Esophageal Cancer, Stomach Cancer
Conditions
Keywords
cancer, stomach, esophagus, gastroesophageal
Brief summary
The purpose of this study is to determine whether ramucirumab when used in conjunction with chemotherapy treatment can help participants with stomach, esophagus, and gastroesophageal cancer.
Interventions
BIOLOGICALRamucirumab
Administered intravenously
DRUGPlacebo
Administered intravenously
DRUGOxaliplatin
Administered intravenously
DRUGLeucovorin
Administered intravenously
DRUG5-Fluorouracil
Administered intravenously
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologic or cytologic confirmation of adenocarcinoma of the esophagus, gastroesophageal junction (GEJ), or stomach * Metastatic or locally advanced, unresectable disease at time of study entry * Provided signed informed consent and is amenable to compliance with protocol schedules and testing * Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1 at study entry * Adequate renal, hematological, and hepatic function * Measurable or non-measurable disease at the time of study entry * Resolution to Grade less than or equal to 1 by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0, of all clinically significant toxic effects of prior locoregional therapy, surgery, or other anticancer therapy, except where otherwise mentioned in the eligibility criteria * Eligible participants of reproductive potential (both sexes) must agree to use adequate contraceptive methods (hormonal or barrier methods) during the study period and at least 12 weeks after the last dose of study therapy * Life expectancy of greater than or equal to 3 months * Willingness to provide blood and tissue samples for research purposes. Submission of tumor specimen is mandatory for participation in this study, if a histologic, paraffin-embedded specimen exists (either from a surgical resection or biopsy); submission of paraffin block or a minimum of 8 unstained slides is required if sufficient sample. NOTE: If insufficient additional tissue exists (that is, all tissue has been utilized for prior diagnostic purposes), participation in the study is allowable without the requirement for an additional biopsy; this situation must be discussed with the study principal investigator and/or the ImClone medical monitor or designee.
Exclusion criteria
* The participant has received prior first-line systemic therapy for advanced/unresectable and/or metastatic disease (prior adjuvant or neo-adjuvant therapy is permitted) * Previous or concurrent malignancy except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumors treated curatively and without evidence of recurrence for at least 3 years prior to study entry * Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the participant ineligible for entry into this study * The participant is receiving chronic therapy with nonsteroidal anti-inflammatory agents (NSAIDs; for example, indomethacin, ibuprofen, naproxen, or similar agents) or other antiplatelet agents (for example, clopidogrel, ticlopidine, dipyridamole, anagrelide). Aspirin use at doses up to 325 milligrams per day (mg/day) is permitted. * The participant has significant third-space fluid retention (for example, ascites or pleural effusion), and is not amenable for required repeated drainage * The participant is pregnant or breastfeeding * Uncontrolled intercurrent illness including, but not limited to, active or uncontrolled clinically serious infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled thromboembolic, or hemorrhagic disorder, psychiatric illness/social situations, or other co-morbid systemic illnesses, or other severe concurrent disease * Immunocompromised participants including participants known to be human immunodeficiency virus (HIV) positive. * Progressive disease less than or equal to 12 months of completing platinum or 5-FU treatment, including capecitabine, if given previously in the perioperative (adjuvant or neoadjuvant) setting * Current or recent (within 28 days prior to randomization) treatment with an investigational drug that has not received regulatory approval for any indication at the time of study entry, or participation in another interventional clinical trial. Participants participating in surveys or observational studies are eligible to participate in this study. * Are currently enrolled in, or discontinued within the last 28 days from, a clinical trial involving ramucirumab drug product (DP), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study * Received prior therapy with an antiangiogenic agent (including but not limited to bevacizumab, sunitinib, or sorafenib) * Major surgical procedure or significant traumatic injury less than 28 days prior to randomization, or anticipation of need for elective or planned major surgical procedure during the course of the study. Subcutaneous venous access device placement within 7 days prior to randomization * Clinically significant peripheral neuropathy at the time of registration * Known central nervous system metastases that are symptomatic or untreated * New York Heart Association (NYHA) classification III-IV congestive heart failure * Greater than normal risk of bleeding or coagulopathy in the absence of therapeutic anticoagulation; Grade 3/4 gastrointestinal bleeding within 3 months prior to registration; active bleeding (that is, within 14 days prior to first dose of study therapy); or pathological condition present that carries a high risk of bleeding (for example, tumor involving major vessels or known varices) * Participant has experienced any arterial thromboembolic events, including but not limited to myocardial infarction, stroke, transient ischemic attack (TIA), cerebrovascular accident, or unstable angina, less than or equal to 6 months prior to registration * Clinically significant vascular disease (for example, aortic aneurysm, aortic dissection) for which more than minimal intervention is being administered or planned * History of hypertensive crisis or hypertensive encephalopathy or current poorly-controlled hypertension despite standard medical management * History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess less than 6 months prior to registration * Known hypersensitivity to any of the treatment components of modified FOLFOX6 (mFOLFOX6) (oxaliplatin, 5-FU, and leucovorin) or ramucirumab DP
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Randomization to measured PD or date of death from any cause (up to Month 25.0) | PFS was defined using Response Evaluation Criteria in Solid Tumors \[RECIST version (v.) 1.1\] as the time from randomization to the first observation of progressive disease (PD) or death due to any cause, whichever came first. PD was a ≥20% increase in the sum of the diameters of target lesions with the sum demonstrating an absolute increase of ≥5 millimeters (mm); the appearance of ≥1 new lesions or unequivocal progression of non-target lesions. If a participant did not have a baseline disease assessment, PFS time was censored at the randomization date, regardless of whether or not PD or death was observed. Participants not known to have died or have objective PD were censored at the last post-baseline radiological assessment date. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Randomization to date of death from any cause (up to Month 28.3) | OS was defined as the time from randomization to death due to any cause. OS was censored at the date of the last follow-up visit for participants who were alive or lost to follow-up. |
| Percentage of Participants Achieving an Objective Response (Objective Response Rate) | Randomization to measured PD (up to Month 23.0) | The percentage of participants who achieved a best overall response of partial response (PR) or complete response (CR) is reported. Response was defined using RECIST, v. 1.1 criteria. CR was the disappearance of all lesions and pathological lymph node reduction in the short axis to \<10 mm. PR was a ≥30% decrease in the sum of the diameters of target lesions. The percentage of participants with objective response=(number of participants whose best overall response achieved was CR or PR/number of participants treated)\*100. |
| Time to Disease Progression (TTP) | Randomization to measured PD (up to Month 25.0) | TTP was defined using RECIST v. 1.1 as the time from study randomization to the first date of PD. PD was a ≥20% increase in the sum of the diameters of target lesions with the sum demonstrating an absolute increase of ≥5 mm; the appearance of ≥1 new lesions or unequivocal progression of non-target lesions. TTP was censored at the date of last adequate tumor assessment if death was due to causes other than PD. |
| Number of Participants With Treatment-Emergent Anti-Ramucirumab Antibodies | Months 1, 2, 4, 6, and 8 | Participants with treatment-emergent anti-ramucirumab antibodies were participants with a 4-fold increase (2 dilution increase) in immunogenicity titer over baseline titer, or participants who tested negative at baseline and positive post-baseline (at titer of ≥1:20). |
| Duration of Response | Time of first response to measured PD (up to Month 23.0) | Duration of response was defined using RECIST v. 1.1 criteria as the time from the date criteria were met for the first objectively recorded CR or PR until the first date criteria for PD were met or death from any cause. CR was the disappearance of all lesions and pathological lymph node reduction in the short axis to \<10 mm. PR was a ≥30% decrease in the sum of the diameters of target lesions. PD was a ≥20% increase in the sum of the diameters of target lesions with the sum demonstrating an absolute increase of ≥5 mm; the appearance of ≥1 new lesions or unequivocal progression of non-target lesions. Participants who were not known to have died and who did not have PD were censored at the date of the last tumor assessment prior to the date of any subsequent systemic anticancer therapy. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) | Baseline through study completion (up to Month 28.3) | Reported are the number of participants who had ramucirumab/placebo-related: AEs, serious AEs (SAEs), AEs based on common terminology criteria for adverse events (CTCAE) ≥Grade 3, AEs = CTCAE Grade 5, as well as, AEs leading to treatment discontinuation and AEs resulting in death. A summary of serious and other non-serious AEs regardless of causality is located in the Reported Adverse Events module. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ramucirumab and mFOLFOX6 Ramucirumab: 8 mg/kg intravenous infusion administered on Day 1 of each cycle (14 days/cycle). In Cycles 1 and 2, there was a 1-hour observation prior to administering mFOLFOX6.
mFOLFOX6: Administered intravenously per manufacturer's instructions for each drug substance on Day 1 of each cycle (14 days/cycle).
* Oxaliplatin: 85 mg/m\^2
* Leucovorin: 400 mg/m\^2
* 5-FU: 400 mg/m\^2 bolus
* 5-FU: 2400 mg/m\^2 continuous given over 46-48 hours
Participants received study treatment every 2 weeks until disease progression, unacceptable toxicity, or another withdrawal criterion was met. | 84 |
| Placebo and mFOLFOX6 Placebo: intravenous infusion administered on Day 1 of each cycle (14 days/cycle). In Cycles 1 and 2, there was a 1-hour observation prior to administering mFOLFOX6.
mFOLFOX6: Administered intravenously per manufacturer's instructions for each drug substance on Day 1 of each cycle (14 days/cycle).
* Oxaliplatin: 85 mg/m\^2
* Leucovorin: 400 mg/m\^2
* 5-FU: 400 mg/m\^2 bolus
* 5-FU: 2400 mg/m\^2 continuous given over 46-48 hours
Participants received study treatment every 2 weeks until disease progression, unacceptable toxicity, or another withdrawal criterion was met. | 84 |
| Total | 168 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 3 | 1 |
| Overall Study | Withdrawal (by participant or physician) | 3 | 3 |
Baseline characteristics
| Characteristic | Ramucirumab and mFOLFOX6 | Placebo and mFOLFOX6 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 42 Participants | 28 Participants | 70 Participants |
| Age, Categorical Between 18 and 65 years | 42 Participants | 56 Participants | 98 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 9 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 80 Participants | 75 Participants | 155 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 2 participants | 4 participants | 6 participants |
| Race/Ethnicity, Customized Black or African American | 3 participants | 3 participants | 6 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 2 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized White | 77 participants | 76 participants | 153 participants |
| Region of Enrollment United States | 84 participants | 84 participants | 168 participants |
| Sex: Female, Male Female | 21 Participants | 23 Participants | 44 Participants |
| Sex: Female, Male Male | 63 Participants | 61 Participants | 124 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 82 / 82 | 79 / 80 |
| serious Total, serious adverse events | 48 / 82 | 32 / 80 |
Outcome results
Primary
Progression-Free Survival (PFS)
PFS was defined using Response Evaluation Criteria in Solid Tumors \[RECIST version (v.) 1.1\] as the time from randomization to the first observation of progressive disease (PD) or death due to any cause, whichever came first. PD was a ≥20% increase in the sum of the diameters of target lesions with the sum demonstrating an absolute increase of ≥5 millimeters (mm); the appearance of ≥1 new lesions or unequivocal progression of non-target lesions. If a participant did not have a baseline disease assessment, PFS time was censored at the randomization date, regardless of whether or not PD or death was observed. Participants not known to have died or have objective PD were censored at the last post-baseline radiological assessment date.
Time frame: Randomization to measured PD or date of death from any cause (up to Month 25.0)
Population: ITT population: all randomized participants. Fourteen participants in the Ramucirumab and mFOLFOX6 treatment arm and 15 participants in the Placebo and mFOLFOX6 treatment arm were censored.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ramucirumab and mFOLFOX6 | Progression-Free Survival (PFS) | 6.4 months |
| Placebo and mFOLFOX6 | Progression-Free Survival (PFS) | 6.7 months |
p-value: 0.88695% CI: [0.69, 1.37]Stratified Log Rank
Secondary
Duration of Response
Duration of response was defined using RECIST v. 1.1 criteria as the time from the date criteria were met for the first objectively recorded CR or PR until the first date criteria for PD were met or death from any cause. CR was the disappearance of all lesions and pathological lymph node reduction in the short axis to \<10 mm. PR was a ≥30% decrease in the sum of the diameters of target lesions. PD was a ≥20% increase in the sum of the diameters of target lesions with the sum demonstrating an absolute increase of ≥5 mm; the appearance of ≥1 new lesions or unequivocal progression of non-target lesions. Participants who were not known to have died and who did not have PD were censored at the date of the last tumor assessment prior to the date of any subsequent systemic anticancer therapy.
Time frame: Time of first response to measured PD (up to Month 23.0)
Population: Randomized participants who achieved an objective response of CR or PR. Eight participants in the Ramucirumab and mFOLFOX6 treatment arm and 8 participants in the Placebo and mFOLFOX6 treatment arm were censored.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ramucirumab and mFOLFOX6 | Duration of Response | 7.4 months |
| Placebo and mFOLFOX6 | Duration of Response | 5.8 months |
Secondary
Number of Participants With Treatment-Emergent Anti-Ramucirumab Antibodies
Participants with treatment-emergent anti-ramucirumab antibodies were participants with a 4-fold increase (2 dilution increase) in immunogenicity titer over baseline titer, or participants who tested negative at baseline and positive post-baseline (at titer of ≥1:20).
Time frame: Months 1, 2, 4, 6, and 8
Population: Randomized participants who received any quantity of ramucirumab or placebo, and were evaluated for the presence of anti-ramucirumab antibodies.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ramucirumab and mFOLFOX6 | Number of Participants With Treatment-Emergent Anti-Ramucirumab Antibodies | 0 participants |
| Placebo and mFOLFOX6 | Number of Participants With Treatment-Emergent Anti-Ramucirumab Antibodies | 1 participants |
Secondary
Overall Survival (OS)
OS was defined as the time from randomization to death due to any cause. OS was censored at the date of the last follow-up visit for participants who were alive or lost to follow-up.
Time frame: Randomization to date of death from any cause (up to Month 28.3)
Population: ITT population: all randomized participants. Twenty-seven participants in the Ramucirumab and mFOLFOX6 treatment arm and 32 participants in the Placebo and mFOLFOX6 treatment arm were censored.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ramucirumab and mFOLFOX6 | Overall Survival (OS) | 11.7 months |
| Placebo and mFOLFOX6 | Overall Survival (OS) | 11.5 months |
p-value: 0.71295% CI: [0.73, 1.58]Stratified Log Rank
Secondary
Percentage of Participants Achieving an Objective Response (Objective Response Rate)
The percentage of participants who achieved a best overall response of partial response (PR) or complete response (CR) is reported. Response was defined using RECIST, v. 1.1 criteria. CR was the disappearance of all lesions and pathological lymph node reduction in the short axis to \<10 mm. PR was a ≥30% decrease in the sum of the diameters of target lesions. The percentage of participants with objective response=(number of participants whose best overall response achieved was CR or PR/number of participants treated)\*100.
Time frame: Randomization to measured PD (up to Month 23.0)
Population: ITT population: all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ramucirumab and mFOLFOX6 | Percentage of Participants Achieving an Objective Response (Objective Response Rate) | 45.2 percentage of participants |
| Placebo and mFOLFOX6 | Percentage of Participants Achieving an Objective Response (Objective Response Rate) | 46.4 percentage of participants |
Secondary
Time to Disease Progression (TTP)
TTP was defined using RECIST v. 1.1 as the time from study randomization to the first date of PD. PD was a ≥20% increase in the sum of the diameters of target lesions with the sum demonstrating an absolute increase of ≥5 mm; the appearance of ≥1 new lesions or unequivocal progression of non-target lesions. TTP was censored at the date of last adequate tumor assessment if death was due to causes other than PD.
Time frame: Randomization to measured PD (up to Month 25.0)
Population: ITT population: all randomized participants. Thirty-five participants in the Ramucirumab and mFOLFOX6 treatment arm and 31 participants in the Placebo and mFOLFOX6 treatment arm were censored.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ramucirumab and mFOLFOX6 | Time to Disease Progression (TTP) | 8.7 months |
| Placebo and mFOLFOX6 | Time to Disease Progression (TTP) | 7.1 months |
p-value: 0.51695% CI: [0.59, 1.3]Stratified Log Rank
Other Pre-specified
Number of Participants With Adverse Events (AEs)
Reported are the number of participants who had ramucirumab/placebo-related: AEs, serious AEs (SAEs), AEs based on common terminology criteria for adverse events (CTCAE) ≥Grade 3, AEs = CTCAE Grade 5, as well as, AEs leading to treatment discontinuation and AEs resulting in death. A summary of serious and other non-serious AEs regardless of causality is located in the Reported Adverse Events module.
Time frame: Baseline through study completion (up to Month 28.3)
Population: Safety population: randomized participants who received any quantity of study drug (Ramucirumab, mFOLFOX6, or placebo).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ramucirumab and mFOLFOX6 | Number of Participants With Adverse Events (AEs) | Any Ramucirumab/Placebo-Related AE | 64 participants |
| Ramucirumab and mFOLFOX6 | Number of Participants With Adverse Events (AEs) | Any Ramucirumab/Placebo-Related SAE | 10 participants |
| Ramucirumab and mFOLFOX6 | Number of Participants With Adverse Events (AEs) | Any Ramucirumab/Placebo-Related ≥Grade 3 AE | 36 participants |
| Ramucirumab and mFOLFOX6 | Number of Participants With Adverse Events (AEs) | Any Ramucirumab/Placebo-Related Grade 5 AE | 0 participants |
| Ramucirumab and mFOLFOX6 | Number of Participants With Adverse Events (AEs) | Any AE Leading to Treatment Discontinuation | 18 participants |
| Ramucirumab and mFOLFOX6 | Number of Participants With Adverse Events (AEs) | Any AE with Outcome of Death | 5 participants |
| Placebo and mFOLFOX6 | Number of Participants With Adverse Events (AEs) | Any AE Leading to Treatment Discontinuation | 5 participants |
| Placebo and mFOLFOX6 | Number of Participants With Adverse Events (AEs) | Any Ramucirumab/Placebo-Related AE | 64 participants |
| Placebo and mFOLFOX6 | Number of Participants With Adverse Events (AEs) | Any Ramucirumab/Placebo-Related Grade 5 AE | 3 participants |
| Placebo and mFOLFOX6 | Number of Participants With Adverse Events (AEs) | Any Ramucirumab/Placebo-Related SAE | 12 participants |
| Placebo and mFOLFOX6 | Number of Participants With Adverse Events (AEs) | Any AE with Outcome of Death | 2 participants |
| Placebo and mFOLFOX6 | Number of Participants With Adverse Events (AEs) | Any Ramucirumab/Placebo-Related ≥Grade 3 AE | 33 participants |