Esophageal Cancer, Gastric Cancer
Conditions
Keywords
Advanced
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.
Interventions
DRUGOxaliplatin
DRUGLeucovorin
DRUGFluorouracil
DRUGZiv-aflibercept
Sponsors
Dana-Farber Cancer Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Recruitment details
Patients enrolled from January 2013 through April 2015.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 43 |
| 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. | 21 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 7 | 1 |
| Overall Study | Death | 3 | 1 |
| Overall Study | Other | 2 | 0 |
| Overall Study | Physician Decision | 2 | 1 |
| Overall Study | Progressive Disease | 24 | 17 |
| Overall Study | Prolonged Treatment Delay | 2 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | mFOLFOX6 + Placebo | Total | mFOLFOX6 + Ziv-aflibercept |
|---|---|---|---|
| Age, Continuous | 62 years | 62 years | 62 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) White | 18 Participants | 59 Participants | 41 Participants |
| Region of Enrollment United States | 21 Participants | 64 Participants | 43 Participants |
| Sex: Female, Male Female | 3 Participants | 9 Participants | 6 Participants |
| Sex: Female, Male Male | 18 Participants | 55 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 43 | 0 / 21 |
| other Total, other adverse events | 43 / 43 | 21 / 21 |
| serious Total, serious adverse events | 34 / 43 | 9 / 21 |
Outcome results
Primary
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.
Time frame: Tumor assessments were performed every 8 weeks and evaluated by independent, blinded radiologists. Patient follow-up was 6 months.
Population: The analysis dataset is comprised of all randomized patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| mFOLFOX6 + Ziv-aflibercept | 6-month Progression-free Survival (PFS) | 60.5 percent probability |
| mFOLFOX6 + Placebo | 6-month Progression-free Survival (PFS) | 57.1 percent probability |
p-value: 0.72Log Rank
Secondary
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.
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.
Population: The analysis dataset is comprised of patients who achieved objective response except one patient on the mFOLFOX6+Placebo is missing data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| mFOLFOX6 + Ziv-aflibercept | Duration of Objective Response | 9.0 months |
| mFOLFOX6 + Placebo | Duration of Objective Response | 8.0 months |
Secondary
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.
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| mFOLFOX6 + Ziv-aflibercept | Grade 4 Treatment-Related Toxicity Rate | 11.6 percentage of participants |
| mFOLFOX6 + Placebo | Grade 4 Treatment-Related Toxicity Rate | 9.5 percentage of participants |
Secondary
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.
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.
Population: The analysis dataset is comprised of all patients with measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| mFOLFOX6 + Ziv-aflibercept | Objective Response Rate (ORR) | 61.1 percentage of patients |
| mFOLFOX6 + Placebo | Objective Response Rate (ORR) | 75.0 percentage of patients |