Aflibercept and FOLFOX6 Treatment for Previously Untreated Stage IV Colorectal Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by Ohio State University Comprehensive Cancer Center
Sponsor:
Collaborator:
Sanofi
Information provided by (Responsible Party):
Richard Goldberg, Ohio State University Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT01652196
First received: July 25, 2012
Last updated: March 18, 2014
Last verified: March 2014
  Purpose

This phase II trial studies how well giving aflibercept together with combination chemotherapy works in treating patients with previously untreated colon or rectal cancer that is metastatic or locally advanced and cannot be removed by surgery. Aflibercept may stop the growth of colon or rectal cancer by blocking blood flow to the tumor. Drugs used in chemotherapy, such as leucovorin calcium, fluorouracil, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving aflibercept together with combination chemotherapy may kill more tumor cells


Condition Intervention Phase
Mucinous Adenocarcinoma of the Colon
Mucinous Adenocarcinoma of the Rectum
Signet Ring Adenocarcinoma of the Colon
Signet Ring Adenocarcinoma of the Rectum
Stage IV Colon Cancer
Stage IV Rectal Cancer
Biological: aflibercept
Drug: oxaliplatin
Drug: leucovorin
Drug: fluorouracil
Other: Correlative Studies
Procedure: DCE MRI
Radiation: f18FDG-PET
Procedure: PET (positron emission tomography)
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of the Combination of Aflibercept (VEGF-Trap) Plus Modified FOLFOX 6 in Patients With Previously Untreated Metastatic Colorectal Cancer

Resource links provided by NLM:


Further study details as provided by Ohio State University Comprehensive Cancer Center:

Primary Outcome Measures:
  • Proportion of patients alive and progression-free [ Time Frame: At 15 months from initiation of therapy ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • 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 [ Time Frame: Up to 4 weeks post-treatment ] [ Designated as safety issue: No ]
    Summarized as a proportion with corresponding 95% confidence interval.

  • Percentage of patients able to undergo surgery [ Time Frame: Up to 4 weeks post-treatment ] [ Designated as safety issue: No ]
    Summarized as a proportion with corresponding 95% confidence interval.

  • Progression free survival (PFS) [ Time Frame: From study entry to the time of progressive disease and/or death, assessed up to 4 weeks post-treatment ] [ Designated as safety issue: No ]
    Will be evaluated using the methods of Kaplan and Meier.

  • Overall survival [ Time Frame: From study entry to time of death due to any cause, assessed up to 4 weeks post-treatment ] [ Designated as safety issue: No ]
    Will be evaluated using the methods of Kaplan and Meier.

  • Incidence of severe (grade 3+) adverse events or toxicities, assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [ Time Frame: Up to 4 weeks post-treatment ] [ Designated as safety issue: Yes ]
  • Tolerability in terms of number of patients who require dose modifications and/or dose delays [ Time Frame: Up to 4 weeks post-treatment ] [ Designated as safety issue: Yes ]
  • 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 [ Time Frame: Up to 4 weeks post-treatment ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 70
Study Start Date: November 2012
Estimated Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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).
Biological: aflibercept
4 mg/kg as a 1-hour IV(intervenous) infusion
Other Names:
  • vascular endothelial growth factor trap
  • VEGF Trap
  • VEGF Trap R1R2
Drug: oxaliplatin
85 mg/m2 IV infused over 2 hours
Other Names:
  • 1-OHP
  • Dacotin
  • Dacplat
  • Eloxatin
  • L-OHP
Drug: 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
Other Names:
  • CF
  • CFR
  • LV
Drug: fluorouracil
400 mg/m2 IV bolus over 5-15 minutes, then 2400 mg/m2 continuous IV infusion over 46 hours.
Other Names:
  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU
Other: Correlative Studies
Patients are required to have tissue 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.
Other Name: laboratory biomarker analysis
Procedure: DCE MRI
Images at weeks 0, and after 8 weeks +/- 1 week of treatment (after Cycle 2).
Other Name: Dynamic contrast-enhanced magnetic resonance imaging
Radiation: f18FDG-PET
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).
Other Names:
  • 18FDG
  • FDG
  • fludeoxyglucose
  • F 18
Procedure: PET (positron emission tomography)
Correlative studies
Other Names:
  • FDG-PET
  • PET
  • PET scan
  • tomography, emission computed

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01652196

Contacts
Contact: Ohio State University Comprehensive Cancer Center 1-800-293-5066 Jamesline@osumc.edu
Contact: Richard Goldberg, MD 614-366-6355 Richard.Goldberg@osumc.edu

Locations
United States, Alabama
Clearview Cancer Institute Recruiting
Huntsville, Alabama, United States, 35805
Contact: Avitra Bone    256-705-4283    avitrab@ccihsv.com   
Principal Investigator: Clint D Kingsley, MD         
United States, Michigan
University of Michigan Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: John Krauss, MD    734-615-3969    jkrauss@med.umich.edu   
Principal Investigator: John Krauss, MD         
United States, New York
Montefiore Medical Center Not yet recruiting
Bronx, New York, United States, 10461
Contact: Sanjay Goel, MD    719-904-2488    SGOEL@montifiore.org   
Principal Investigator: Sanjay Goel, MD         
Roswell Park Cancer Institute Recruiting
Buffalo, New York, United States, 14263
Contact: Wen W. Ma    716-845-3851    wenwee.ma@roswellpark.org   
Principal Investigator: Wen W. Ma         
United States, North Carolina
University of North Carolina Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Autumn McRee, MD    919-843-6286    autumn_mcree@med.unc.edu   
Contact: Melissa Haines    919-843-7719    Melissa_haines@med.unc.edu   
Principal Investigator: Autumn McRee, MD         
United States, Ohio
Ohio State University Medical Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Goldberg Richard    614-366-6355    Richard.Goldberg@osumc.edu   
Principal Investigator: Goldberg Richard, MD         
United States, Virginia
Virginia Commonwealth University Not yet recruiting
Richmond, Virginia, United States, 23298
Contact: Khalid Martin, MD    804-628-2945    kmartin@vcu.edu   
Principal Investigator: Khalid Martin, MD         
Sponsors and Collaborators
Richard Goldberg
Sanofi
Investigators
Principal Investigator: Goldberg Richard, MD Ohio State University Comprehensive Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: Richard Goldberg, Principal Investigator, Ohio State University Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT01652196     History of Changes
Other Study ID Numbers: OSU 11182, NCI-2012-01167
Study First Received: July 25, 2012
Last Updated: March 18, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Ohio State University Comprehensive Cancer Center:
colorectal cancer
rectal cancer
FOLFOX
Aflibercept

Additional relevant MeSH terms:
Cystadenocarcinoma
Adenocarcinoma
Colonic Neoplasms
Rectal Neoplasms
Adenocarcinoma, Mucinous
Colorectal Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Neoplasms, Cystic, Mucinous, and Serous
Fluorouracil
Oxaliplatin
Leucovorin
Endothelial Growth Factors
Levoleucovorin
Fluorodeoxyglucose F18
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antimetabolites, Antineoplastic

ClinicalTrials.gov processed this record on August 28, 2014