Oxaliplatin) + bevacizumab. * At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. * Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. * Adequate hepatic, renal and bone marrow function. * Further inclusion criteria apply.
Exclusion criteria
* Prior systemic therapy for metastatic disease * Prior therapy with monoclonal antibodies or small molecule inhibitors against Vascular endothelial growth factor (VEGF) or VEGF receptors, including Avastin® or Avastin® biosimilar * Previous malignancy other than Colorectal cancer (CRC) in the last 5 years except for basal cell cancer of the skin or pre-invasive cancer of the cervix * Spinal cord compression or brain metastases unless asymptomatic, stable and not requiring steroids for at least 6 weeks prior to start of study treatment * Any unresolved toxicity \> Common Toxicity Criteria Grade 1 (except alopecia) from previous anticancer therapy (including radiotherapy) * History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding * A thrombotic or hemorrhagic event \<=6 months prior to screening (includes hemoptysis, Gastrointestinal (GI) bleeding, hematemesis, central nervous system hemorrhage, epistaxis, vaginal bleeding, cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and coronary artery disease) * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Treatment-Emergent Adverse Events (TEAEs) in the Specified Categories Selected for Primary Endpoint Assessment | From baseline up to 18 weeks after the last dose of trial medication prior to the Switch Visit. Maximum duration of up to 32 treatment cycles + safety follow up (up to 82 weeks overall). | The primary safety endpoint of the trial was patients with any of the following selected adverse events (AEs): * Infusion reactions (anaphylactic/hypersensitivity/infusion-related reactions), * Thromboembolic events (arterial or venous), * Gastrointestinal perforations, * Hypertension, * Proteinuria, * Pulmonary hemorrhage * All hemorrhages (including pulmonary hemorrhages) * Wound-healing complications/abscess/fistulas * Posterior reversible encephalopathy syndrome * Ovarian failure. All AEs with an onset between start of treatment and end of the residual effect period (REP), a period of 18 weeks after the last dose of trial medication were considered for the primary safety analysis. Confidence interval was calculated using Wilson score method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) as Assessed by Central Imaging Review | Tumor scans were performed at baseline then every ~8 weeks up to 34 weeks, then every ~12 weeks thereafter until confirmed disease progression. Analysis performed for the pre-switch period only; maximum duration of up to 32 treatment cycles (64 weeks). | DOR was the time from first documented Complete Response (CR) (CR is disappearance of all target lesions) or Partial Response (PR) (PR is at least a 30% decrease in the sum of diameters (SoD) of target lesions taking as reference the baseline sum diameters) until time of progression as assessed by central imaging review per Response evaluation criteria in solid tumors (RECIST) 1.1. RECIST is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize) or worsen (progress) during treatment. DOR was calculated using the Kaplan-Meier technique. Confidence interval was calculated based on the Brookmeyer and Crowley method. |
| Time to Progression (TTP) as Assessed by Central Imaging Review | Tumor scans were performed at baseline then every ~8 weeks up to 34 weeks, then every ~12 weeks thereafter until confirmed disease progression. Analysis performed for the pre-switch period only; maximum duration of up to 32 treatment cycles (64 weeks). | TTP was defined as the time from first administration of trial medication to the date of tumor progression as assessed by central imaging review per RECIST 1.1 (RECIST is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize) or worsen (progress) during treatment.). TTP was calculated using the Kaplan-Meier technique. Confidence interval was calculated based on the Brookmeyer and Crowley method. |
| Objective Response (OR) Rate as Assessed by Central Imaging Review | Tumor scans were performed at baseline then every ~8 weeks up to 34 weeks, then every ~12 weeks thereafter until confirmed disease progression. Analysis performed for the pre-switch period only; maximum duration of up to 32 treatment cycles (64 weeks). | OR rate was defined as the percentage of patients who achieved at least one visit response of CR (CR is disappearance of all target lesions) or PR (PR is at least a 30% decrease in the sum of diameters (SoD) of target lesions taking as reference the baseline sum diameters) after the start of treatment. The response criteria evaluation was carried out according to RECIST 1.1. RECIST is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize) or worsen (progress) during treatment. Confidence interval was calculated using Wilson score method. The definition for OR (CR/PR) extends until disease progression/ death/ unacceptable toxicity/ end of the trial, whichever occurred earlier. However for Duration of response this censoring does not apply. Hence the apparent discrepancy. OR = CR + PR. |
| Overall Survival (OS) Time | From date of first dose of trial medication until last date of trial medication + 18 weeks (REP), up to a maximum of 32 treatment cycles + safety follow up (up to 82 weeks overall). | OS was defined as the time from first administration of trial medication until death from any cause. OS was calculated using the Kaplan-Meier technique. Confidence interval was calculated based on the Brookmeyer and Crowley method. |
| Progression-Free Survival (PFS) Time as Assessed by Central Imaging Review | Tumor scans were performed at baseline then every ~8 weeks up to 34 weeks, then every ~12 weeks thereafter until confirmed disease progression. Analysis performed for the pre-switch period only; maximum duration of up to 32 treatment cycles (64 weeks). | PFS was defined as the time from first administration of trial medication until disease progression as assessed by central imaging review or death due to any cause. Disease progression was assessed according to RECIST 1.1. RECIST is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize) or worsen (progress) during treatment. Progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. PFS was calculated using the Kaplan-Meier technique. Confidence interval was calculated based on the Brookmeyer and Crowley method. |
Countries
Japan, Spain, Ukraine, United States
Participant flow
Recruitment details
This was Phase IIIb, open-label, multicenter, multinational, single-arm trial. Patients with previously untreated metastatic colorectal cancer (mCRC) were enrolled. From 21December2017, Sponsor recommended that patients should be switched from BI 695502 to the reference product Avastin® as soon as it was available at the respective clinical site.
Pre-assignment details
All patients were screened for eligibility to participate in the trial. Patients attended specialist sites which would then ensure that they (the patient) met all strictly implemented inclusion/exclusion criteria. Patients were not to be randomised to trial treatment if any one of the specific entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| BI 695502 All patients were to receive BI 695502 (5 milligrams per kilogram \[mg/kg\]) solution for intravenous (i.v.) infusion in combination with mFOLFOX6 chemotherapy every 2 weeks. Patients were to continue to receive treatment during the pre-switch period until disease progression, death, unacceptable toxicity, or the end of the trial, whichever occurred earlier. Based on patient tolerability, at least 8 cycles of mFOLFOX6 were to be given to all patients. | 123 |
| Total | 123 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Post-switch Period | Adverse Event | 0 | 3 |
| Post-switch Period | Other than listed | 0 | 15 |
| Post-switch Period | Physician Decision | 0 | 3 |
| Post-switch Period | Progressive disease | 0 | 20 |
| Post-switch Period | Withdrawal by Subject | 0 | 2 |
| Pre-switch Period | Adverse Event | 21 | 0 |
| Pre-switch Period | Other than listed | 3 | 0 |
| Pre-switch Period | Physician Decision | 7 | 0 |
| Pre-switch Period | Progressive disease | 39 | 0 |
| Pre-switch Period | Protocol Violation | 1 | 0 |
| Pre-switch Period | Withdrawal by Subject | 9 | 0 |
Baseline characteristics
| Characteristic | BI 695502 |
|---|---|
| Age, Continuous | 58.0 Years STANDARD_DEVIATION 11.87 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 106 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 33 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 82 Participants |
| Sex: Female, Male Female | 55 Participants |
| Sex: Female, Male Male | 68 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 41 / 123 |
| other Total, other adverse events | 118 / 123 |
| serious Total, serious adverse events | 33 / 123 |
Outcome results
Primary
Percentage of Patients With Treatment-Emergent Adverse Events (TEAEs) in the Specified Categories Selected for Primary Endpoint Assessment
The primary safety endpoint of the trial was patients with any of the following selected adverse events (AEs): * Infusion reactions (anaphylactic/hypersensitivity/infusion-related reactions), * Thromboembolic events (arterial or venous), * Gastrointestinal perforations, * Hypertension, * Proteinuria, * Pulmonary hemorrhage * All hemorrhages (including pulmonary hemorrhages) * Wound-healing complications/abscess/fistulas * Posterior reversible encephalopathy syndrome * Ovarian failure. All AEs with an onset between start of treatment and end of the residual effect period (REP), a period of 18 weeks after the last dose of trial medication were considered for the primary safety analysis. Confidence interval was calculated using Wilson score method.
Time frame: From baseline up to 18 weeks after the last dose of trial medication prior to the Switch Visit. Maximum duration of up to 32 treatment cycles + safety follow up (up to 82 weeks overall).
Population: Treated set (TS): The TS contained all patients who signed informed consent and who received at least one dose of trial medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BI 695502 | Percentage of Patients With Treatment-Emergent Adverse Events (TEAEs) in the Specified Categories Selected for Primary Endpoint Assessment | Patients with any of the selected AEs | 58.5 Percentage of participants (%) |
| BI 695502 | Percentage of Patients With Treatment-Emergent Adverse Events (TEAEs) in the Specified Categories Selected for Primary Endpoint Assessment | Infusion reactions | 18.7 Percentage of participants (%) |
| BI 695502 | Percentage of Patients With Treatment-Emergent Adverse Events (TEAEs) in the Specified Categories Selected for Primary Endpoint Assessment | Thromboembolic events | 12.2 Percentage of participants (%) |
| BI 695502 | Percentage of Patients With Treatment-Emergent Adverse Events (TEAEs) in the Specified Categories Selected for Primary Endpoint Assessment | Gastrointestinal perforations | 2.4 Percentage of participants (%) |
| BI 695502 | Percentage of Patients With Treatment-Emergent Adverse Events (TEAEs) in the Specified Categories Selected for Primary Endpoint Assessment | Hypertension | 28.5 Percentage of participants (%) |
| BI 695502 | Percentage of Patients With Treatment-Emergent Adverse Events (TEAEs) in the Specified Categories Selected for Primary Endpoint Assessment | Proteinuria | 9.8 Percentage of participants (%) |
| BI 695502 | Percentage of Patients With Treatment-Emergent Adverse Events (TEAEs) in the Specified Categories Selected for Primary Endpoint Assessment | Pulmonary Haemorrhage | 0.00 Percentage of participants (%) |
| BI 695502 | Percentage of Patients With Treatment-Emergent Adverse Events (TEAEs) in the Specified Categories Selected for Primary Endpoint Assessment | Hemorrhages | 22.80 Percentage of participants (%) |
| BI 695502 | Percentage of Patients With Treatment-Emergent Adverse Events (TEAEs) in the Specified Categories Selected for Primary Endpoint Assessment | Wound-healing complications | 1.6 Percentage of participants (%) |
| BI 695502 | Percentage of Patients With Treatment-Emergent Adverse Events (TEAEs) in the Specified Categories Selected for Primary Endpoint Assessment | Reversible Encephalopathy Syndrome | 0.0 Percentage of participants (%) |
| BI 695502 | Percentage of Patients With Treatment-Emergent Adverse Events (TEAEs) in the Specified Categories Selected for Primary Endpoint Assessment | Ovarian failure | 0.00 Percentage of participants (%) |
Secondary
Duration of Response (DOR) as Assessed by Central Imaging Review
DOR was the time from first documented Complete Response (CR) (CR is disappearance of all target lesions) or Partial Response (PR) (PR is at least a 30% decrease in the sum of diameters (SoD) of target lesions taking as reference the baseline sum diameters) until time of progression as assessed by central imaging review per Response evaluation criteria in solid tumors (RECIST) 1.1. RECIST is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize) or worsen (progress) during treatment. DOR was calculated using the Kaplan-Meier technique. Confidence interval was calculated based on the Brookmeyer and Crowley method.
Time frame: Tumor scans were performed at baseline then every ~8 weeks up to 34 weeks, then every ~12 weeks thereafter until confirmed disease progression. Analysis performed for the pre-switch period only; maximum duration of up to 32 treatment cycles (64 weeks).
Population: TS: The TS contained all patients who signed informed consent and who received at least one dose of trial medication. Only patients with complete or partial objective response were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BI 695502 | Duration of Response (DOR) as Assessed by Central Imaging Review | 9.1 Months |
Secondary
Objective Response (OR) Rate as Assessed by Central Imaging Review
OR rate was defined as the percentage of patients who achieved at least one visit response of CR (CR is disappearance of all target lesions) or PR (PR is at least a 30% decrease in the sum of diameters (SoD) of target lesions taking as reference the baseline sum diameters) after the start of treatment. The response criteria evaluation was carried out according to RECIST 1.1. RECIST is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize) or worsen (progress) during treatment. Confidence interval was calculated using Wilson score method. The definition for OR (CR/PR) extends until disease progression/ death/ unacceptable toxicity/ end of the trial, whichever occurred earlier. However for Duration of response this censoring does not apply. Hence the apparent discrepancy. OR = CR + PR.
Time frame: Tumor scans were performed at baseline then every ~8 weeks up to 34 weeks, then every ~12 weeks thereafter until confirmed disease progression. Analysis performed for the pre-switch period only; maximum duration of up to 32 treatment cycles (64 weeks).
Population: TS: The TS contained all patients who signed informed consent and who received at least one dose of trial medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BI 695502 | Objective Response (OR) Rate as Assessed by Central Imaging Review | 61.0 Percentage of participants |
Secondary
Overall Survival (OS) Time
OS was defined as the time from first administration of trial medication until death from any cause. OS was calculated using the Kaplan-Meier technique. Confidence interval was calculated based on the Brookmeyer and Crowley method.
Time frame: From date of first dose of trial medication until last date of trial medication + 18 weeks (REP), up to a maximum of 32 treatment cycles + safety follow up (up to 82 weeks overall).
Population: TS: The TS contained all patients who signed informed consent and who received at least one dose of trial medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BI 695502 | Overall Survival (OS) Time | 19.4 Months |
Secondary
Progression-Free Survival (PFS) Time as Assessed by Central Imaging Review
PFS was defined as the time from first administration of trial medication until disease progression as assessed by central imaging review or death due to any cause. Disease progression was assessed according to RECIST 1.1. RECIST is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize) or worsen (progress) during treatment. Progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. PFS was calculated using the Kaplan-Meier technique. Confidence interval was calculated based on the Brookmeyer and Crowley method.
Time frame: Tumor scans were performed at baseline then every ~8 weeks up to 34 weeks, then every ~12 weeks thereafter until confirmed disease progression. Analysis performed for the pre-switch period only; maximum duration of up to 32 treatment cycles (64 weeks).
Population: TS: The TS contained all patients who signed informed consent and who received at least one dose of trial medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BI 695502 | Progression-Free Survival (PFS) Time as Assessed by Central Imaging Review | 10.5 Months |
Secondary
Time to Progression (TTP) as Assessed by Central Imaging Review
TTP was defined as the time from first administration of trial medication to the date of tumor progression as assessed by central imaging review per RECIST 1.1 (RECIST is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize) or worsen (progress) during treatment.). TTP was calculated using the Kaplan-Meier technique. Confidence interval was calculated based on the Brookmeyer and Crowley method.
Time frame: Tumor scans were performed at baseline then every ~8 weeks up to 34 weeks, then every ~12 weeks thereafter until confirmed disease progression. Analysis performed for the pre-switch period only; maximum duration of up to 32 treatment cycles (64 weeks).
Population: TS: The TS contained all patients who signed informed consent and who received at least one dose of trial medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BI 695502 | Time to Progression (TTP) as Assessed by Central Imaging Review | 11.1 Months |