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

Sponsor
Dana-Farber Cancer Institute (Other)
Overall Status
Completed
CT.gov ID
NCT01747551
Collaborator
(none)
64
Enrollment
2
Locations
2
Arms
54.8
Actual Duration (Months)
32
Patients Per Site
0.6
Patients Per Site Per Month

Study Details

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).

Condition or Disease Intervention/Treatment Phase
Phase 2

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
64 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Care Provider)
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
Actual Study Start Date :
Jan 1, 2013
Actual Primary Completion Date :
Nov 29, 2016
Actual Study Completion Date :
Jul 26, 2017

Arms and Interventions

Arm Intervention/Treatment
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.

Drug: Oxaliplatin
Other Names:
  • Eloxatin

    • Drug: Leucovorin
    Other Names:
  • Folinic Acid

    • Drug: Fluorouracil
    Other Names:
  • 5-FU

    • Drug: Ziv-aflibercept
    Other Names:
  • ZALTRAP
  • Eylea

    		•
    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.

    Drug: Oxaliplatin
    Other Names:
  • Eloxatin

    • Drug: Leucovorin
    Other Names:
  • Folinic Acid

    • Drug: Fluorouracil
    Other Names:
  • 5-FU

    		•

    Outcome Measures

    Primary Outcome Measures

    1. 6-month Progression-free Survival (PFS) [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.

    Secondary Outcome Measures

    1. Grade 4 Treatment-Related Toxicity Rate [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.

    2. Objective Response Rate (ORR) [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.

    3. Duration of Objective Response [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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Locations

    Site City State Country Postal Code
    1 Massachusetts General Hospital Boston Massachusetts United States 02214
    2 Dana-Farber Cancer Institute Boston Massachusetts United States 02215

    Sponsors and Collaborators

    • Dana-Farber Cancer Institute

    Investigators

    • Principal Investigator: Peter Enzinger, MD, Dana-Farber Cancer Institute

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Peter C. Enzinger, MD, Principal Investigator, Dana-Farber Cancer Institute
    ClinicalTrials.gov Identifier:
    NCT01747551
    Other Study ID Numbers:
    • 12-401
    First Posted:
    Dec 11, 2012
    Last Update Posted:
    Feb 10, 2020
    Last Verified:
    Feb 1, 2020
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Peter C. Enzinger, MD, Principal Investigator, Dana-Farber Cancer Institute
    Advanced
    Additional relevant MeSH terms:
    Stomach Neoplasms
    Leucovorin
    Fluorouracil
    Oxaliplatin
    Aflibercept

    Study Results

    Participant Flow

    Recruitment Details Patients enrolled from January 2013 through April 2015.
    Pre-assignment Detail
    Arm/Group Title mFOLFOX6 + Ziv-aflibercept mFOLFOX6 + Placebo
    Arm/Group 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.
    Period Title: Overall Study
    STARTED 43 21
    COMPLETED 0 0
    NOT COMPLETED 43 21

    Baseline Characteristics

    Arm/Group Title mFOLFOX6 + Ziv-aflibercept mFOLFOX6 + Placebo Total
    Arm/Group 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. Total of all reporting groups
    Overall Participants 43 21 64
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    62
    62
    62
    Sex: Female, Male (Count of Participants)
    Female
    6
    14%
    3
    14.3%
    9
    14.1%
    Male
    37
    86%
    18
    85.7%
    55
    85.9%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    1
    4.8%
    1
    1.6%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    1
    4.8%
    1
    1.6%
    White
    41
    95.3%
    18
    85.7%
    59
    92.2%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    2
    4.7%
    1
    4.8%
    3
    4.7%
    Region of Enrollment (Count of Participants)
    United States
    43
    100%
    21
    100%
    64
    100%

    Outcome Measures

    1. Primary Outcome
    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.

    Outcome Measure Data

    Analysis Population Description
    The analysis dataset is comprised of all randomized patients.
    Arm/Group Title mFOLFOX6 + Ziv-aflibercept mFOLFOX6 + Placebo
    Arm/Group 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.
    Measure Participants 43 21
    Number (95% Confidence Interval) [percent probability]
    60.5
    57.1
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection mFOLFOX6 + Ziv-aflibercept, mFOLFOX6 + Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.72
    Comments
    Method Log Rank
    Comments
    2. Secondary Outcome
    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.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title mFOLFOX6 + Ziv-aflibercept mFOLFOX6 + Placebo
    Arm/Group 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.
    Measure Participants 43 21
    Number (95% Confidence Interval) [percentage of participants]
    11.6
    27%
    9.5
    45.2%
    3. Secondary Outcome
    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.

    Outcome Measure Data

    Analysis Population Description
    The analysis dataset is comprised of all patients with measurable disease at baseline.
    Arm/Group Title mFOLFOX6 + Ziv-aflibercept mFOLFOX6 + Placebo
    Arm/Group 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.
    Measure Participants 36 16
    Number (95% Confidence Interval) [percentage of patients]
    61.1
    75.0
    4. Secondary Outcome
    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.

    Outcome Measure Data

    Analysis Population Description
    The analysis dataset is comprised of patients who achieved objective response except one patient on the mFOLFOX6+Placebo is missing data.
    Arm/Group Title mFOLFOX6 + Ziv-aflibercept mFOLFOX6 + Placebo
    Arm/Group 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.
    Measure Participants 22 11
    Mean (Full Range) [months]
    9.0
    8.0

    Adverse Events

    Time Frame Adverse events were assessed day 1 of each cycle. 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.
    Adverse Event Reporting Description Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv4. All remaining events regardless of treatment attribution were classified as Other AEs. Per the source vocabulary (CTCAEv4.0) there is a category "Other, specify" for each system organ class. No further data is available to specify classification beyond this general term.
    Arm/Group Title mFOLFOX6 + Ziv-aflibercept mFOLFOX6 + Placebo
    Arm/Group 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.
    All Cause Mortality
    mFOLFOX6 + Ziv-aflibercept mFOLFOX6 + Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/43 (4.7%) 0/21 (0%)
    Serious Adverse Events
    mFOLFOX6 + Ziv-aflibercept mFOLFOX6 + Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 34/43 (79.1%) 9/21 (42.9%)
    Blood and lymphatic system disorders
    Anemia 1/43 (2.3%) 0/21 (0%)
    Febrile neutropenia 0/43 (0%) 1/21 (4.8%)
    Cardiac disorders
    Cardiac disorders -Other 1/43 (2.3%) 0/21 (0%)
    Heart failure 1/43 (2.3%) 0/21 (0%)
    Myocardial infarction 1/43 (2.3%) 0/21 (0%)
    Ear and labyrinth disorders
    Middle ear inflammation 0/43 (0%) 1/21 (4.8%)
    Gastrointestinal disorders
    Abdominal pain 1/43 (2.3%) 0/21 (0%)
    Constipation 1/43 (2.3%) 0/21 (0%)
    Dysphagia 0/43 (0%) 1/21 (4.8%)
    Gastric hemorrhage 1/43 (2.3%) 0/21 (0%)
    Gastrointestinal disorders -Other 2/43 (4.7%) 0/21 (0%)
    Mucositis oral 3/43 (7%) 0/21 (0%)
    Nausea 1/43 (2.3%) 0/21 (0%)
    Upper gastrointestinal hemorrhage 1/43 (2.3%) 1/21 (4.8%)
    Vomiting 0/43 (0%) 1/21 (4.8%)
    General disorders
    Fatigue 3/43 (7%) 1/21 (4.8%)
    Malaise 1/43 (2.3%) 0/21 (0%)
    Infections and infestations
    Infections and infestations -Other 0/43 (0%) 1/21 (4.8%)
    Sepsis 1/43 (2.3%) 0/21 (0%)
    Investigations
    Investigations -Other 0/43 (0%) 1/21 (4.8%)
    Neutrophil count decreased 12/43 (27.9%) 4/21 (19%)
    White blood cell decreased 1/43 (2.3%) 1/21 (4.8%)
    Metabolism and nutrition disorders
    Anorexia 3/43 (7%) 0/21 (0%)
    Dehydration 1/43 (2.3%) 0/21 (0%)
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorder - Other 1/43 (2.3%) 0/21 (0%)
    Nervous system disorders
    Intracranial hemorrhage 1/43 (2.3%) 0/21 (0%)
    Peripheral sensory neuropathy 3/43 (7%) 2/21 (9.5%)
    Syncope 0/43 (0%) 1/21 (4.8%)
    Respiratory, thoracic and mediastinal disorders
    Epistaxis 1/43 (2.3%) 0/21 (0%)
    Hiccups 1/43 (2.3%) 0/21 (0%)
    Hoarseness 2/43 (4.7%) 0/21 (0%)
    Respiratory, thoracic and mediastinal disorders -Other 1/43 (2.3%) 0/21 (0%)
    Vascular disorders
    Hypertension 21/43 (48.8%) 1/21 (4.8%)
    Hypotension 0/43 (0%) 1/21 (4.8%)
    Superior vena cava syndrome 0/43 (0%) 1/21 (4.8%)
    Thromboembolic event 4/43 (9.3%) 0/21 (0%)
    Vascular disorders -Other 1/43 (2.3%) 0/21 (0%)
    Other (Not Including Serious) Adverse Events
    mFOLFOX6 + Ziv-aflibercept mFOLFOX6 + Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 43/43 (100%) 21/21 (100%)
    Blood and lymphatic system disorders
    Anemia 32/43 (74.4%) 13/21 (61.9%)
    Blood and lymphatic system disorders - Other 3/43 (7%) 0/21 (0%)
    Febrile neutropenia 2/43 (4.7%) 1/21 (4.8%)
    Leukocytosis 4/43 (9.3%) 2/21 (9.5%)
    Thrombotic thrombocytopenic purpura 1/43 (2.3%) 0/21 (0%)
    Cardiac disorders
    Atrial fibrillation 0/43 (0%) 1/21 (4.8%)
    Cardiac disorders - Other 1/43 (2.3%) 0/21 (0%)
    Chest pain - cardiac 2/43 (4.7%) 0/21 (0%)
    Heart failure 1/43 (2.3%) 0/21 (0%)
    Sinus bradycardia 0/43 (0%) 1/21 (4.8%)
    Sinus tachycardia 2/43 (4.7%) 1/21 (4.8%)
    Ventricular tachycardia 1/43 (2.3%) 0/21 (0%)
    Eye disorders
    Blurred vision 1/43 (2.3%) 2/21 (9.5%)
    Dry eye 2/43 (4.7%) 0/21 (0%)
    Eye disorders - Other 1/43 (2.3%) 0/21 (0%)
    Photophobia 1/43 (2.3%) 0/21 (0%)
    Watering eyes 2/43 (4.7%) 0/21 (0%)
    Watering eyes 0/43 (0%) 1/21 (4.8%)
    Gastrointestinal disorders
    Abdominal distension 1/43 (2.3%) 2/21 (9.5%)
    Abdominal pain 20/43 (46.5%) 9/21 (42.9%)
    Anal pain 1/43 (2.3%) 0/21 (0%)
    Bloating 4/43 (9.3%) 1/21 (4.8%)
    Colitis 0/43 (0%) 1/21 (4.8%)
    Constipation 26/43 (60.5%) 13/21 (61.9%)
    Diarrhea 25/43 (58.1%) 9/21 (42.9%)
    Dry mouth 4/43 (9.3%) 0/21 (0%)
    Dyspepsia 1/43 (2.3%) 1/21 (4.8%)
    Dysphagia 19/43 (44.2%) 9/21 (42.9%)
    Esophageal pain 1/43 (2.3%) 0/21 (0%)
    Fecal incontinence 1/43 (2.3%) 0/21 (0%)
    Flatulence 0/43 (0%) 2/21 (9.5%)
    Gastritis 0/43 (0%) 1/21 (4.8%)
    Gastroesophageal reflux disease 5/43 (11.6%) 3/21 (14.3%)
    Gastrointestinal disorders - Other 13/43 (30.2%) 10/21 (47.6%)
    Gastrointestinal pain 9/43 (20.9%) 2/21 (9.5%)
    Hemorrhoids 4/43 (9.3%) 0/21 (0%)
    Lip pain 1/43 (2.3%) 0/21 (0%)
    Mucositis oral 20/43 (46.5%) 6/21 (28.6%)
    Nausea 32/43 (74.4%) 15/21 (71.4%)
    Oral dysesthesia 8/43 (18.6%) 1/21 (4.8%)
    Oral hemorrhage 1/43 (2.3%) 1/21 (4.8%)
    Oral pain 9/43 (20.9%) 0/21 (0%)
    Rectal hemorrhage 1/43 (2.3%) 0/21 (0%)
    Rectal pain 2/43 (4.7%) 0/21 (0%)
    Rectal perforation 0/43 (0%) 1/21 (4.8%)
    Stomach pain 1/43 (2.3%) 0/21 (0%)
    Vomiting 10/43 (23.3%) 0/21 (0%)
    Vomiting 0/43 (0%) 5/21 (23.8%)
    General disorders
    Chills 2/43 (4.7%) 1/21 (4.8%)
    Death neonatal 1/43 (2.3%) 0/21 (0%)
    Edema limbs 0/43 (0%) 2/21 (9.5%)
    Facial pain 1/43 (2.3%) 1/21 (4.8%)
    Fatigue 37/43 (86%) 19/21 (90.5%)
    Fever 3/43 (7%) 3/21 (14.3%)
    Gait disturbance 0/43 (0%) 1/21 (4.8%)
    General disorders and administration site conditions - Other 0/43 (0%) 1/21 (4.8%)
    Infusion related reaction 3/43 (7%) 0/21 (0%)
    Injection site reaction 1/43 (2.3%) 0/21 (0%)
    Localized edema 3/43 (7%) 3/21 (14.3%)
    Malaise 9/43 (20.9%) 2/21 (9.5%)
    Non-cardiac chest pain 4/43 (9.3%) 2/21 (9.5%)
    Pain 11/43 (25.6%) 5/21 (23.8%)
    Hepatobiliary disorders
    Gallbladder pain 1/43 (2.3%) 0/21 (0%)
    Infections and infestations
    Infections and infestations - Other 0/43 (0%) 1/21 (4.8%)
    Paronychia 1/43 (2.3%) 0/21 (0%)
    Sinusitis 1/43 (2.3%) 0/21 (0%)
    Skin infection 0/43 (0%) 1/21 (4.8%)
    Tooth infection 1/43 (2.3%) 0/21 (0%)
    Upper respiratory infection 3/43 (7%) 1/21 (4.8%)
    Injury, poisoning and procedural complications
    Bruising 2/43 (4.7%) 2/21 (9.5%)
    Fracture 0/43 (0%) 1/21 (4.8%)
    Hip fracture 1/43 (2.3%) 0/21 (0%)
    Injury, poisoning and procedural complications - Other 1/43 (2.3%) 1/21 (4.8%)
    Intraoperative hepatobiliary injury 0/43 (0%) 1/21 (4.8%)
    Vascular access complication 1/43 (2.3%) 0/21 (0%)
    Wound dehiscence 2/43 (4.7%) 0/21 (0%)
    Investigations
    Alanine aminotransferase increased 10/43 (23.3%) 4/21 (19%)
    Alkaline phosphatase increased 21/43 (48.8%) 10/21 (47.6%)
    Aspartate aminotransferase increased 19/43 (44.2%) 10/21 (47.6%)
    Blood bilirubin increased 3/43 (7%) 2/21 (9.5%)
    Cholesterol high 1/43 (2.3%) 0/21 (0%)
    Creatinine increased 4/43 (9.3%) 1/21 (4.8%)
    Haptoglobin decreased 1/43 (2.3%) 2/21 (9.5%)
    Hemoglobin increased 0/43 (0%) 1/21 (4.8%)
    INR increased 1/43 (2.3%) 0/21 (0%)
    Investigations - Other 7/43 (16.3%) 3/21 (14.3%)
    Lymphocyte count decreased 1/43 (2.3%) 0/21 (0%)
    Neutrophil count decreased 17/43 (39.5%) 7/21 (33.3%)
    Platelet count decreased 23/43 (53.5%) 13/21 (61.9%)
    Weight gain 1/43 (2.3%) 0/21 (0%)
    Weight loss 11/43 (25.6%) 4/21 (19%)
    White blood cell decreased 8/43 (18.6%) 3/21 (14.3%)
    Metabolism and nutrition disorders
    Alkalosis 1/43 (2.3%) 0/21 (0%)
    Anorexia 27/43 (62.8%) 8/21 (38.1%)
    Dehydration 6/43 (14%) 1/21 (4.8%)
    Glucose intolerance 0/43 (0%) 1/21 (4.8%)
    Hypercalcemia 1/43 (2.3%) 0/21 (0%)
    Hyperglycemia 35/43 (81.4%) 16/21 (76.2%)
    Hyperkalemia 2/43 (4.7%) 2/21 (9.5%)
    Hypermagnesemia 1/43 (2.3%) 1/21 (4.8%)
    Hypernatremia 2/43 (4.7%) 1/21 (4.8%)
    Hypoalbuminemia 31/43 (72.1%) 5/21 (23.8%)
    Hypocalcemia 6/43 (14%) 3/21 (14.3%)
    Hypoglycemia 4/43 (9.3%) 1/21 (4.8%)
    Hypokalemia 9/43 (20.9%) 2/21 (9.5%)
    Hypomagnesemia 5/43 (11.6%) 3/21 (14.3%)
    Hyponatremia 17/43 (39.5%) 7/21 (33.3%)
    Hypophosphatemia 2/43 (4.7%) 0/21 (0%)
    Iron overload 1/43 (2.3%) 0/21 (0%)
    Metabolism and nutrition disorders - Other, specify 4/43 (9.3%) 4/21 (19%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 3/43 (7%) 0/21 (0%)
    Arthritis 1/43 (2.3%) 0/21 (0%)
    Back pain 6/43 (14%) 3/21 (14.3%)
    Flank pain 1/43 (2.3%) 0/21 (0%)
    Generalized muscle weakness 3/43 (7%) 2/21 (9.5%)
    Growth suppression 3/43 (7%) 0/21 (0%)
    Joint range of motion decreased cervical spine 1/43 (2.3%) 0/21 (0%)
    Musculoskeletal and connective tissue disorder - Other 4/43 (9.3%) 0/21 (0%)
    Neck pain 0/43 (0%) 1/21 (4.8%)
    Pain in extremity 5/43 (11.6%) 2/21 (9.5%)
    Nervous system disorders
    Dizziness 10/43 (23.3%) 4/21 (19%)
    Dysesthesia 27/43 (62.8%) 12/21 (57.1%)
    Dysgeusia 11/43 (25.6%) 6/21 (28.6%)
    Dysphasia 2/43 (4.7%) 0/21 (0%)
    Headache 13/43 (30.2%) 1/21 (4.8%)
    Movements involuntary 1/43 (2.3%) 0/21 (0%)
    Nervous system disorders - Other 2/43 (4.7%) 2/21 (9.5%)
    Paresthesia 1/43 (2.3%) 2/21 (9.5%)
    Peripheral motor neuropathy 0/43 (0%) 1/21 (4.8%)
    Peripheral sensory neuropathy 36/43 (83.7%) 16/21 (76.2%)
    Presyncope 0/43 (0%) 1/21 (4.8%)
    Sinus pain 1/43 (2.3%) 0/21 (0%)
    Tremor 0/43 (0%) 1/21 (4.8%)
    Psychiatric disorders
    Anxiety 4/43 (9.3%) 2/21 (9.5%)
    Confusion 1/43 (2.3%) 0/21 (0%)
    Depression 4/43 (9.3%) 1/21 (4.8%)
    Insomnia 11/43 (25.6%) 3/21 (14.3%)
    Renal and urinary disorders
    Acute kidney injury 1/43 (2.3%) 0/21 (0%)
    Proteinuria 8/43 (18.6%) 0/21 (0%)
    Renal and urinary disorders - Other 2/43 (4.7%) 1/21 (4.8%)
    Urinary retention 0/43 (0%) 1/21 (4.8%)
    Urinary tract pain 2/43 (4.7%) 0/21 (0%)
    Reproductive system and breast disorders
    Pelvic pain 1/43 (2.3%) 0/21 (0%)
    Reproductive system and breast disorders - Other, specify 2/43 (4.7%) 0/21 (0%)
    Respiratory, thoracic and mediastinal disorders
    Cough 15/43 (34.9%) 3/21 (14.3%)
    Dyspnea 12/43 (27.9%) 3/21 (14.3%)
    Epistaxis 16/43 (37.2%) 2/21 (9.5%)
    Hiccups 3/43 (7%) 1/21 (4.8%)
    Hoarseness 13/43 (30.2%) 1/21 (4.8%)
    Hypoxia 1/43 (2.3%) 0/21 (0%)
    Nasal congestion 3/43 (7%) 0/21 (0%)
    Nasal congestion 0/43 (0%) 1/21 (4.8%)
    Pharyngeal necrosis 0/43 (0%) 1/21 (4.8%)
    Pneumonitis 0/43 (0%) 1/21 (4.8%)
    Postnasal drip 5/43 (11.6%) 0/21 (0%)
    Respiratory, thoracic and mediastinal disorders - Other 4/43 (9.3%) 0/21 (0%)
    Sinus disorder 1/43 (2.3%) 0/21 (0%)
    Sore throat 2/43 (4.7%) 1/21 (4.8%)
    Voice alteration 4/43 (9.3%) 0/21 (0%)
    Wheezing 0/43 (0%) 1/21 (4.8%)
    Skin and subcutaneous tissue disorders
    Alopecia 1/43 (2.3%) 2/21 (9.5%)
    Dry skin 1/43 (2.3%) 1/21 (4.8%)
    Erythema multiforme 1/43 (2.3%) 0/21 (0%)
    Nail discoloration 2/43 (4.7%) 0/21 (0%)
    Nail ridging 1/43 (2.3%) 0/21 (0%)
    Palmar-plantar erythrodysesthesia syndrome 6/43 (14%) 2/21 (9.5%)
    Photosensitivity 0/43 (0%) 2/21 (9.5%)
    Rash acneiform 0/43 (0%) 1/21 (4.8%)
    Rash maculo-papular 1/43 (2.3%) 0/21 (0%)
    Skin and subcutaneous tissue disorders - Other 12/43 (27.9%) 4/21 (19%)
    Skin hyperpigmentation 3/43 (7%) 1/21 (4.8%)
    Skin ulceration 1/43 (2.3%) 0/21 (0%)
    Urticaria 0/43 (0%) 1/21 (4.8%)
    Vascular disorders
    Flushing 1/43 (2.3%) 1/21 (4.8%)
    Hematoma 0/43 (0%) 2/21 (9.5%)
    Hot flashes 1/43 (2.3%) 2/21 (9.5%)
    Hypertension 36/43 (83.7%) 12/21 (57.1%)
    Hypotension 3/43 (7%) 1/21 (4.8%)
    Thromboembolic event 1/43 (2.3%) 1/21 (4.8%)
    Vascular disorders - Other 2/43 (4.7%) 0/21 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Peter Enzinger
    Organization Dana-Farber Cancer Institute
    Phone 617-632-3029
    Email
    Responsible Party:
    Peter C. Enzinger, MD, Principal Investigator, Dana-Farber Cancer Institute
    ClinicalTrials.gov Identifier:
    NCT01747551
    Other Study ID Numbers:
    • 12-401
    First Posted:
    Dec 11, 2012
    Last Update Posted:
    Feb 10, 2020
    Last Verified:
    Feb 1, 2020