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

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ClinicalTrials.gov Identifier: NCT01747551
Recruitment Status : Completed
First Posted : December 11, 2012
Results First Posted : May 8, 2018
Last Update Posted : May 8, 2018
Sponsor:
Information provided by (Responsible Party):
Peter C. Enzinger, MD, Dana-Farber Cancer Institute

December 5, 2012
December 11, 2012
April 5, 2018
May 8, 2018
May 8, 2018
January 2013
November 29, 2016   (Final data collection date for primary outcome measure)
6-month Progression-free Survival (PFS) [ Time Frame: Tumor assessments were performed every 8 weeks and evaluated by independent, blinded radiologists. Patient follow-up was 6 months. ]
6-month PFS is the percent probability of patients remaining alive and progression-free at 6-months from randomization estimated using Kaplan-Meier methods. PFS was measured as the time from randomization to 1st documented disease progression (PD) or death. Patients alive without PD were censored at the earliest of the date of last progression-free disease assessment or start of non-protocol therapy. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.
Estimate efficacy of Ziv-aflibercept+mFOLFOX6 in esophagogastric adenocarcinomas, as measured by progression-free survival (PFS). [ Time Frame: 2 years ]
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.
Complete list of historical versions of study NCT01747551 on ClinicalTrials.gov Archive Site
  • Grade 4 Treatment-Related Toxicity Rate [ Time Frame: Adverse events were collected each cycle on treatment. Patients received a median (range) treatment duration (months) of 6.9 (0-23.3) and 6.4 (0-43.9) for mFOLFOX6/ziv-aflibercept and mFOLFOX6/placebo, respectively. ]
    The percentage of patients who experienced maximum grade 4 treatment-related adverse event based on CTCAEv4 as reported on case report forms.
  • Objective Response Rate (ORR) [ Time Frame: Tumor assessments were performed every 8 weeks and evaluated by independent, blinded radiologists. Patients received a median (range) treatment duration (m) of 6.9 (0-23.3) and 6.4 (0-43.9) for mFOLFOX6/ziv-aflibercept and mFOLFOX6/placebo, respectively. ]
    ORR was defined as the percentage of patients achieving complete response (CR) or partial response (PR) on treatment based on RECIST 1.1 criteria. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.
  • Duration of Objective Response [ Time Frame: Tumor assessments were performed every 8 weeks and evaluated by independent, blinded radiologists. Patient follow-up (months) median (range) was 14.5 (1.1-49.8) and 18.8 (0.6-49.8) for mFOLFOX6/ziv-aflibercept and mFOLFOX6/placebo, respectively. ]
    Duration of response is the time from date of first documented confirmed objective response to date of first documented progressive disease. Per RECIST 1.1 for target lesions: PD is at least a 20% increase in sum LD, taking as reference the smallest sum on study with at least 5 mm absolute increase. For non-target lesions, progression-free means no new lesions or unequivocal progression on existing non-target lesions or not evaluated.
  • Evaluate safety and tolerability of Ziv-aflibercept+mFOLFOX6 by evaluating toxicity and the number of adverse events. [ Time Frame: 2 years ]
    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 ]
    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 ]
    To estimate duration of objective response and overall survival in patients treated with Ziv-aflibercept in combination with mFOLFOX6 vs. mFOLFOX6 alone
Not Provided
  • Evaluate blood plasma levels [ Time Frame: 2 years ]
    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 ]
    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.
 
FOLFOX +/- Ziv-Aflibercept for Esophageal and Gastric Cancer
Randomized, Double-Blind, Placebo Controlled Phase II Study of FOLFOX +/- Ziv-Aflibercept in Patients With Advanced Esophageal and Gastric Cancer

Anti-angiogenic therapy is a proven therapeutic target in refractory gastric and gastroesophageal junction adenocarcinoma. This trial assessed whether the addition of a high affinity angiogenesis inhibitor, ziv-aflibercept, could improve the efficacy of first-line mFOLFOX6 (oxaliplatin, leucovorin, and bolus plus infusional 5- fluorouracil) chemotherapy in metastatic esophagogastric adenocarcinoma.

In this study (ZAMEGA), patients with treatment-naïve esophagogastric adenocarcinoma were randomly assigned 2:1 in a multicenter, placebo-controlled double-blind trial to receive first-line mFOLFOX6 with or without ziv-aflibercept 4mg/kg every 2 weeks. Randomization was stratified by ECOG performance status (0-1 vs. 2) and primary site of disease (esophagus or GE junction vs stomach).

In patients with esophagogastric cancer, mFOLFOX6 is considered standard of care. 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.

The study was designed to have an 80% power, at a 0.20 significance level, to detect a difference in 6-month progression-free survival of 15%, between 65% and 50%. A one-sided log rank test was utilized and all patients treated with at least one dose of mFOLFOX6 and ziv-aflibercept/placebo were included in the statistical analysis.

Interventional
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary Purpose: Treatment
  • Esophageal Cancer
  • Gastric Cancer
  • Drug: Oxaliplatin
    Other Name: Eloxatin
  • Drug: Leucovorin
    Other Name: Folinic Acid
  • Drug: Fluorouracil
    Other Name: 5-FU
  • Drug: Ziv-aflibercept
    Other Names:
    • ZALTRAP
    • Eylea
  • Active Comparator: mFOLFOX6 + Ziv-aflibercept
    Patients received mFOLFOX6 and ziv-aflibercept every 2 weeks. Ziv-aflibercept 4mg/kg was given via intravenous (IV) infusion over 1 hour. Immediately following this was administration of mFOLFOX6: oxaliplatin 85 mg/m2 IV and leucovorin 400 mg/m2 IV were given concurrently over 120 minutes, followed by fluorouracil 400 mg/m2 IV bolus injection and then fluorouracil 2,400 mg/m2 IV infusion over 46 hours. Patients continued on treatment until radiological or clinical progression, unacceptable toxicity, or death.
    Interventions:
    • Drug: Oxaliplatin
    • Drug: Leucovorin
    • Drug: Fluorouracil
    • Drug: Ziv-aflibercept
  • Active Comparator: mFOLFOX6 + Placebo
    Patients received mFOLFOX6 and placebo every 2 weeks. Placebo was given via intravenous (IV) infusion over 1 hour. Immediately following this was administration of mFOLFOX6: oxaliplatin 85 mg/m2 IV and leucovorin 400 mg/m2 IV were given concurrently over 120 minutes, followed by fluorouracil 400 mg/m2 IV bolus injection and then fluorouracil 2,400 mg/m2 IV infusion over 46 hours. Patients continued on treatment until radiological or clinical progression, unacceptable toxicity, or death.
    Interventions:
    • Drug: Oxaliplatin
    • Drug: Leucovorin
    • Drug: Fluorouracil
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
64
Same as current
July 26, 2017
November 29, 2016   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT01747551
12-401
Yes
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Plan to Share IPD: No
Peter C. Enzinger, MD, Dana-Farber Cancer Institute
Dana-Farber Cancer Institute
Not Provided
Principal Investigator: Peter Enzinger, MD Dana-Farber Cancer Institute
Dana-Farber Cancer Institute
April 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP