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

Primary Purpose

Esophageal Cancer, Gastric Cancer

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Oxaliplatin
Leucovorin
Fluorouracil
Ziv-aflibercept
Sponsored by
Dana-Farber Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Esophageal Cancer focused on measuring Advanced

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Massachusetts General Hospital
  • Dana-Farber Cancer Institute

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

mFOLFOX6 + Ziv-aflibercept

mFOLFOX6 + Placebo

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

6-month Progression-free Survival (PFS)
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.

Secondary Outcome Measures

Grade 4 Treatment-Related Toxicity Rate
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)
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
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.

Full Information

First Posted
December 5, 2012
Last Updated
February 6, 2020
Sponsor
Dana-Farber Cancer Institute
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1. Study Identification

Unique Protocol Identification Number
NCT01747551
Brief Title
FOLFOX +/- Ziv-Aflibercept for Esophageal and Gastric Cancer
Official Title
Randomized, Double-Blind, Placebo Controlled Phase II Study of FOLFOX +/- Ziv-Aflibercept in Patients With Advanced Esophageal and Gastric Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
February 2020
Overall Recruitment Status
Completed
Study Start Date
January 2013 (Actual)
Primary Completion Date
November 29, 2016 (Actual)
Study Completion Date
July 26, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Dana-Farber Cancer Institute

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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).
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Esophageal Cancer, Gastric Cancer
Keywords
Advanced

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare Provider
Allocation
Randomized
Enrollment
64 (Actual)

8. Arms, Groups, and Interventions

Arm Title
mFOLFOX6 + Ziv-aflibercept
Arm Type
Active Comparator
Arm Description
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.
Arm Title
mFOLFOX6 + Placebo
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Oxaliplatin
Other Intervention Name(s)
Eloxatin
Intervention Type
Drug
Intervention Name(s)
Leucovorin
Other Intervention Name(s)
Folinic Acid
Intervention Type
Drug
Intervention Name(s)
Fluorouracil
Other Intervention Name(s)
5-FU
Intervention Type
Drug
Intervention Name(s)
Ziv-aflibercept
Other Intervention Name(s)
ZALTRAP, Eylea
Primary Outcome Measure Information:
Title
6-month Progression-free Survival (PFS)
Description
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.
Time Frame
Tumor assessments were performed every 8 weeks and evaluated by independent, blinded radiologists. Patient follow-up was 6 months.
Secondary Outcome Measure Information:
Title
Grade 4 Treatment-Related Toxicity Rate
Description
The percentage of patients who experienced maximum grade 4 treatment-related adverse event based on CTCAEv4 as reported on case report forms.
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.
Title
Objective Response Rate (ORR)
Description
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.
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.
Title
Duration of Objective Response
Description
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.
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.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Peter Enzinger, MD
Organizational Affiliation
Dana-Farber Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02214
Country
United States
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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

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