Aflibercept and FOLFOX6 Treatment for Previously Untreate... | NCT01652196

NCT01652196

ID	Type	Description	Link
NCI-2012-01167	Registry Identifier	CTRP (Clinical Trial Reporting Program)

Status Module

Sponsor/Collaborators Module

Name	Class
Sanofi	INDUSTRY

Oversight Module

Description Module

Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate the progression free survival (PFS) of patients with untreated metastatic colorectal cancer (mCRC) receiving the combination of modified leucovorin calcium, fluorouracil, oxaliplatin (FOLFOX6) (mFOLFOX6) and aflibercept.

SECONDARY OBJECTIVES:

I. To evaluate the objective response rate (complete response [CR] + partial response [PR]) and the disease control rate (CR + PR + stable disease [SD]), as determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, of patients with untreated mCRC receiving the combination of mFOLFOX6 and aflibercept.

II. To evaluate overall survival of patients with untreated mCRC receiving the combination of mFOLFOX6 and aflibercept.

III. To further characterize the safety and toxicity of the combination of mFOLFOX6 and aflibercept, including 60 day all-cause mortality.

IV. To describe patients with mCRC whose disease is rendered resectable as a consequence of therapy with the combination of mFOLFOX 6 and aflibercept.

TERTIARY OBJECTIVES:

I. To assess the use of dynamic imaging modalities including dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) and fluorodeoxyglucose (FDG)-positron emission tomography (PET) to evaluate changes in vascular permeability and FDG avidity and correlate with clinical efficacy (PFS, overall survival [OS], and response by RECIST 1.1).

II. To evaluate circulating levels of vascular endothelial growth factor A (VEGFA), phosphatidylinositol glycan anchor biosynthesis, class F (PlGF), soluble vascular endothelial growth factor receptor 2 (VEGF-R2), chemokine (C-X-C motif) ligand 12 (CXCL12) and chemokine (C-X-C motif) receptor 4 (CXCR4) as potential biomarkers for efficacy of aflibercept.

III. To evaluate for the presence of VEGF single nucleotide polymorphisms (SNPs) and whether any SNP(s), when detected, may be predictive of efficacy and/or toxicity of aflibercept.

IV. To assess microvessel density/tumor blood flow, capillary permeability and vessel normalization by tumor biopsy pre and post treatment with aflibercept.

V. To evaluate the presence of hypertension as a predictive biomarker for clinical efficacy of aflibercept.

OUTLINE:

Patients receive aflibercept intravenously (IV) over 1 hour followed by oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 5-15 minutes and then continuously over 46 hours on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks.

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Aflibercept (combination chemotherapy)	Experimental	Patients receive aflibercept and fluorouracil and then continuously over 46 hours on days 1 and 15.If leucovorin is not available due to drug shortages the regimen should be administered with the leucovorin omitted. Correlative Studies are required to be available before enrolling on the study. A fresh biopsy is only required if there is insufficient material for analysis. Repeat tumor biopsies after 8 weeks of therapy are optional and will only be performed at the Ohio State University Medical Center.DCE MRI (dynamic contrast-enhanced magnetic resonance imaging)images at weeks 0, and after 8 weeks +/- 1 week of treatment(after Cycle 2). 18FDG-PET is a functional imaging technique that relies on tumor uptake of radiolabeled tracer 18 fluorodeoxyglucose (18FDG).FDG-PET is a widely-used imaging modality in the detection and monitoring of a variety of metastatic cancers,including colorectal cancer (99-102).	Biological: aflibercept Drug: oxaliplatin Drug: leucovorin Drug: fluorouracil Other: Correlative Studies Procedure: DCE MRI Radiation: f18FDG-PET Procedure: PET (positron emission tomography)

Name	Type	Description	Arm Group Labels	Other Names
aflibercept	Biological	4 mg/kg as a 1-hour IV(intervenous) infusion	Aflibercept (combination chemotherapy)

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Proportion of Patients Alive and Progression-free at 15 Months	Assuming that the number of treatment successes (alive and progression-free) is binomially distributed, proportion estimates along with their corresponding exact 95% confidence intervals will be calculated.	At 15 months from initiation of therapy

Secondary Outcomes

Measure	Description	Time Frame
Objective Response Rate (ORR) Defined as the Proportion of Patients Who Achieve a PR or CR Based on RECIST 1.1 Criteria Divided by the Total Number of Evaluable Patients	Summarized as a proportion with corresponding 95% confidence interval.	Up to 4 weeks post-treatment
Percentage of Patients Able to Undergo Surgery

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Histologically confirmed adenocarcinoma of colorectal origin that is metastatic or locally advanced and unresectable
Measurable disease, as defined by RECIST 1.1 criteria: one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 10 mm with spiral computed tomography (CT) scan (CT scan slice thickness no greater than 5 mm) malignant lymph nodes will be considered measurable if they are >= 15 mm in short axis
Must not have received any prior systemic therapy for metastatic or locally advanced CRC; prior VEGF inhibitors are not allowed
Prior adjuvant therapy for CRC including fluoropyrimidines either alone or in combination with oxaliplatin is allowed, provided that all therapy was completed >= 12 months from cancer recurrence, therapy duration was =< 6 months, and all prior toxicities have completely resolved (residual grade 1 neuropathy is allowed)
Life expectancy >= 12 weeks
Eastern Cooperative Oncology Group (ECOG) performance status 0-1
Hemoglobin >= 9 g/dL (blood transfusion permitted to attain this value)
Absolute neutrophil count >= 1,500/uL
Platelets >= 100,000/uL
Total bilirubin =< 2 x institutional upper limit of normal (ULN)
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN (may be =< 5x ULN if increase is due to metastatic disease)
Creatinine =< 1.5 x institutional ULN or creatinine clearance >= 60 mL/min/1.73 m2 for patients with creatinine levels above institutional U
Urine protein:creatinine ratio (UPCR) < 1 or < 500 mg protein/24 hr
Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

May not be receiving any other investigational agents
Patients who have received any prior locoregional therapy for metastatic disease (e.g. radiofrequency/microwave ablation, Yttrium-90 radioembolization, transarterial chemoembolization, or surgical resection) are excluded
Patients with known or suspected brain metastases, carcinomatous meningitis, uncontrolled seizure disorder, active intracranial bleeding or active neurologic disorder are excluded
Patients with an active second primary malignancy or history of malignancy within the 5 years of enrollment are excluded, with the exception of non-melanoma skin cancers and cervical cancer which has been treated with curative therapy
Grade >= 2 sensory neuropathy at the time of enrollment
Major surgery within 4 weeks of study start date; the surgical incision should be fully healed prior to initiation of aflibercept
Female or male patients of reproductive capacity unwilling to use methods appropriate to prevent pregnancy are excluded; effective contraception is required for at least 3 months following the last administration of aflibercept
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, uncontrolled hypertension (blood pressure [BP] must be well controlled < 160/90), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, or any condition that the principal investigator (PI) feels would make the patient ineligible
Positive pregnancy screening test with a minimum sensitivity of 25 IU/L of human chorionic gonadotropin (hCG) within 72 hours of registration; breastfeeding women are also excluded
History of pulmonary embolus within 3 months or deep venous thrombosis (DVT) within 4 weeks of enrollment; patients on anticoagulation must be on a stable dose of warfarin with a therapeutic-range international normalized ratio (INR) or on a stable dose of low molecular weight heparin
Active congestive heart failure (New York Heart Association [NYHA] class II-IV)
History of an arterial thrombotic vascular event including cerebrovascular accident (CVA), myocardial infarction (MI), unstable angina, coronary or peripheral arterial bypass graft, or transient ischemic attack (TIA) within 6 months
Serious or non-healing wound, ulcer or bone fracture at the time of medication administration
History of treatment-resistant peptic ulcer disease, erosive esophagitis, gastritis, or diverticulitis within 3 months
History of gastrointestinal (GI) perforation within 5 years; current or prior intestinal fistulas are also excluded
Known chronic infectious disease including human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS)
History of major hemorrhage including gastrointestinal bleeding (grade 2-4), pulmonary hemorrhage, or clinically significant hemoptysis (> 1 tsp in 24 hours) within the last 5 years; patients with underling conditions that predispose to bleeding, such as bleeding diathesis, known esophageal varices, or tumor involving major vessels, are also excluded
Inability to understand or comply with study protocol
Known hypersensitivity to Chinese hamster ovary cell products or to recombinant human or murine antibodies, or any of the treatments in this protocol

Contacts/Locations Module

Name	Affiliation	Role
John Hays, MD	Ohio State University Comprehensive Cancer Center	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
University of Michigan		Ann Arbor	Michigan	48109	United States
Roswell Park Cancer Institute

References Module

Label	URL
Jamesline	View source

IPD Sharing Statement Module

No data available

No data is available for this block.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Aflibercept (Combination Chemotherapy)	Patients receive aflibercept and fluorouracil and then continuously over 46 hours on days 1 and 15.If leucovorin is not available due to drug shortages the regimen should be administered with the leucovorin omitted. Correlative Studies are required to be available before enrolling on the study. A fresh biopsy is only required if there is insufficient material for analysis. Repeat tumor biopsies after 8 weeks of therapy are optional and will only be performed at the Ohio State University Medical Center.DCE MRI (dynamic contrast-enhanced magnetic resonance imaging)images at weeks 0, and after 8 weeks +/- 1 week of treatment(after Cycle 2). 18FDG-PET is a functional imaging technique that relies on tumor uptake of radiolabeled tracer 18 fluorodeoxyglucose (18FDG).FDG-PET is a widely-used imaging modality in the detection and monitoring of a variety of metastatic cancers,including colorectal cancer (99-102). aflibercept: 4 mg/kg as a 1-hour IV(intervenous) infusion oxaliplatin: 85 mg/m2 IV infused over 2 hours leucovorin: 200 mg/m2 (Or levoleucovorin 100 mg/m2. If leucovorin is not available due to drug shortages the regimen should be administered with the leucovorin omitted) IV over 2 hours. Alternatively, leucovorin may be administered (via separate infusion lines) concurrently with oxaliplatin fluorouracil: 400 mg/m2 IV bolus over 5-15 minutes, then 2400 mg/m2 continuous IV infusion over 46 hours.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Uploaded Document Information

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP	Yes	Yes	No	Study Protocol and Statistical Analysis Plan	May 15, 2018

Derived Section

Miscellaneous Info Module

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

Intervention Browse Module

Masking Info

vascular endothelial growth factor trap
VEGF Trap
VEGF Trap R1R2

Type of Units Analyzed

Arm/Group Information

ID	Title	Description
BG000	Aflibercept (Combination Chemotherapy)	Patients receive aflibercept and fluorouracil and then continuously over 46 hours on days 1 and 15.If leucovorin is not available due to drug shortages the regimen should be administered with the leucovorin omitted. Correlative Studies are required to be available before enrolling on the study. A fresh biopsy is only required if there is insufficient material for analysis. Repeat tumor biopsies after 8 weeks of therapy are optional and will only be performed at the Ohio State University Medical Center.DCE MRI (dynamic contrast-enhanced magnetic resonance imaging)images at weeks 0, and after 8 weeks +/- 1 week of treatment(after Cycle 2). 18FDG-PET is a functional imaging technique that relies on tumor uptake of radiolabeled tracer 18 fluorodeoxyglucose (18FDG).FDG-PET is a widely-used imaging modality in the detection and monitoring of a variety of metastatic cancers,including colorectal cancer (99-102). aflibercept: 4 mg/kg as a 1-hour IV(intervenous) infusion oxaliplatin: 85 mg/m2 IV infused over 2 hours leucovorin: 200 mg/m2 (Or levoleucovorin 100 mg/m2. If leucovorin is not available due to drug shortages the regimen should be administered with the leucovorin omitted) IV over 2 hours. Alternatively, leucovorin may be administered (via separate infusion lines) concurrently with oxaliplatin fluorouracil: 400 mg/m2 IV bolus over 5-15 minutes, then 2400 mg/m2 continuous IV infusion over 46 hours.

Units	Counts
Participants	BG00056

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Median

Full Range

years

Title

Denominators

Categories

Title	Measurements
	BG00056.9(31 to 79)

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG00027
Male	BG00029

Race (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
American Indian or Alaska Native	BG0000
Asian	BG0002

Region of Enrollment

Number

participants

Title

Denominators

Categories

United States

Title	Measurements
	BG00056

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Proportion of Patients Alive and Progression-free at 15 Months

Assuming that the number of treatment successes (alive and progression-free) is binomially distributed, proportion estimates along with their corresponding exact 95% confidence intervals will be calculated.

Posted

Number

proportion of participants

At 15 months from initiation of therapy

ID	Title	Description
OG000	Aflibercept (Combination Chemotherapy)	Patients receive aflibercept and fluorouracil and then continuously over 46 hours on days 1 and 15.If leucovorin is not available due to drug shortages the regimen should be administered with the leucovorin omitted. Correlative Studies are required to be available before enrolling on the study. A fresh biopsy is only required if there is insufficient material for analysis. Repeat tumor biopsies after 8 weeks of therapy are optional and will only be performed at the Ohio State University Medical Center.DCE MRI (dynamic contrast-enhanced magnetic resonance imaging)images at weeks 0, and after 8 weeks +/- 1 week of treatment(after Cycle 2). 18FDG-PET is a functional imaging technique that relies on tumor uptake of radiolabeled tracer 18 fluorodeoxyglucose (18FDG).FDG-PET is a widely-used imaging modality in the detection and monitoring of a variety of metastatic cancers,including colorectal cancer (99-102). aflibercept: 4 mg/kg as a 1-hour IV(intervenous) infusion oxaliplatin: 85 mg/m2 IV infused over 2 hours leucovorin: 200 mg/m2 (Or levoleucovorin 100 mg/m2. If leucovorin is not available due to drug shortages the regimen should be administered with the leucovorin omitted) IV over 2 hours. Alternatively, leucovorin may be administered (via separate infusion lines) concurrently with oxaliplatin fluorouracil: 400 mg/m2 IV bolus over 5-15 minutes, then 2400 mg/m2 continuous IV infusion over 46 hours.

Units	Counts
Participants	OG00056

Title

Denominators

Categories

Title	Measurements
	OG000.482

Secondary

Objective Response Rate (ORR) Defined as the Proportion of Patients Who Achieve a PR or CR Based on RECIST 1.1 Criteria Divided by the Total Number of Evaluable Patients

Summarized as a proportion with corresponding 95% confidence interval.

Posted

Number

proportion of participants

Up to 4 weeks post-treatment

ID	Title	Description
OG000	Aflibercept (Combination Chemotherapy)	Patients receive aflibercept and fluorouracil and then continuously over 46 hours on days 1 and 15.If leucovorin is not available due to drug shortages the regimen should be administered with the leucovorin omitted. Correlative Studies are required to be available before enrolling on the study. A fresh biopsy is only required if there is insufficient material for analysis. Repeat tumor biopsies after 8 weeks of therapy are optional and will only be performed at the Ohio State University Medical Center.DCE MRI (dynamic contrast-enhanced magnetic resonance imaging)images at weeks 0, and after 8 weeks +/- 1 week of treatment(after Cycle 2). 18FDG-PET is a functional imaging technique that relies on tumor uptake of radiolabeled tracer 18 fluorodeoxyglucose (18FDG).FDG-PET is a widely-used imaging modality in the detection and monitoring of a variety of metastatic cancers,including colorectal cancer (99-102). aflibercept: 4 mg/kg as a 1-hour IV(intervenous) infusion oxaliplatin: 85 mg/m2 IV infused over 2 hours leucovorin: 200 mg/m2 (Or levoleucovorin 100 mg/m2. If leucovorin is not available due to drug shortages the regimen should be administered with the leucovorin omitted) IV over 2 hours. Alternatively, leucovorin may be administered (via separate infusion lines) concurrently with oxaliplatin fluorouracil: 400 mg/m2 IV bolus over 5-15 minutes, then 2400 mg/m2 continuous IV infusion over 46 hours.

Secondary

Percentage of Patients Able to Undergo Surgery

Summarized as a proportion with corresponding 95% confidence interval.

Posted

Number

percentage of participants

Up to 4 weeks post-treatment

ID	Title	Description
OG000	Aflibercept (Combination Chemotherapy)	Patients receive aflibercept and fluorouracil and then continuously over 46 hours on days 1 and 15.If leucovorin is not available due to drug shortages the regimen should be administered with the leucovorin omitted. Correlative Studies are required to be available before enrolling on the study. A fresh biopsy is only required if there is insufficient material for analysis. Repeat tumor biopsies after 8 weeks of therapy are optional and will only be performed at the Ohio State University Medical Center.DCE MRI (dynamic contrast-enhanced magnetic resonance imaging)images at weeks 0, and after 8 weeks +/- 1 week of treatment(after Cycle 2). 18FDG-PET is a functional imaging technique that relies on tumor uptake of radiolabeled tracer 18 fluorodeoxyglucose (18FDG).FDG-PET is a widely-used imaging modality in the detection and monitoring of a variety of metastatic cancers,including colorectal cancer (99-102). aflibercept: 4 mg/kg as a 1-hour IV(intervenous) infusion oxaliplatin: 85 mg/m2 IV infused over 2 hours leucovorin: 200 mg/m2 (Or levoleucovorin 100 mg/m2. If leucovorin is not available due to drug shortages the regimen should be administered with the leucovorin omitted) IV over 2 hours. Alternatively, leucovorin may be administered (via separate infusion lines) concurrently with oxaliplatin fluorouracil: 400 mg/m2 IV bolus over 5-15 minutes, then 2400 mg/m2 continuous IV infusion over 46 hours.

Secondary

Progression Free Survival (PFS)

Will be evaluated using the methods of Kaplan and Meier.

Posted

Median

95% Confidence Interval

months

From study entry to the time of progressive disease and/or death, assessed up to 4 weeks post-treatment, assessed up to 4 years and 2 months

ID	Title	Description
OG000	Aflibercept (Combination Chemotherapy)	Patients receive aflibercept and fluorouracil and then continuously over 46 hours on days 1 and 15.If leucovorin is not available due to drug shortages the regimen should be administered with the leucovorin omitted. Correlative Studies are required to be available before enrolling on the study. A fresh biopsy is only required if there is insufficient material for analysis. Repeat tumor biopsies after 8 weeks of therapy are optional and will only be performed at the Ohio State University Medical Center.DCE MRI (dynamic contrast-enhanced magnetic resonance imaging)images at weeks 0, and after 8 weeks +/- 1 week of treatment(after Cycle 2). 18FDG-PET is a functional imaging technique that relies on tumor uptake of radiolabeled tracer 18 fluorodeoxyglucose (18FDG).FDG-PET is a widely-used imaging modality in the detection and monitoring of a variety of metastatic cancers,including colorectal cancer (99-102). aflibercept: 4 mg/kg as a 1-hour IV(intervenous) infusion oxaliplatin: 85 mg/m2 IV infused over 2 hours leucovorin: 200 mg/m2 (Or levoleucovorin 100 mg/m2. If leucovorin is not available due to drug shortages the regimen should be administered with the leucovorin omitted) IV over 2 hours. Alternatively, leucovorin may be administered (via separate infusion lines) concurrently with oxaliplatin fluorouracil: 400 mg/m2 IV bolus over 5-15 minutes, then 2400 mg/m2 continuous IV infusion over 46 hours.

Secondary

Overall Survival

Will be evaluated using the methods of Kaplan and Meier.

Posted

Median

95% Confidence Interval

months

From study entry to time of death due to any cause, assessed up to 4 weeks post-treatment

ID	Title	Description
OG000	Aflibercept (Combination Chemotherapy)	Patients receive aflibercept and fluorouracil and then continuously over 46 hours on days 1 and 15.If leucovorin is not available due to drug shortages the regimen should be administered with the leucovorin omitted. Correlative Studies are required to be available before enrolling on the study. A fresh biopsy is only required if there is insufficient material for analysis. Repeat tumor biopsies after 8 weeks of therapy are optional and will only be performed at the Ohio State University Medical Center.DCE MRI (dynamic contrast-enhanced magnetic resonance imaging)images at weeks 0, and after 8 weeks +/- 1 week of treatment(after Cycle 2). 18FDG-PET is a functional imaging technique that relies on tumor uptake of radiolabeled tracer 18 fluorodeoxyglucose (18FDG).FDG-PET is a widely-used imaging modality in the detection and monitoring of a variety of metastatic cancers,including colorectal cancer (99-102). aflibercept: 4 mg/kg as a 1-hour IV(intervenous) infusion oxaliplatin: 85 mg/m2 IV infused over 2 hours leucovorin: 200 mg/m2 (Or levoleucovorin 100 mg/m2. If leucovorin is not available due to drug shortages the regimen should be administered with the leucovorin omitted) IV over 2 hours. Alternatively, leucovorin may be administered (via separate infusion lines) concurrently with oxaliplatin fluorouracil: 400 mg/m2 IV bolus over 5-15 minutes, then 2400 mg/m2 continuous IV infusion over 46 hours.

Secondary

Incidence of Severe (Grade 3+) Adverse Events or Toxicities, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0

Posted

Number

percentage of patients

Up to 4 weeks post-treatment

ID	Title	Description
OG000	Aflibercept (Combination Chemotherapy)	Patients receive aflibercept and fluorouracil and then continuously over 46 hours on days 1 and 15.If leucovorin is not available due to drug shortages the regimen should be administered with the leucovorin omitted. Correlative Studies are required to be available before enrolling on the study. A fresh biopsy is only required if there is insufficient material for analysis. Repeat tumor biopsies after 8 weeks of therapy are optional and will only be performed at the Ohio State University Medical Center.DCE MRI (dynamic contrast-enhanced magnetic resonance imaging)images at weeks 0, and after 8 weeks +/- 1 week of treatment(after Cycle 2). 18FDG-PET is a functional imaging technique that relies on tumor uptake of radiolabeled tracer 18 fluorodeoxyglucose (18FDG).FDG-PET is a widely-used imaging modality in the detection and monitoring of a variety of metastatic cancers,including colorectal cancer (99-102). aflibercept: 4 mg/kg as a 1-hour IV(intervenous) infusion oxaliplatin: 85 mg/m2 IV infused over 2 hours leucovorin: 200 mg/m2 (Or levoleucovorin 100 mg/m2. If leucovorin is not available due to drug shortages the regimen should be administered with the leucovorin omitted) IV over 2 hours. Alternatively, leucovorin may be administered (via separate infusion lines) concurrently with oxaliplatin fluorouracil: 400 mg/m2 IV bolus over 5-15 minutes, then 2400 mg/m2 continuous IV infusion over 46 hours.

Secondary

Tolerability in Terms of Number of Patients Who Require Dose Modifications and/or Dose Delays

Posted

Count of Participants

Participants

Up to 4 weeks post-treatment

ID	Title	Description
OG000	Aflibercept (Combination Chemotherapy)	Patients receive aflibercept and fluorouracil and then continuously over 46 hours on days 1 and 15.If leucovorin is not available due to drug shortages the regimen should be administered with the leucovorin omitted. Correlative Studies are required to be available before enrolling on the study. A fresh biopsy is only required if there is insufficient material for analysis. Repeat tumor biopsies after 8 weeks of therapy are optional and will only be performed at the Ohio State University Medical Center.DCE MRI (dynamic contrast-enhanced magnetic resonance imaging)images at weeks 0, and after 8 weeks +/- 1 week of treatment(after Cycle 2). 18FDG-PET is a functional imaging technique that relies on tumor uptake of radiolabeled tracer 18 fluorodeoxyglucose (18FDG).FDG-PET is a widely-used imaging modality in the detection and monitoring of a variety of metastatic cancers,including colorectal cancer (99-102). aflibercept: 4 mg/kg as a 1-hour IV(intervenous) infusion oxaliplatin: 85 mg/m2 IV infused over 2 hours leucovorin: 200 mg/m2 (Or levoleucovorin 100 mg/m2. If leucovorin is not available due to drug shortages the regimen should be administered with the leucovorin omitted) IV over 2 hours. Alternatively, leucovorin may be administered (via separate infusion lines) concurrently with oxaliplatin fluorouracil: 400 mg/m2 IV bolus over 5-15 minutes, then 2400 mg/m2 continuous IV infusion over 46 hours.

Secondary

Proportion of Patients Who go Off Treatment Due to Adverse Reactions or Even Those Who Refuse Further Treatment for Lesser Toxicities That Inhibit Their Willingness to Continue Participation on the Trial

Posted

Count of Participants

Participants

Up to 4 weeks post-treatment

ID	Title	Description
OG000	Aflibercept (Combination Chemotherapy)	Patients receive aflibercept and fluorouracil and then continuously over 46 hours on days 1 and 15.If leucovorin is not available due to drug shortages the regimen should be administered with the leucovorin omitted. Correlative Studies are required to be available before enrolling on the study. A fresh biopsy is only required if there is insufficient material for analysis. Repeat tumor biopsies after 8 weeks of therapy are optional and will only be performed at the Ohio State University Medical Center.DCE MRI (dynamic contrast-enhanced magnetic resonance imaging)images at weeks 0, and after 8 weeks +/- 1 week of treatment(after Cycle 2). 18FDG-PET is a functional imaging technique that relies on tumor uptake of radiolabeled tracer 18 fluorodeoxyglucose (18FDG).FDG-PET is a widely-used imaging modality in the detection and monitoring of a variety of metastatic cancers,including colorectal cancer (99-102). aflibercept: 4 mg/kg as a 1-hour IV(intervenous) infusion oxaliplatin: 85 mg/m2 IV infused over 2 hours leucovorin: 200 mg/m2 (Or levoleucovorin 100 mg/m2. If leucovorin is not available due to drug shortages the regimen should be administered with the leucovorin omitted) IV over 2 hours. Alternatively, leucovorin may be administered (via separate infusion lines) concurrently with oxaliplatin fluorouracil: 400 mg/m2 IV bolus over 5-15 minutes, then 2400 mg/m2 continuous IV infusion over 46 hours.

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Aflibercept (Combination Chemotherapy)	Patients receive aflibercept and fluorouracil and then continuously over 46 hours on days 1 and 15.If leucovorin is not available due to drug shortages the regimen should be administered with the leucovorin omitted. Correlative Studies are required to be available before enrolling on the study. A fresh biopsy is only required if there is insufficient material for analysis. Repeat tumor biopsies after 8 weeks of therapy are optional and will only be performed at the Ohio State University Medical Center.DCE MRI (dynamic contrast-enhanced magnetic resonance imaging)images at weeks 0, and after 8 weeks +/- 1 week of treatment(after Cycle 2). 18FDG-PET is a functional imaging technique that relies on tumor uptake of radiolabeled tracer 18 fluorodeoxyglucose (18FDG).FDG-PET is a widely-used imaging modality in the detection and monitoring of a variety of metastatic cancers,including colorectal cancer (99-102). aflibercept: 4 mg/kg as a 1-hour IV(intervenous) infusion oxaliplatin: 85 mg/m2 IV infused over 2 hours leucovorin: 200 mg/m2 (Or levoleucovorin 100 mg/m2. If leucovorin is not available due to drug shortages the regimen should be administered with the leucovorin omitted) IV over 2 hours. Alternatively, leucovorin may be administered (via separate infusion lines) concurrently with oxaliplatin fluorouracil: 400 mg/m2 IV bolus over 5-15 minutes, then 2400 mg/m2 continuous IV infusion over 46 hours.	1	56	7	56	56	56

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Hypertension	Vascular disorders	CTCAE (4.0)	Systematic Assessment	EG0004 events4 affected56 at risk
Infusion related reaction	Injury, poisoning and procedural complications	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected56 at risk
Nausea	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected56 at risk
Non-Cardiac Chest Pain	General disorders	CTCAE (4.0)	Systematic Assessment	EG0002 events2 affected56 at risk
Palmar-plantar erythrodysesthesia	Skin and subcutaneous tissue disorders	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected56 at risk
Pericardial effusion	Cardiac disorders	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected56 at risk
Pleural effusion	Respiratory, thoracic and mediastinal disorders	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected56 at risk
Thromboembolic event	Vascular disorders	CTCAE (4.0)	Systematic Assessment	EG0007 events7 affected56 at risk
Vascular access complication	Injury, poisoning and procedural complications	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected56 at risk
Vomiting	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected56 at risk
Wound complication	Injury, poisoning and procedural complications	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected56 at risk
Abdominal Pain	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG0002 events2 affected56 at risk
Colonic perforation	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected56 at risk
Colonic obstruction	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected56 at risk
Constipation	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected56 at risk
Diarrhea	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected56 at risk
Catheter related infection	Infections and infestations	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected56 at risk
Dyspnea	Respiratory, thoracic and mediastinal disorders	CTCAE (4.0)	Systematic Assessment	EG0002 events2 affected56 at risk
Ileal obststruction	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected56 at risk
Fever	General disorders	CTCAE (4.0)	Systematic Assessment	EG0002 events2 affected56 at risk
Pain	General disorders	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected56 at risk
Syncope	Nervous system disorders	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected56 at risk
Headache	Nervous system disorders	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected56 at risk
Acute Kidney Injury	Renal and urinary disorders	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected56 at risk
Creatinine increased	Investigations	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected56 at risk
Dizziness	Nervous system disorders	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected56 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Abdominal pain	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG00011 events11 affected56 at risk
Alanine aminotransferase increased	Investigations	CTCAE (4.0)	Systematic Assessment	EG00015 events15 affected56 at risk
Alkaline phosphatase increased	Investigations	CTCAE (4.0)	Systematic Assessment	EG00024 events24 affected56 at risk
Alopecia	Skin and subcutaneous tissue disorders	CTCAE (4.0)	Systematic Assessment	EG0003 events3 affected56 at risk
Anemia	Blood and lymphatic system disorders	CTCAE (4.0)	Systematic Assessment	EG00031 events31 affected56 at risk
Anorexia	Metabolism and nutrition disorders	CTCAE (4.0)	Systematic Assessment	EG00018 events18 affected56 at risk
Anxiety	Psychiatric disorders	CTCAE (4.0)	Systematic Assessment	EG0007 events7 affected56 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	CTCAE (4.0)	Systematic Assessment	EG0003 events3 affected56 at risk
Aspartate aminotransferase increased	Investigations	CTCAE (4.0)	Systematic Assessment	EG00025 events25 affected56 at risk
Back pain	Musculoskeletal and connective tissue disorders	CTCAE (4.0)	Systematic Assessment	EG00010 events10 affected56 at risk
Blood bilirubin increased	Investigations	CTCAE (4.0)	Systematic Assessment	EG0008 events8 affected56 at risk
Blurred vision	Eye disorders	CTCAE (4.0)	Systematic Assessment	EG0006 events6 affected56 at risk
Chills	General disorders	CTCAE (4.0)	Systematic Assessment	EG0004 events4 affected56 at risk
Cholesterol high	Investigations	CTCAE (4.0)	Systematic Assessment	EG00021 events21 affected56 at risk
Constipation	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG00025 events25 affected56 at risk
Cough	Respiratory, thoracic and mediastinal disorders	CTCAE (4.0)	Systematic Assessment	EG0007 events7 affected56 at risk
Creatinine increased	Renal and urinary disorders	CTCAE (4.0)	Systematic Assessment	EG00010 events10 affected56 at risk
Dehydration	Metabolism and nutrition disorders	CTCAE (4.0)	Systematic Assessment	EG0006 events6 affected56 at risk
Depression	Psychiatric disorders	CTCAE (4.0)	Systematic Assessment	EG0005 events5 affected56 at risk
Diarrhea	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG00031 events31 affected56 at risk
Dizziness	Nervous system disorders	CTCAE (4.0)	Systematic Assessment	EG00016 events16 affected56 at risk
Dry mouth	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG0003 events3 affected56 at risk
Dry skin	Skin and subcutaneous tissue disorders	CTCAE (4.0)	Systematic Assessment	EG0003 events3 affected56 at risk
Dysgeusia	Nervous system disorders	CTCAE (4.0)	Systematic Assessment	EG00011 events11 affected56 at risk
Dyspepsia	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG0004 events4 affected56 at risk
Dyspnea	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG00017 events17 affected56 at risk
Epistaxis	Respiratory, thoracic and mediastinal disorders	CTCAE (4.0)	Systematic Assessment	EG00011 events11 affected56 at risk
Fatigue	General disorders	CTCAE (4.0)	Systematic Assessment	EG00034 events34 affected56 at risk
Fever	General disorders	CTCAE (4.0)	Systematic Assessment	EG0003 events3 affected56 at risk
Flatulence	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG0003 events3 affected56 at risk
Gastrointestinal disorders - Other, specify	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG0005 events5 affected56 at risk
Headache	Nervous system disorders	CTCAE (4.0)	Systematic Assessment	EG00016 events16 affected56 at risk
Hematuria	Renal and urinary disorders	CTCAE (4.0)	Systematic Assessment	EG00010 events10 affected56 at risk
Hemorrhoids	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG0003 events3 affected56 at risk
Hiccups	Respiratory, thoracic and mediastinal disorders	CTCAE (4.0)	Systematic Assessment	EG0004 events4 affected56 at risk
Hoarseness	Respiratory, thoracic and mediastinal disorders	CTCAE (4.0)	Systematic Assessment	EG00011 events11 affected56 at risk
Hypercalcemia	Metabolism and nutrition disorders	CTCAE (4.0)	Systematic Assessment	EG0006 events6 affected56 at risk
Hyperglycemia	Metabolism and nutrition disorders	CTCAE (4.0)	Systematic Assessment	EG00023 events23 affected56 at risk
Hyperkalemia	Investigations	CTCAE (4.0)	Systematic Assessment	EG0007 events7 affected56 at risk
Hypernatremia	Metabolism and nutrition disorders	CTCAE (4.0)	Systematic Assessment	EG0005 events5 affected56 at risk
Hypertension	Vascular disorders	CTCAE (4.0)	Systematic Assessment	EG00037 events37 affected56 at risk
Hypertriglyceridemia	Metabolism and nutrition disorders	CTCAE (4.0)	Systematic Assessment	EG00022 events22 affected56 at risk
Hypoalbuminemia	Metabolism and nutrition disorders	CTCAE (4.0)	Systematic Assessment	EG00020 events20 affected56 at risk
Hypocalcemia	Metabolism and nutrition disorders	CTCAE (4.0)	Systematic Assessment	EG0004 events4 affected56 at risk
Hypoglycemia	Metabolism and nutrition disorders	CTCAE (4.0)	Systematic Assessment	EG0004 events4 affected56 at risk
Hypokalemia	Metabolism and nutrition disorders	CTCAE (4.0)	Systematic Assessment	EG00010 events10 affected56 at risk
Hypomagnesemia	Metabolism and nutrition disorders	CTCAE (4.0)	Systematic Assessment	EG0003 events3 affected56 at risk
Hyponatremia	Metabolism and nutrition disorders	CTCAE (4.0)	Systematic Assessment	EG00013 events13 affected56 at risk
Hypotension	Vascular disorders	CTCAE (4.0)	Systematic Assessment	EG0006 events6 affected56 at risk
Insomnia	Psychiatric disorders	CTCAE (4.0)	Systematic Assessment	EG0005 events5 affected56 at risk
Lymphocyte count decreased	Investigations	CTCAE (4.0)	Systematic Assessment	EG00022 events22 affected56 at risk
Mucositis oral	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG00031 events31 affected56 at risk
Musculoskeletal and connective tissue disorder - Other, specify	Musculoskeletal and connective tissue disorders	CTCAE (4.0)	Systematic Assessment	EG0004 events4 affected56 at risk
Myalgia	Musculoskeletal and connective tissue disorders	CTCAE (4.0)	Systematic Assessment	EG0003 events3 affected56 at risk
Nail discoloration	Skin and subcutaneous tissue disorders	CTCAE (4.0)	Systematic Assessment	EG0003 events3 affected56 at risk
Nasal congestion	Respiratory, thoracic and mediastinal disorders	CTCAE (4.0)	Systematic Assessment	EG0004 events4 affected56 at risk
Nausea	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG00040 events40 affected56 at risk
Cold Sensitivity	Nervous system disorders	CTCAE (4.0)	Systematic Assessment	EG0004 events4 affected56 at risk
Neutrophil count decreased	Investigations	CTCAE (4.0)	Systematic Assessment	EG00028 events28 affected56 at risk
Non cardiac chest pain	General disorders	CTCAE (4.0)	Systematic Assessment	EG0006 events6 affected56 at risk
Oral pain	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG0005 events5 affected56 at risk
Pain	General disorders	CTCAE (4.0)	Systematic Assessment	EG00010 events10 affected56 at risk
Pain in Extremity	Musculoskeletal and connective tissue disorders	CTCAE (4.0)	Systematic Assessment	EG00013 events13 affected56 at risk
Palmar-plantar erythrodysesthesia syndrome	Skin and subcutaneous tissue disorders	CTCAE (4.0)	Systematic Assessment	EG00019 events19 affected56 at risk
Paresthesia	Nervous system disorders	CTCAE (4.0)	Systematic Assessment	EG00014 events14 affected56 at risk
Peripheral sensory neuropathy	Nervous system disorders	CTCAE (4.0)	Systematic Assessment	EG00033 events33 affected56 at risk
Platelet count decreased	Investigations	CTCAE (4.0)	Systematic Assessment	EG00029 events29 affected56 at risk
Proteinuria	Renal and urinary disorders	CTCAE (4.0)	Systematic Assessment	EG00021 events21 affected56 at risk
Pruritus	Skin and subcutaneous tissue disorders	CTCAE (4.0)	Systematic Assessment	EG0003 events3 affected56 at risk
Rash acneiform	Skin and subcutaneous tissue disorders	CTCAE (4.0)	Systematic Assessment	EG0003 events3 affected56 at risk
Rash maculo-papular	Skin and subcutaneous tissue disorders	CTCAE (4.0)	Systematic Assessment	EG00010 events10 affected56 at risk
Rectal hemorrhage	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG0003 events3 affected56 at risk
Rectal pain	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG0007 events7 affected56 at risk
Renal and urinary disorders - Other, specify	Renal and urinary disorders	CTCAE (4.0)	Systematic Assessment	EG0005 events5 affected56 at risk
Respiratory, thoracic and mediastinal disorders - Other, specify	Respiratory, thoracic and mediastinal disorders	CTCAE (4.0)	Systematic Assessment	EG0004 events4 affected56 at risk
Skin and subcutaneous tissue disorders - Other, specify	Skin and subcutaneous tissue disorders	CTCAE (4.0)	Systematic Assessment	EG00011 events11 affected56 at risk
Skin hyperpigmentation	Skin and subcutaneous tissue disorders	CTCAE (4.0)	Systematic Assessment	EG00010 events10 affected56 at risk
Sore throat	Respiratory, thoracic and mediastinal disorders	CTCAE (4.0)	Systematic Assessment	EG0005 events5 affected56 at risk
Thromboembolic event	Vascular disorders	CTCAE (4.0)	Systematic Assessment	EG00011 events11 affected56 at risk
Tremor	Nervous system disorders	CTCAE (4.0)	Systematic Assessment	EG0004 events4 affected56 at risk
Upper respiratory infection	Infections and infestations	CTCAE (4.0)	Systematic Assessment	EG0003 events3 affected56 at risk
Urinary tract infection	Infections and infestations	CTCAE (4.0)	Systematic Assessment	EG0008 events8 affected56 at risk
Voice alteration	Respiratory, thoracic and mediastinal disorders	CTCAE (4.0)	Systematic Assessment	EG0004 events4 affected56 at risk
Vomiting	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG00030 events30 affected56 at risk
Weight loss	Investigations	CTCAE (4.0)	Systematic Assessment	EG00016 events16 affected56 at risk
White blood cell decreased	Investigations	CTCAE (4.0)	Systematic Assessment	EG00024 events24 affected56 at risk

ID	Term
D003110	Colonic Neoplasms
D012004	Rectal Neoplasms
D015179	Colorectal Neoplasms

Ancestor Terms

ID	Term
D007414	Intestinal Neoplasms
D005770	Gastrointestinal Neoplasms
D004067	Digestive System Neoplasms
D009371	Neoplasms by Site
D009369	Neoplasms
D004066	Digestive System Diseases
D005767	Gastrointestinal Diseases
D003108	Colonic Diseases
D007410	Intestinal Diseases
D012002	Rectal Diseases

ID	Term
C533178	aflibercept
D000077150	Oxaliplatin
D002955	Leucovorin
D005472	Fluorouracil
D019788	Fluorodeoxyglucose F18
D009682	Magnetic Resonance Spectroscopy
C062942	2-phenyl-6-(2'-(4'-(ethoxycarbonyl)thiazolyl))thiazolo(3,2-b)(1,2,4)triazole

Ancestor Terms

ID	Term
D056831	Coordination Complexes
D009930	Organic Chemicals
D005575	Formyltetrahydrofolates
D013763	Tetrahydrofolates
D005492	Folic Acid
D011622	Pterins
D011621	Pteridines
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring
D006571	Heterocyclic Compounds
D003067	Coenzymes
D045762	Enzymes and Coenzymes
D014498	Uracil
D011744	Pyrimidinones
D011743	Pyrimidines
D006573	Heterocyclic Compounds, 1-Ring
D003847	Deoxyglucose
D003837	Deoxy Sugars
D002241	Carbohydrates
D013057	Spectrum Analysis
D002623	Chemistry Techniques, Analytical
D008919	Investigative Techniques

Units	Counts
Participants	OG00056

Units	Counts
Participants	OG00056

Units	Counts
Participants	OG00056

Units	Counts
Participants	OG00056