FOLFOX +/- Ziv-Aflibercept for Esophageal and Gastric Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Dana-Farber Cancer Institute
Sponsor:
Information provided by (Responsible Party):
Peter C. Enzinger, MD, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier:
NCT01747551
First received: December 5, 2012
Last updated: August 7, 2014
Last verified: August 2014
  Purpose

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.


Condition Intervention Phase
Esophageal Cancer
Gastric Cancer
Drug: Oxaliplatin
Drug: Folinic Acid
Drug: 5-Fluorouracil
Drug: Ziv-aflibercept
Drug: Ziv-aflibercept Placebo
Phase 2

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by Dana-Farber Cancer Institute:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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


Other Outcome Measures:
  • 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.


Estimated Enrollment: 64
Study Start Date: September 2013
Estimated Primary Completion Date: February 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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: Oxaliplatin Drug: Folinic Acid
Other Name: Leucovorin
Drug: 5-Fluorouracil
Other Name: 5-FU
Drug: 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: Oxaliplatin Drug: Folinic Acid
Other Name: Leucovorin
Drug: 5-Fluorouracil
Other Name: 5-FU
Drug: Ziv-aflibercept Placebo

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Confirmed adenocarcinoma of esophagus, GE junction or gastric origin
  • Disease is not amenable to curative resection and is unresectable, locally advanced or metastatic
  • Have not received any prior chemotherapy, investigative or biologic agents for esophagogastric cancer except in the neoadjuvant or adjuvant setting
  • Any major surgery must be completed at least 4 weeks prior to study entry, minor procedures must be completed at least 2 weeks prior to study entry
  • Vascular access device insertion should be performed at least 1 week prior to study entry. A central line is recommended for all participants
  • Willing to use adequate contraception prior to study entry, for the duration of study participation and for 3 months after the last dose of Ziv-aflibercept/placebo

Exclusion Criteria:

  • History of hypertension unless adequately controlled
  • Evidence of active bleeding from primary tumor at time of study entry
  • Pregnant or breastfeeding
  • Squamous cell carcinoma histology
  • Prior treatment for advanced or metastatic disease
  • Palliative radiation to < 25% of bone marrow must have been completed 2 weeks prior to study entry, palliative RT to > 25% must have been completed 4 weeks prior to study entry
  • Known allergy to study agents
  • Known dihydropyrimidine dehydrogenase deficiency or thymidylate kinase gene polymorphism predisposing participant to 5-FU toxicity
  • History of symptomatic congestive heart failure
  • Clinically significant peripheral arterial disease
  • Grade 2 or higher sensory or motor neuropathy
  • Serious unhealed wound, ulcers or bone fractures
  • History of HIV positivity or hepatitis B or C
  • History of abdominal fistula, wound dehiscence, GI perforation, intra abdominal abscess, uncontrolled GI bleeding or diverticulitis that required hospitalization within 6 months of study entry
  • History of arterial thrombotic events
  • History of CNS hemorrhage in past 6 months
  • Use of warfarin
  • History of prior or synchronous malignancy except if treated with curative intent more than 3 years prior to enrollment, or adequately treated non-melanoma skin cancers, cervical carcinoma in situ or prostatic intraepithelial neoplasia without evidence of prostate cancer
  • Uncontrolled non-malignant illness
  • Uncontrolled psychiatric illness
  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: NCT01747551

Contacts
Contact: Reasearch Line 617-632-5960

Locations
United States, Massachusetts
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Peter Enzinger, MD    617-632-5960      
Principal Investigator: Peter Enzinger, MD         
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02214
Contact: Eunice Kwak, MD    617-724-4000      
Principal Investigator: Eunice Kwak, MD, PhD         
Sponsors and Collaborators
Dana-Farber Cancer Institute
Investigators
Principal Investigator: Peter Enzinger, MD Dana-Farber Cancer Institute
  More Information

No publications provided

Responsible Party: Peter C. Enzinger, MD, Principal Investigator, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT01747551     History of Changes
Other Study ID Numbers: 12-401
Study First Received: December 5, 2012
Last Updated: August 7, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Dana-Farber Cancer Institute:
Advanced

Additional relevant MeSH terms:
Stomach Neoplasms
Esophageal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases
Head and Neck Neoplasms
Esophageal Diseases
Levoleucovorin
Folic Acid
Fluorouracil
Oxaliplatin
Antidotes
Protective Agents
Physiological Effects of Drugs
Pharmacologic Actions
Hematinics
Hematologic Agents
Therapeutic Uses
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antineoplastic Agents

ClinicalTrials.gov processed this record on October 19, 2014