FOLFOX +/- Ziv-Aflibercept for Esophageal and Gastric Cancer
This research study is a Phase II clinical trial to test the safety and effectiveness of the investigational drug Ziv-aflibercept in combination with mFOLFOX6 compared to mFOLFOX6 alone. The drugs used in mFOLFOX6 include Fluorouracil (5-FU), Leucovorin and Oxaliplatin.
In patients with esophagogastric cancer, mFOLFOX6 has been used in both clinical trials and standard of care. "Investigational" means that the FDA has not yet approved this combination for the treatment of esophagogastric cancer.
Every person has molecules in their bloodstream called vascular endothelial growth factors (VEGFs). These molecules help grow and sustain new blood vessels needed by the human body. Cancer tumors hijack this mechanism because they need new blood vessels and oxygen to grow. Ziv-aflibercept is an antibody, a "targeted therapy" called a "VEGF Trap", that "traps" (binds) these VEGFs and prevents the cancer from using them to grow. Ziv-aflibercept has recently been approved by the FDA for patients with treatment-resistant colorectal cancer. Patients who received standard 5-fluoruracil based chemotherapy pus ziv-aflibercept lived significantly longer than those patients who received standard 5-fluoruracil alone.
In this research study, investigators will see if adding ziv-aflibercept to standard chemotherapy (mFOLFOX6) works better than mFOLFOX6 chemotherapy alone in patients with metastatic or unresectable esophagogastric cancer.
Drug: Folinic Acid
Drug: Ziv-aflibercept Placebo
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver)
Primary Purpose: Treatment
|Official Title:||Randomized, Double-Blind, Placebo Controlled Phase II Study of FOLFOX +/- Ziv-Aflibercept in Patients With Advanced Esophageal and Gastric Cancer|
- Estimate efficacy of Ziv-aflibercept+mFOLFOX6 in esophagogastric adenocarcinomas, as measured by progression-free survival (PFS). [ Time Frame: 2 years ] [ Designated as safety issue: No ]To estimate the efficacy of Ziv-aflibercept used in combination with mFOLFOX6 in patients with previously untreated advanced esophagogastric adenocarcinoma, as measured by progression-free survival (PFS), measured from the date of initial treatment to first objective documentation of progressive disease or date of death, whichever occurs first.
- Evaluate safety and tolerability of Ziv-aflibercept+mFOLFOX6 by evaluating toxicity and the number of adverse events. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]To evaluate the safety and tolerability of Ziv-aflibercept in combination with mFOLFOX6 vs. mFOLFOX6 alone in previously untreated patients with advanced esophagogastric adenocarcinoma
- Evaluate response rate using RECIST 1.1. [ Time Frame: 2 years ] [ Designated as safety issue: No ]To evaluate the response rate in previously untreated patients with advanced esophagogastric adenocarcinoma treated with Ziv-aflibercept in combination with mFOLFOX6 vs. mFOLFOX6 alone, using RECIST version 1.1 (Partial Response[PR], Complete Response [CR], Stable Disease [SD])
- Estimate duration of objective response [ Time Frame: 2 years ] [ Designated as safety issue: No ]To estimate duration of objective response and overall survival in patients treated with Ziv-aflibercept in combination with mFOLFOX6 vs. mFOLFOX6 alone
- Evaluate blood plasma levels [ Time Frame: 2 years ] [ Designated as safety issue: No ]To evaluate blood plasma levels of VEGFA and VEGFR2 (pVEGFA, pVEGFR2) as potential predictive biomarkers for treatment with Ziv-aflibercept, comparing patients treated with mFOLFOX6 alone versus mFOLFOX6 plus Ziv-aflibercept.
- Evaluate baseline expression of tumor tissue [ Time Frame: 2 years ] [ Designated as safety issue: No ]To evaluate the baseline expression of tumor tissue neuropilin 1 (NRP 1), neuropilin 2 (NRP 2), transforming growth factor-b1 (TGFb-type1 receptor), and Smad 2/3 as potential predictive biomarkers for response to treatment with mFOLFOX 6 versus mFOLFOX6 plus Ziv-aflibercept.
|Study Start Date:||September 2013|
|Estimated Primary Completion Date:||September 2016 (Final data collection date for primary outcome measure)|
Active Comparator: mFOLFOX6 + Ziv-aflibercept
Ziv-aflibercept given via intravenous infusion over 1 hour every 2 weeks mFOLFOX6 will be infused every 2 weeks: oxaliplatin IV over 2 hours, Folinic Acid IV over 2 hours, 5-FU IV bolus followed by continuous infusion via ambulatory infusion pump for 46-48 hours
Drug: Folinic Acid
Other Name: LeucovorinDrug: 5-Fluorouracil
Other Name: 5-FUDrug: Ziv-aflibercept
Active Comparator: mFOLFOX6 + Placebo
Ziv-aflibercept placebo given via intravenous infusion over 1 hour every 2 weeks mFOLFOX6 will be infused every 2 weeks: oxaliplatin IV over 2 hours, Folinic Acid IV over 2 hours, 5-FU IV bolus followed by continuous infusion via ambulatory infusion pump for 46-48 hours
Drug: Folinic Acid
Other Name: LeucovorinDrug: 5-Fluorouracil
Other Name: 5-FUDrug: Ziv-aflibercept Placebo
If patients agree to participate in this research study, they will be asked to undergo some screening tests or procedures to find out if they are eligible. Many of these tests and procedures are likely to be part of regular cancer care and may be done even if it turns out that patients do not take part in this research study. If patients have had some of these tests or procedures recently, they may or may not have to be repeated. These tests and procedures include: a medical history, physical examination, EKG, CT, Blood tests, pregnancy test, urine test, additional blood tests for research and a collection of archival tumor tissue. The screening tests will be reviewed by the doctor and the study team and if the patient meets the eligibility criteria for this study, they will begin treatment. If the patient does not meet the eligibility criteria, they will not be able to participate in this research study.
After the screening procedures confirm that a participant is eligible to participate in the research study, they will be "randomized" into one of two groups. A participant will receive either:
mFOLFOX6 with Ziv-aflibercept -or- mFOLFOX6 with Placebo (A Placebo contains no medicine)
Randomization means that a participant is put into a group by chance (like flipping a coin). Neither the participant nor the research doctor will choose what group the participant will be in. Randomization will be 2:1 (twice as many of the participants in this study will receive mFOLFOX6+Ziv-aflibercept). This study is "blinded", which means neither the patient nor the doctor will know if the patient is getting the investigational drug or the placebo with the mFOLFOX6.
Before a participant begins mFOLFOX6 chemotherapy, they will have a central venous line inserted for the intravenous (in a vein) chemotherapy administration. This is called a "port" or vascular access device. Insertion of the port is a minor outpatient surgical procedure that is performed by a surgeon or interventional radiologist depending on where it is done. The doctor will arrange for the participant to have this procedure done before the participant begins.
mFOLFOX6 is a combination of chemotherapy including oxaliplatin, leucovorin, and 5-FU. The oxaliplatin and leucovorin are given intravenously over 2 hours. The 5-FU is also given intravenously. The participant will get a shot of 5-FU by the infusion nurse and then will be hooked up to a portable pump which will infuse the rest of the 5-FU slowly over the next 46-48 hours. The participant can either disconnect the pump at home, or return to the infusion unit to have it disconnected. The participant, the caregivers and the nurse will discuss the best option for disconnecting the pump and the patient will receive instructions on how to do this at home, if applicable.
Ziv-aflibercept/Placebo will be given over 1 hour intravenously.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01747551
|United States, Massachusetts|
|Massachusetts General Hospital|
|Boston, Massachusetts, United States, 02214|
|Dana-Farber Cancer Institute|
|Boston, Massachusetts, United States, 02215|
|Principal Investigator:||Peter Enzinger, MD||Dana-Farber Cancer Institute|