Aflibercept and FOLFOX6 Treatment for Previously Untreated Stage IV Colorectal Cancer
|ClinicalTrials.gov Identifier: NCT01652196|
Recruitment Status : Active, not recruiting
First Posted : July 27, 2012
Last Update Posted : May 24, 2018
|Condition or disease||Intervention/treatment||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|
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.
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.
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.
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||56 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
|Actual Study Start Date :||November 14, 2012|
|Estimated Primary Completion Date :||December 31, 2018|
|Estimated Study Completion Date :||December 31, 2018|
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).
4 mg/kg as a 1-hour IV(intervenous) infusion
Other Names:Drug: oxaliplatin
85 mg/m2 IV infused over 2 hours
Other Names: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:Drug: fluorouracil
400 mg/m2 IV bolus over 5-15 minutes, then 2400 mg/m2 continuous IV infusion over 46 hours.
Other Names: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 analysisProcedure: DCE MRI
Images at weeks 0, and after 8 weeks +/- 1 week of treatment (after Cycle 2).
Other Name: Dynamic contrast-enhanced magnetic resonance imagingRadiation: 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:Procedure: PET (positron emission tomography)
- Proportion of patients alive and progression-free [ Time Frame: At 15 months from initiation of therapy ]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.
- 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 ]Summarized as a proportion with corresponding 95% confidence interval.
- Percentage of patients able to undergo surgery [ Time Frame: Up to 4 weeks post-treatment ]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 ]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 ]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 ]
- Tolerability in terms of number of patients who require dose modifications and/or dose delays [ Time Frame: Up to 4 weeks post-treatment ]
- 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 ]
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01652196
|United States, Michigan|
|University of Michigan|
|Ann Arbor, Michigan, United States, 48109|
|United States, New York|
|Montefiore Medical Center|
|Bronx, New York, United States, 10461|
|Roswell Park Cancer Institute|
|Buffalo, New York, United States, 14263|
|United States, North Carolina|
|University of North Carolina|
|Chapel Hill, North Carolina, United States, 27599|
|United States, Ohio|
|Ohio State University Medical Center|
|Columbus, Ohio, United States, 43210|
|United States, Virginia|
|Virginia Commonwealth University|
|Richmond, Virginia, United States, 23298|
|Principal Investigator:||John Hays, MD||Ohio State University Comprehensive Cancer Center|