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Open-label, Single Arm Trial of BI 695502 in Patients With Previously Untreated Metastatic Colorectal Cancer (INVICTAN®-3)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02776683
Recruitment Status : Completed
First Posted : May 18, 2016
Results First Posted : November 21, 2019
Last Update Posted : November 21, 2019
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Colorectal Neoplasms
Interventions Drug: BI 695502
Drug: Avastin
Enrollment 123
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.
Arm/Group Title BI 695502 BI 695502 to Avastin®
Hide Arm/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. 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.
Period Title: Pre-switch Period
Started [1] 123 [2] 0
Completed 43 [3] 0
Not Completed 80 0
Reason Not Completed
Protocol Violation             1             0
Adverse Event             21             0
Withdrawal by Subject             9             0
Physician Decision             7             0
Progressive disease             39             0
Other than listed             3             0
[1]
Only the BI 695502 arm was applicable for Period 1
[2]
Assigned to trial medication or enrolled/treated
[3]
Entered into Switch Set
Period Title: Post-switch Period
Started [1] 0 43 [2]
Completed 0 0
Not Completed 0 43
Reason Not Completed
Adverse Event             0             3
Withdrawal by Subject             0             2
Physician Decision             0             3
Progressive disease             0             20
Other than listed             0             15
[1]
Only the BI 695502 to Avastin arm was applicable to Period 2
[2]
Entered into Switch Set
Arm/Group Title BI 695502
Hide Arm/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.
Overall Number of Baseline Participants 123
Hide Baseline Analysis Population Description
Treated set (TS): The TS contained all participants who signed informed consent and who received at least one dose of trial medication.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 123 participants
58.0  (11.87)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 123 participants
Female
55
  44.7%
Male
68
  55.3%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 123 participants
Hispanic or Latino
15
  12.2%
Not Hispanic or Latino
106
  86.2%
Unknown or Not Reported
2
   1.6%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 123 participants
American Indian or Alaska Native
0
   0.0%
Asian
33
  26.8%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
6
   4.9%
White
82
  66.7%
More than one race
0
   0.0%
Unknown or Not Reported
2
   1.6%
1.Primary Outcome
Title Percentage of Patients With Treatment-Emergent Adverse Events (TEAEs) in the Specified Categories Selected for Primary Endpoint Assessment
Hide 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.
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).
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set (TS): The TS contained all patients who signed informed consent and who received at least one dose of trial medication.
Arm/Group Title BI 695502
Hide Arm/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.
Overall Number of Participants Analyzed 123
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants (%)
Patients with any of the selected AEs
58.5
(49.70 to 66.86)
Infusion reactions
18.7
(12.80 to 26.50)
Thromboembolic events
12.2
(7.53 to 19.15)
Gastrointestinal perforations
2.4
(0.83 to 6.93)
Hypertension
28.5
(21.23 to 36.99)
Proteinuria
9.8
(5.67 to 16.28)
Pulmonary Haemorrhage
0.00
(0.00 to 3.03)
Hemorrhages
22.80
(16.25 to 30.93)
Wound-healing complications
1.6
(0.45 to 5.74)
Reversible Encephalopathy Syndrome
0.0
(0.00 to 3.03)
Ovarian failure
0.00
(0.00 to 6.53)
2.Secondary Outcome
Title Duration of Response (DOR) as Assessed by Central Imaging Review
Hide 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.
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).
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title BI 695502
Hide Arm/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.
Overall Number of Participants Analyzed 77
Median (95% Confidence Interval)
Unit of Measure: Months
9.1 [1] 
(7.3 to NA)
[1]
The upper limit confidence interval was not determined as it was not reached
3.Secondary Outcome
Title Time to Progression (TTP) as Assessed by Central Imaging Review
Hide 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.
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).
Hide Outcome Measure Data
Hide Analysis Population Description
TS: The TS contained all patients who signed informed consent and who received at least one dose of trial medication.
Arm/Group Title BI 695502
Hide Arm/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.
Overall Number of Participants Analyzed 123
Median (95% Confidence Interval)
Unit of Measure: Months
11.1
(9.5 to 12.9)
4.Secondary Outcome
Title Objective Response (OR) Rate as Assessed by Central Imaging Review
Hide 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. 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).
Hide Outcome Measure Data
Hide Analysis Population Description
TS: The TS contained all patients who signed informed consent and who received at least one dose of trial medication.
Arm/Group Title BI 695502
Hide Arm/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.
Overall Number of Participants Analyzed 123
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
61.0
(52.1 to 69.1)
5.Secondary Outcome
Title Overall Survival (OS) Time
Hide 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.
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).
Hide Outcome Measure Data
Hide Analysis Population Description
TS: The TS contained all patients who signed informed consent and who received at least one dose of trial medication.
Arm/Group Title BI 695502
Hide Arm/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.
Overall Number of Participants Analyzed 123
Median (95% Confidence Interval)
Unit of Measure: Months
19.4
(16.7 to 21.1)
6.Secondary Outcome
Title Progression-Free Survival (PFS) Time as Assessed by Central Imaging Review
Hide 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.
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).
Hide Outcome Measure Data
Hide Analysis Population Description
TS: The TS contained all patients who signed informed consent and who received at least one dose of trial medication.
Arm/Group Title BI 695502
Hide Arm/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.
Overall Number of Participants Analyzed 123
Median (95% Confidence Interval)
Unit of Measure: Months
10.5
(9.4 to 11.8)
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).
Adverse Event Reporting 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) data is based on on-treatment adverse events.
 
Arm/Group Title BI 695502
Hide Arm/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.
All-Cause Mortality
BI 695502
Affected / at Risk (%)
Total   41/123 (33.33%) 
Hide Serious Adverse Events
BI 695502
Affected / at Risk (%)
Total   33/123 (26.83%) 
Blood and lymphatic system disorders   
Febrile neutropenia  1  2/123 (1.63%) 
Disseminated intravascular coagulation  1  1/123 (0.81%) 
Hypersplenism  1  1/123 (0.81%) 
Neutropenia  1  1/123 (0.81%) 
Splenomegaly  1  1/123 (0.81%) 
Ear and labyrinth disorders   
Sudden hearing loss  1  1/123 (0.81%) 
Gastrointestinal disorders   
Ileus  1  2/123 (1.63%) 
Abdominal hernia  1  1/123 (0.81%) 
Diarrhoea  1  1/123 (0.81%) 
Intestinal perforation  1  1/123 (0.81%) 
Intra-abdominal fluid collection  1  1/123 (0.81%) 
Large intestinal stenosis  1  1/123 (0.81%) 
Large intestine perforation  1  1/123 (0.81%) 
Mesenteric vein thrombosis  1  1/123 (0.81%) 
Vomiting  1  1/123 (0.81%) 
Gastrointestinal perforation  1  0/123 (0.00%) 
Hepatobiliary disorders   
Jaundice cholestatic  1  1/123 (0.81%) 
Liver disorder  1  1/123 (0.81%) 
Portal vein thrombosis  1  1/123 (0.81%) 
Immune system disorders   
Drug hypersensitivity  1  1/123 (0.81%) 
Hypersensitivity  1  1/123 (0.81%) 
Infections and infestations   
Sepsis  1  2/123 (1.63%) 
Bacterial sepsis  1  1/123 (0.81%) 
Biliary tract infection  1  1/123 (0.81%) 
Device related infection  1  1/123 (0.81%) 
Gastroenteritis viral  1  1/123 (0.81%) 
Vulval abscess  1  1/123 (0.81%) 
Injury, poisoning and procedural complications   
Cervical vertebral fracture  1  1/123 (0.81%) 
Thoracic vertebral fracture  1  1/123 (0.81%) 
Metabolism and nutrition disorders   
Dehydration  1  1/123 (0.81%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Colon cancer  1  1/123 (0.81%) 
Meningioma benign  1  1/123 (0.81%) 
Tumour necrosis  1  1/123 (0.81%) 
Nervous system disorders   
Cervical radiculopathy  1  1/123 (0.81%) 
Myelopathy  1  1/123 (0.81%) 
Seizure  1  1/123 (0.81%) 
Spinal cord compression  1  1/123 (0.81%) 
Renal and urinary disorders   
Acute kidney injury  1  1/123 (0.81%) 
Hydronephrosis  1  1/123 (0.81%) 
Renal haematoma  1  1/123 (0.81%) 
Respiratory, thoracic and mediastinal disorders   
Pulmonary embolism  1  6/123 (4.88%) 
Chronic obstructive pulmonary disease  1  1/123 (0.81%) 
Pulmonary artery thrombosis  1  1/123 (0.81%) 
Skin and subcutaneous tissue disorders   
Skin necrosis  1  1/123 (0.81%) 
Vascular disorders   
Deep vein thrombosis  1  2/123 (1.63%) 
Accelerated hypertension  1  1/123 (0.81%) 
Brachiocephalic vein thrombosis  1  1/123 (0.81%) 
Pelvic venous thrombosis  1  1/123 (0.81%) 
Subclavian vein thrombosis  1  1/123 (0.81%) 
Vena cava thrombosis  1  1/123 (0.81%) 
1
Term from vocabulary, MedDRA 21.1
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
BI 695502
Affected / at Risk (%)
Total   118/123 (95.93%) 
Blood and lymphatic system disorders   
Neutropenia  1  32/123 (26.02%) 
Anaemia  1  21/123 (17.07%) 
Thrombocytopenia  1  20/123 (16.26%) 
Leukopenia  1  7/123 (5.69%) 
Gastrointestinal disorders   
Nausea  1  57/123 (46.34%) 
Diarrhoea  1  41/123 (33.33%) 
Stomatitis  1  37/123 (30.08%) 
Constipation  1  27/123 (21.95%) 
Vomiting  1  19/123 (15.45%) 
Abdominal pain  1  17/123 (13.82%) 
Abdominal pain upper  1  12/123 (9.76%) 
Dyspepsia  1  9/123 (7.32%) 
General disorders   
Fatigue  1  45/123 (36.59%) 
Pyrexia  1  17/123 (13.82%) 
Malaise  1  10/123 (8.13%) 
Asthenia  1  9/123 (7.32%) 
Infections and infestations   
Urinary tract infection  1  8/123 (6.50%) 
Investigations   
Neutrophil count decreased  1  25/123 (20.33%) 
Platelet count decreased  1  18/123 (14.63%) 
Weight decreased  1  18/123 (14.63%) 
White blood cell count decreased  1  18/123 (14.63%) 
Gamma-glutamyltransferase increased  1  12/123 (9.76%) 
Aspartate aminotransferase increased  1  7/123 (5.69%) 
Weight increased  1  7/123 (5.69%) 
Metabolism and nutrition disorders   
Decreased appetite  1  26/123 (21.14%) 
Hypokalaemia  1  10/123 (8.13%) 
Musculoskeletal and connective tissue disorders   
Arthralgia  1  9/123 (7.32%) 
Back pain  1  9/123 (7.32%) 
Pain in extremity  1  7/123 (5.69%) 
Nervous system disorders   
Peripheral sensory neuropathy  1  44/123 (35.77%) 
Neuropathy peripheral  1  21/123 (17.07%) 
Dysgeusia  1  18/123 (14.63%) 
Headache  1  14/123 (11.38%) 
Dizziness  1  8/123 (6.50%) 
Neurotoxicity  1  7/123 (5.69%) 
Psychiatric disorders   
Insomnia  1  9/123 (7.32%) 
Renal and urinary disorders   
Proteinuria  1  11/123 (8.94%) 
Respiratory, thoracic and mediastinal disorders   
Epistaxis  1  18/123 (14.63%) 
Rhinorrhoea  1  8/123 (6.50%) 
Dyspnoea  1  7/123 (5.69%) 
Skin and subcutaneous tissue disorders   
Alopecia  1  16/123 (13.01%) 
Palmar-plantar erythrodysaesthesia syndrome  1  11/123 (8.94%) 
Skin hyperpigmentation  1  7/123 (5.69%) 
Vascular disorders   
Hypertension  1  34/123 (27.64%) 
1
Term from vocabulary, MedDRA 21.1
Indicates events were collected by systematic assessment
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).
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI’s intellectual property rights.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Boehringer Ingelheim, Call Centre
Organization: Boehringer Ingelheim
Phone: 1-800-243-0127
EMail: clintriage.rdg@boehringer-ingelheim.com
Layout table for additonal information
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT02776683    
Other Study ID Numbers: 1302.3
2015-003718-25 ( EudraCT Number )
First Submitted: May 17, 2016
First Posted: May 18, 2016
Results First Submitted: October 2, 2019
Results First Posted: November 21, 2019
Last Update Posted: November 21, 2019