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

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02776683
• Collaborator: (none)
• Enrollment: 123
• Locations: 46
• Arm: 1
• Actual Duration (Months): 27.8
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Colorectal Neoplasms	Drug: BI 695502; Drug: Avastin	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 123 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Jun 8, 2016
• Actual Primary Completion Date: Oct 3, 2018
• Actual Study Completion Date: Oct 3, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: All patients	Drug: BI 695502; Drug: Avastin

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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 exclusion criteria apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic-Arizona	Phoenix	Arizona	United States	85054
2	Pacific Cancer Medical Center, Inc.	Anaheim	California	United States	92801
3	The Oncology Institute of Hope and Innovation	Anaheim	California	United States	92801
4	Rocky Mountain Cancer Centers	Denver	Colorado	United States	80218
5	Ashland Bellefonte Cancer Center	Ashland	Kentucky	United States	41101
6	University of Michigan Health System	Ann Arbor	Michigan	United States	48109
7	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
8	Aultman Hospital	Canton	Ohio	United States	44710
9	Oncology Hematology Care	Cincinnati	Ohio	United States	45242
10	Northwest Cancer Specialists PC	Portland	Oregon	United States	97225
11	Willamette Valley Cancer Institute and Research Center	Springfield	Oregon	United States	97477
12	Texas Oncology, P.A.	Abilene	Texas	United States	79606
13	Texas Oncology, PA,	Amarillo	Texas	United States	79106
14	Texas Oncology, P.A.	Austin	Texas	United States	78705
15	Texas Oncology, P.A.	Flower Mound	Texas	United States	75028
16	Texas Oncology, P.A.	Garland	Texas	United States	75042-5788
17	Oncology Consultants, P.A.	Houston	Texas	United States	77030
18	Texas Oncology, P.A.	McAllen	Texas	United States	78503-1298
19	Texas Oncology, PA	Mesquite	Texas	United States	75150
20	Texas Oncology-San Antonio Northeast	San Antonio	Texas	United States	78217
21	Texas Oncology San Antonio Medical Center	San Antonio	Texas	United States	78229
22	Tyler Hematology-Oncology, PA	Tyler	Texas	United States	75701
23	Texas Oncology, P.A.	Tyler	Texas	United States	75702
24	Texas Oncology, P.A., Deke Slayton Cancer Center	Webster	Texas	United States	77598
25	Virginia Cancer Institute	Richmond	Virginia	United States	23226
26	Chiba Cancer Center	Chiba, Chiba		Japan	260-8717
27	National Hospital Organization Shikoku Cancer Center	Ehime, Matsuyama		Japan	791-0280
28	Hokkaido University Hospital	Hokkaido, Sapporo		Japan	060-8648
29	Japan Organization of Occupational Health and Safety Kansai Rosai Hospital	Hyogo, Amagasaki		Japan	660-8511
30	Kagawa University Hospital	Kagawa, Kita-gun		Japan	761-0793
31	Osaka University Hospital	Osaka, Suita		Japan	565-0871
32	Jananese Foundation for Cancer Research	Tokyo, Koto-ku		Japan	135-8550
33	Hospital Vall d'Hebron	Barcelona		Spain	08035
34	Hospital Duran i Reynals	L'Hospitalet de Llobregat		Spain	08907
35	Hospital Clínico de Valencia	Valencia		Spain	46010
36	CI Chernivtsi RC Oncological Dispensary Bukovinian SMU	Chernivtsi		Ukraine	58013
37	Munic.Instit."City Clin.Hosp.#4" of Dnipro City Council	Dnipropetrovsk		Ukraine	49102
38	Regional Clinical Oncological Dispensary, Ivano-Frankivsk	Ivano-Frankivsk		Ukraine	76018
39	CI of PH Kharkiv CCH #2	Kharkiv		Ukraine	61037
40	Treatment-Diagnostic CTR of Private Enterprise, Kirovohrad	Kirovohrad		Ukraine	25006
41	CI Kryvyi Rih Oncological Dispensary of DRC	Kryvyi Rih, Dnipropetrovsk		Ukraine	50048
42	National Institute of Cancer	Kyiv		Ukraine	03022
43	CI of LRC Lviv Onco.Reg.Treat.&Diag.Cent.	Lviv		Ukraine	79031
44	Poltava Regional Clinical Oncological Dispensary, Poltava	Poltava		Ukraine	38011
45	Sumy Regional Oncology Center	Sumy		Ukraine	40022
46	Vinnytsia Regional Clinical Oncological Dispensary	Vinnytsia		Ukraine	21029

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

• Statistical Analysis Plan - Dec 13, 2018
• Study Protocol - Jan 17, 2018

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT02776683
• Other Study ID Numbers: 1302.3; 2015-003718-25
• First Posted: May 18, 2016
• Last Update Posted: Nov 21, 2019
• Last Verified: Oct 1, 2019

• Additional relevant MeSH terms: Colorectal Neoplasms; Bevacizumab

Study Results

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 Detail	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®
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	123	0
COMPLETED	43	0
NOT COMPLETED	80	0
Period Title: Pre-switch Period
STARTED	0	43
COMPLETED	0	0
NOT COMPLETED	0	43

Baseline Characteristics

Arm/Group Title	BI 695502
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 Participants	123
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	58.0 (11.87)
Sex: Female, Male (Count of Participants)
Female	55 44.7%
Male	68 55.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	15 12.2%
Not Hispanic or Latino	106 86.2%
Unknown or Not Reported	2 1.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	33 26.8%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	6 4.9%
White	82 66.7%
More than one race	0 0%
Unknown or Not Reported	2 1.6%

Outcome Measures

1. Primary Outcome

Title	Percentage of Patients With Treatment-Emergent Adverse Events (TEAEs) in the Specified Categories Selected for Primary Endpoint Assessment
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).

Outcome Measure Data

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
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.
Measure Participants	123
Patients with any of the selected AEs	58.5 47.6%
Infusion reactions	18.7 15.2%
Thromboembolic events	12.2 9.9%
Gastrointestinal perforations	2.4 2%
Hypertension	28.5 23.2%
Proteinuria	9.8 8%
Pulmonary Haemorrhage	0.00 0%
Hemorrhages	22.80 18.5%
Wound-healing complications	1.6 1.3%
Reversible Encephalopathy Syndrome	0.0 0%
Ovarian failure	0.00 0%

2. Secondary Outcome

Title	Duration of Response (DOR) as Assessed by Central Imaging Review
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).

Outcome Measure Data

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
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.
Measure Participants	77
Median (95% Confidence Interval) [Months]	9.1

3. Secondary Outcome

Title	Time to Progression (TTP) as Assessed by Central Imaging Review
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).

Outcome Measure Data

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
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.
Measure Participants	123
Median (95% Confidence Interval) [Months]	11.1

4. Secondary Outcome

Title	Objective Response (OR) Rate as Assessed by Central Imaging Review
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).

Outcome Measure Data

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
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.
Measure Participants	123
Number (95% Confidence Interval) [Percentage of participants]	61.0 49.6%

5. Secondary Outcome

Title	Overall Survival (OS) Time
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).

Outcome Measure Data

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
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.
Measure Participants	123
Median (95% Confidence Interval) [Months]	19.4

6. Secondary Outcome

Title	Progression-Free Survival (PFS) Time as Assessed by Central Imaging Review
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).

Outcome Measure Data

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
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.
Measure Participants	123
Median (95% Confidence Interval) [Months]	10.5

Adverse Events

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
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 (%)	# Events
Total	41/123 (33.3%)
Serious Adverse Events
	BI 695502
	Affected / at Risk (%)	# Events
Total	33/123 (26.8%)
Blood and lymphatic system disorders
Febrile neutropenia	2/123 (1.6%)
Disseminated intravascular coagulation	1/123 (0.8%)
Hypersplenism	1/123 (0.8%)
Neutropenia	1/123 (0.8%)
Splenomegaly	1/123 (0.8%)
Ear and labyrinth disorders
Sudden hearing loss	1/123 (0.8%)
Gastrointestinal disorders
Ileus	2/123 (1.6%)
Abdominal hernia	1/123 (0.8%)
Diarrhoea	1/123 (0.8%)
Intestinal perforation	1/123 (0.8%)
Intra-abdominal fluid collection	1/123 (0.8%)
Large intestinal stenosis	1/123 (0.8%)
Large intestine perforation	1/123 (0.8%)
Mesenteric vein thrombosis	1/123 (0.8%)
Vomiting	1/123 (0.8%)
Gastrointestinal perforation	0/123 (0%)
Hepatobiliary disorders
Jaundice cholestatic	1/123 (0.8%)
Liver disorder	1/123 (0.8%)
Portal vein thrombosis	1/123 (0.8%)
Immune system disorders
Drug hypersensitivity	1/123 (0.8%)
Hypersensitivity	1/123 (0.8%)
Infections and infestations
Sepsis	2/123 (1.6%)
Bacterial sepsis	1/123 (0.8%)
Biliary tract infection	1/123 (0.8%)
Device related infection	1/123 (0.8%)
Gastroenteritis viral	1/123 (0.8%)
Vulval abscess	1/123 (0.8%)
Injury, poisoning and procedural complications
Cervical vertebral fracture	1/123 (0.8%)
Thoracic vertebral fracture	1/123 (0.8%)
Metabolism and nutrition disorders
Dehydration	1/123 (0.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer	1/123 (0.8%)
Meningioma benign	1/123 (0.8%)
Tumour necrosis	1/123 (0.8%)
Nervous system disorders
Cervical radiculopathy	1/123 (0.8%)
Myelopathy	1/123 (0.8%)
Seizure	1/123 (0.8%)
Spinal cord compression	1/123 (0.8%)
Renal and urinary disorders
Acute kidney injury	1/123 (0.8%)
Hydronephrosis	1/123 (0.8%)
Renal haematoma	1/123 (0.8%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	6/123 (4.9%)
Chronic obstructive pulmonary disease	1/123 (0.8%)
Pulmonary artery thrombosis	1/123 (0.8%)
Skin and subcutaneous tissue disorders
Skin necrosis	1/123 (0.8%)
Vascular disorders
Deep vein thrombosis	2/123 (1.6%)
Accelerated hypertension	1/123 (0.8%)
Brachiocephalic vein thrombosis	1/123 (0.8%)
Pelvic venous thrombosis	1/123 (0.8%)
Subclavian vein thrombosis	1/123 (0.8%)
Vena cava thrombosis	1/123 (0.8%)
Other (Not Including Serious) Adverse Events
	BI 695502
	Affected / at Risk (%)	# Events
Total	118/123 (95.9%)
Blood and lymphatic system disorders
Neutropenia	32/123 (26%)
Anaemia	21/123 (17.1%)
Thrombocytopenia	20/123 (16.3%)
Leukopenia	7/123 (5.7%)
Gastrointestinal disorders
Nausea	57/123 (46.3%)
Diarrhoea	41/123 (33.3%)
Stomatitis	37/123 (30.1%)
Constipation	27/123 (22%)
Vomiting	19/123 (15.4%)
Abdominal pain	17/123 (13.8%)
Abdominal pain upper	12/123 (9.8%)
Dyspepsia	9/123 (7.3%)
General disorders
Fatigue	45/123 (36.6%)
Pyrexia	17/123 (13.8%)
Malaise	10/123 (8.1%)
Asthenia	9/123 (7.3%)
Infections and infestations
Urinary tract infection	8/123 (6.5%)
Investigations
Neutrophil count decreased	25/123 (20.3%)
Platelet count decreased	18/123 (14.6%)
Weight decreased	18/123 (14.6%)
White blood cell count decreased	18/123 (14.6%)
Gamma-glutamyltransferase increased	12/123 (9.8%)
Aspartate aminotransferase increased	7/123 (5.7%)
Weight increased	7/123 (5.7%)
Metabolism and nutrition disorders
Decreased appetite	26/123 (21.1%)
Hypokalaemia	10/123 (8.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	9/123 (7.3%)
Back pain	9/123 (7.3%)
Pain in extremity	7/123 (5.7%)
Nervous system disorders
Peripheral sensory neuropathy	44/123 (35.8%)
Neuropathy peripheral	21/123 (17.1%)
Dysgeusia	18/123 (14.6%)
Headache	14/123 (11.4%)
Dizziness	8/123 (6.5%)
Neurotoxicity	7/123 (5.7%)
Psychiatric disorders
Insomnia	9/123 (7.3%)
Renal and urinary disorders
Proteinuria	11/123 (8.9%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	18/123 (14.6%)
Rhinorrhoea	8/123 (6.5%)
Dyspnoea	7/123 (5.7%)
Skin and subcutaneous tissue disorders
Alopecia	16/123 (13%)
Palmar-plantar erythrodysaesthesia syndrome	11/123 (8.9%)
Skin hyperpigmentation	7/123 (5.7%)
Vascular disorders
Hypertension	34/123 (27.6%)

Limitations/Caveats

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).

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.