Clinical Trial Results:
A single-arm, open-label, multicenter, multinational, safety and efficacy Phase IIIb trial of BI 695502 plus mFOLFOX6 in patients with previously untreated metastatic colorectal cancer
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Summary
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EudraCT number |
2015-003718-25 |
Trial protocol |
ES |
Global end of trial date |
03 Oct 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
17 Oct 2019
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First version publication date |
17 Oct 2019
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
1302.3
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02776683 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Boehringer Ingelheim
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Sponsor organisation address |
Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
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Public contact |
QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
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Scientific contact |
QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
12 Nov 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
03 Oct 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
03 Oct 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of this trial was to evaluate the safety and tolerability of BI 695502 in combination with leucovorin/5-fluorouracil (5FU)/oxaliplatin (mFOLFOX6) and as maintenance therapy (when applicable).
The secondary objectives of this trial were to evaluate the following efficacy parameters: Progression-free survival (PFS), objective response rate (proportion of patients with complete response [CR] plus partial response [PR]), duration of response (DOR), time to progression (TTP), and overall survival (OS).
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Protection of trial subjects |
Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. If a subject continued to take trial medication, close monitoring was adhered to and all adverse events recorded. Rules were implemented in all trials whereby doses would be reduced if required. Thereafter, if further events were reported, the subject would be withdrawn from the trial. Symptomatic treatment of tumour associated symptoms were allowed throughout.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
08 Jun 2016
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
4 Months | ||
Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United States: 68
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Country: Number of subjects enrolled |
Japan: 41
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Country: Number of subjects enrolled |
Spain: 10
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Country: Number of subjects enrolled |
Ukraine: 63
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Worldwide total number of subjects |
182
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EEA total number of subjects |
10
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
114
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From 65 to 84 years |
67
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85 years and over |
1
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Recruitment
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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. | ||||||||||||||||||||
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Pre-assignment
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Screening details |
All patients were screened for eligibility to participate in the trial. Patients attended specialist sites which would then ensure that they (the patients) 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. | ||||||||||||||||||||
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Period 1
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Period 1 title |
Pre-switch period
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Is this the baseline period? |
Yes | ||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||
Blinding implementation details |
This was an open-label trial. Blinding was not performed for this trial.
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Arms
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Arm title
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BI 695502 | ||||||||||||||||||||
Arm description |
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. | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
BI 695502
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
A dose of 5 mg/kg body weight of BI 695502 was administered by i.v. infusion every 2 weeks.
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Investigational medicinal product name |
mFOLFOX6
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
For mFOLFOX6 chemotherapy, oxaliplatin 85 mg/m2 i.v. over 2 hours on Day 1 of cycle, leucovorin 400 mg/m2 i.v. (or levoleucovorin 200 mg/m2 i.v.) over 2 hours on Day 1 of cycle, 5-fluorouracil 400 mg/m2 i.v. bolus on Day 1 of cycle, then 1200 mg/m2/day x 2 days (total 2400 mg/m2 over 46-48 hours) i.v. continuous infusion were to be administered. 1 cycle = 2 weeks.
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| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication. |
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Period 2
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Period 2 title |
Post-switch period
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Is this the baseline period? |
No | ||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||
Blinding implementation details |
This was an open-label trial. Blinding was not performed for this trial.
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Arms
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Arm title
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BI 695502 to Avastin® | ||||||||||||||||||||
Arm description |
At the switch visit, patients were to be switched from BI 695502 to Avastin®. Post-switch, patients were to receive Avastin® (5 mg/kg) solution for i.v. infusion in combination with mFOLFOX6 chemotherapy every 2 weeks. Patients were to continue to receive treatment until disease progression, death, unacceptable toxicity, or the end of the trial, whichever occurred earlier. | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
mFOLFOX6
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
For mFOLFOX6 chemotherapy, oxaliplatin 85 mg/m2 i.v. over 2 hours on Day 1 of cycle, leucovorin 400 mg/m2 i.v. (or levoleucovorin 200 mg/m2 i.v.) over 2 hours on Day 1 of cycle, 5-fluorouracil 400 mg/m2 i.v. bolus on Day 1 of cycle, then 1200 mg/m2/day x 2 days (total 2400 mg/m2 over 46-48 hours) i.v. continuous infusion were to be administered. 1 cycle = 2 weeks.
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Investigational medicinal product name |
Avastin®
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Investigational medicinal product code |
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Other name |
Bevacizumab
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
A dose of 5 mg/kg body weight of Avastin® was administered by i.v. infusion every 2 weeks.
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Baseline characteristics reporting groups
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Reporting group title |
BI 695502
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Reporting group description |
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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
BI 695502
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Reporting group description |
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. | ||
Reporting group title |
BI 695502 to Avastin®
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Reporting group description |
At the switch visit, patients were to be switched from BI 695502 to Avastin®. Post-switch, patients were to receive Avastin® (5 mg/kg) solution for i.v. infusion in combination with mFOLFOX6 chemotherapy every 2 weeks. Patients were to continue to receive treatment until disease progression, death, unacceptable toxicity, or the end of the trial, whichever occurred earlier. | ||
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End point title |
Percentage of Patients with Treatment-Emergent Adverse Events (TEAEs) in the Specified Categories Selected for Primary Endpoint Assessment [1] | ||||||||||||||||||||||||||||||
End point description |
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. TS: The TS contained all patients who signed informed consent and who received at least one dose of trial medication.
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End point type |
Primary
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End point timeframe |
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).
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested. |
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| Notes [2] - TS |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Duration of Response (DOR) as Assessed by Central Imaging Review | ||||||||
End point description |
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. 99999= NA= The upper limit confidence interval was not determined as it was not reached. Only patients with complete or partial objective response were included in the analysis.
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End point type |
Secondary
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End point timeframe |
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).
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| Notes [3] - TS (complete or partial objective response) |
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| No statistical analyses for this end point | |||||||||
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End point title |
Time to Progression (TTP) as Assessed by Central Imaging Review | ||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
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).
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| Notes [4] - TS |
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| No statistical analyses for this end point | |||||||||
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End point title |
Objective Response (OR) Rate as Assessed by Central Imaging Review | ||||||||
End point description |
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. OR = CR + PR.
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End point type |
Secondary
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End point timeframe |
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).
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| Notes [5] - TS |
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| No statistical analyses for this end point | |||||||||
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End point title |
Overall Survival (OS) Time | ||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
From baseline until death due to any cause. Analysis performed for the pre-switch period only; maximum duration of up to 32 treatment cycles (64 weeks).
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| Notes [6] - TS |
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| No statistical analyses for this end point | |||||||||
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End point title |
Progression-Free Survival (PFS) Time as Assessed by Central Imaging Review | ||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
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).
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| Notes [7] - TS |
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
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).
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Adverse event reporting additional description |
All-Cause mortality is defined as death due to any cause (including disease progression) and is reported for the overall study period, including both the pre-switch period for BI 695502 treatment and post-switch period for Avastin® treatment. Serious and Other(non-serious) TEAE data is reported for the BI695502 treatment period only(ie pre-switch).
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.1
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Reporting groups
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Reporting group title |
BI 695502
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Reporting group description |
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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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22 Apr 2016 |
‘Locally advanced’ was removed from the trial title and inclusion criteria to allow all patients with untreated metastatic colorectal cancer to be included in the trial. The Benefit-Risk Assessment was updated to alert Investigators of the risks of fetal harm in women taking Avastin and to update the protocol in line with the revised labelling. The overall design section was updated to remove provision of an interim analysis, as this was no longer needed for the trial. Changes to the mFOLFOX6 regimen were to be allowed following agreement by the Sponsor due to some sites not being able to obtain leucovorin. Inclusion criteria were updated to exclude patients with measurable lesions that had been irradiated within 12 weeks prior to enrollment. Exclusion criterion 4 was updated to provide more detailed information in exclusion in patients with brain metastases. Exclusion criterion 10 was updated to allow use of corticosteroids as antiemetics for oxaliplatin and 5-fluorouracil according to regular institutional practice. Exclusion criterion 15 was updated to allow inclusion of patients with history of gastroduodenal ulcer more than 18 months prior to Screening. Radiotherapy was added as a restriction to prevent concomitant radiotherapy during the trial. Restrictions information was updated to prevent trial medication being given within 28 days of any surgical procedure needed to obtain a biopsy. The description of the safety laboratory parameters was clarified. Coagulation tests were added to the Chemistry parameter. Number of electrocardiograms (ECGs) was updated to clarify that 2 consecutive ECGs were to be performed. A full definition of TEAEs suggestive of hepatic injury was added to assist Investigators in deciding whether the drug-induced liver injury checklist needed to be completed. Pharmacokinetic (PK) analyses were updated to remove population PK modeling and to state that plasma BI 695502 levels were to be compared to historical controls instead. |
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25 May 2016 |
• It was clarified that coagulation tests were to be performed post-screening. |
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13 Apr 2017 |
• The rectal examination was made optional since it is not routinely done in all United States practices. |
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26 Oct 2017 |
• The trial number was updated to include the new brand name, INVICTAN®-3.
• The timing of the tumor assessments was clarified, specifically that if an assessment was done at Visit 27 then another assessment was not required at Visit 28.
• The criteria for dose deviations which were to be considered protocol deviations were clarified.
• The mandatory concentration of BI 695502 for i.v. infusion was updated. |
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17 Jan 2018 |
• As a consequence of the observation of particles for certain investigational medicinal product batches, the Sponsor recommended that patients were switched from BI 695502 to the reference medicinal product as soon as it was available at the respective clinical site. The protocol was updated throughout to clarify that trial medication may be either BI 695502 or Avastin®.
• It was clarified that the REP was 18 weeks after the last dose of trial medication and thus this was when the Safety Follow-up (SFU) should be performed. Patients who were still being seen at the site every 3 weeks did not need an additional SFU Visit.
• The end of trial definition was updated to take account of patients that may continue to receive Avastin® beyond the 18-week SFU Visit.
• It was clarified that filters were still to be used for Avastin® administration the same as for BI 695502 administration.
• The statistical methods were updated to clarify the period covered by the main analyses plus that appropriate censoring methods were to be applied at the time of switching from BI 695502 to Avastin®.
• The visits required at the Switch Visit were clarified in the flow chart.
• Additional information was added to describe the 5 Data Safety Monitoring Board meetings that had been held for trial 1302.5 and that they had all recommended continuation of that trial without modification.
• The reasons for patient discontinuation of trial medication were updated to include ‘Congestive heart failure, any degree’.
• Clarification on the dose of Avastin and the administration instructions was added.
• Clarification of the Avastin supply and labeling, storage conditions, and accountability was added to the protocol. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| From 21 December 2017, the Sponsor recommended for patients to be switched from BI 695502 to Avastin®. The main analyses for reporting primary and secondary endpoints was clarified as the pre-switch period (i.e., all receiving BI 695502). | |||
