Gastric Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma
Conditions
Keywords
stomach cancer
Brief summary
The main purpose of this study was to evaluate the safety and pharmacokinetics of administering various dose regimens of ramucirumab in participants with advanced gastric cancer whose disease has progressed during or following prior chemotherapy.
Interventions
DRUGRamucirumab
Administered IV
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The participant has a histopathologically or cytologically confirmed diagnosis of gastric or gastroesophageal junction (GEJ). * The participant has documented disease progression during or within 4 months after the last dose of first-line chemotherapy for metastatic disease, or during or within 6 months after the last dose of neoadjuvant or adjuvant therapy. * The participant received combination chemotherapy prior to disease progression. * Prior chemotherapy regimens must include a platinum and/or a fluoropyrimidine component and must not include a taxane or antiangiogenic agent. * The participant has metastatic disease or locally advanced disease that is measurable or nonmeasurable, but is evaluable disease by radiological imaging per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1). * Patients are eligible if they are considered not appropriate, for whatever reason, for treatment with ramucirumab in combination with paclitaxel. * The participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * The participant has adequate organ function, including: * Total bilirubin 1.5 × the upper limit of institutional normal (ULN) and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 3 × ULN. If the liver has tumor involvement, AST and ALT \<5 × ULN are acceptable. * Serum creatinine 1.5 × ULN or calculated creatinine clearance (per the Cockcroft-Gault formula or equivalent and/or 24-hour urine collection) 60 milliliters/minute (mL/min). * Urinary protein is \<2+ on dipstick or routine urinalysis. * Absolute neutrophil count 1.5 × 10\^9/Liter (L), platelets 100 × 10\^9/L, and hemoglobin 9 g/deciliter (dL) (5.58 millimoles/Liter). * International normalized ratio 1.5 × ULN or prothrombin time 5 seconds above ULN. * Partial thromboplastin time 5 seconds above ULN. * The participant has an estimated life expectancy of 12 weeks in the judgment of the investigator. * The participant, if female and of child-bearing potential, must have a negative serum or urine pregnancy test within 7 days prior to randomization.
Exclusion criteria
* The participant has squamous cell or undifferentiated gastric cancer. * The participant is receiving chronic therapy with any of the following within 7 days prior to randomization: * Nonsteroidal anti-inflammatory agents (NSAIDs; such as indomethacin, ibuprofen, naproxen, or similar agents), or * Other anti-platelet agents (such as clopidogrel, ticlopidine, dipyridamole, or anagrelide). Aspirin use at doses up to 325 milligrams (mg)/day is permitted. * The participant received radiotherapy within 14 days prior to randomization. * The participant received \>1 line of prior therapy for the treatment of locally advanced and unresectable or metastatic gastric or GEJ (Siewert Types I-III) adenocarcinoma. * The participant received previous treatment with agents targeting the vascular endothelial growth factor (VEGF)/VEGF receptor 2 signaling pathway. * The participant has documented brain metastases, leptomeningeal disease, or uncontrolled spinal cord compression. * The participant experienced any arterial thromboembolic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to randomization. * The participant has symptomatic congestive heart failure (New York Heart Association II-IV) or symptomatic or poorly controlled cardiac arrhythmia. * The participant has uncontrolled hypertension, as defined in Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0, prior to initiating study treatment, despite antihypertensive intervention. * The participant underwent major surgery within 28 days prior to randomization or central venous access device placement within 7 days prior to randomization. * The participant has a history of gastrointestinal perforation or fistula within 6 months prior to randomization. * The participant has any condition (for example, psychological, geographical, or medical) that does not permit compliance with the study and follow-up procedures or suggests that the participant is, in the investigator's opinion, not an appropriate candidate for the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Day 29, 43, 71 and 85: predose | The Cmin is the minimum observed serum concentration of ramucirumab. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Immunogenicity: Number of Participants With Anti-Ramucirumab Antibodies | Predose Cycle 1 Through Short Term Follow Up (Up to 5 Months) | Number of participants with positive treatment emergent anti-ramucirumab antibodies was summarized by treatment group. A treatment-emergent anti-drug antibodies (TEADA) sample was defined as: a post treatment sample with at least a 4-fold increase in titer from pre treatment sample; or 1:20 post treatment titer for participants that had no detectable ADA titer at baseline. |
| Rate of Progression Free Survival (PFS) at the First 6-Week Tumor Assessment | Baseline until the first 6-week tumor assessment | PFS defined as the time from first day of therapy to first evidence of disease progression per response evaluation criteria in solid tumors version 1.1 (RECIST v1.1) or death from any cause up to the first 6-week tumor assessment. Progressive Disease (PD) is at least 20% increase in sum of diameters of target lesions,taking as reference smallest sum on study and absolute increase of at least 5 mm.Appearance of 1 or more new lesions was also considered progression. Nontarget PD is unequivocal progression of existing nontarget lesions.Appearance of 1 or more new nontarget lesions was also considered PD.Participants with no baseline disease assessment: PFS time was censored at the randomization date,regardless of whether or not objectively determined disease progression or death has been observed. |
Countries
Argentina, Australia, France, Hungary, New Zealand, Poland, Romania, Russia, Slovakia, Turkey (Türkiye), United Kingdom, United States
Participant flow
Pre-assignment details
Study completion was defined as death due to any cause or disease progression.
Participants by arm
| Arm | Count |
|---|---|
| Ramucirumab Regimen 1 Ramucirumab (8 mg/kg) given IV on day 1 and day 15 of each cycle (28-day cycle) until discontinuation criteria are met. | 40 |
| Ramucirumab Regimen 2 Ramucirumab (12 mg/kg) given IV on day 1 and day 15 of each cycle (28-day cycle) until discontinuation criteria are met. | 42 |
| Ramucirumab Regimen 3 Ramucirumab (6 mg/kg) given IV on day 1, 8, 15 and 22 of each cycle (28-day cycle) until discontinuation criteria are met. | 41 |
| Ramucirumab Regimen 4 Ramucirumab (8 mg/kg) given IV on day 1 and day 8 of each cycle (21-day cycle) until discontinuation criteria are met. | 41 |
| Total | 164 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 3 | 2 | 1 | 0 |
| Overall Study | Physician Decision | 1 | 1 | 0 | 3 |
| Overall Study | Randomized, but never treated | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Ramucirumab Regimen 1 | Total | Ramucirumab Regimen 4 | Ramucirumab Regimen 3 | Ramucirumab Regimen 2 |
|---|---|---|---|---|---|
| Age, Continuous | 58.5 years STANDARD_DEVIATION 14 | 58.5 years STANDARD_DEVIATION 12.4 | 56.2 years STANDARD_DEVIATION 12.9 | 60.5 years STANDARD_DEVIATION 12.3 | 58.7 years STANDARD_DEVIATION 10.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 22 Participants | 7 Participants | 6 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants | 134 Participants | 32 Participants | 33 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 8 Participants | 2 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 24 Participants | 6 Participants | 5 Participants | 7 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 32 Participants | 135 Participants | 33 Participants | 35 Participants | 35 Participants |
| Region of Enrollment Argentina | 5 Participants | 14 Participants | 6 Participants | 2 Participants | 1 Participants |
| Region of Enrollment Australia | 1 Participants | 8 Participants | 5 Participants | 0 Participants | 2 Participants |
| Region of Enrollment France | 1 Participants | 5 Participants | 1 Participants | 2 Participants | 1 Participants |
| Region of Enrollment Hungary | 0 Participants | 7 Participants | 1 Participants | 3 Participants | 3 Participants |
| Region of Enrollment New Zealand | 2 Participants | 7 Participants | 3 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Poland | 6 Participants | 24 Participants | 5 Participants | 7 Participants | 6 Participants |
| Region of Enrollment Romania | 4 Participants | 27 Participants | 7 Participants | 10 Participants | 6 Participants |
| Region of Enrollment Russia | 6 Participants | 15 Participants | 3 Participants | 2 Participants | 4 Participants |
| Region of Enrollment Slovakia | 3 Participants | 7 Participants | 1 Participants | 2 Participants | 1 Participants |
| Region of Enrollment Turkey | 3 Participants | 11 Participants | 2 Participants | 2 Participants | 4 Participants |
| Region of Enrollment United Kingdom | 7 Participants | 31 Participants | 6 Participants | 8 Participants | 10 Participants |
| Region of Enrollment United States | 2 Participants | 8 Participants | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Female | 11 Participants | 36 Participants | 9 Participants | 6 Participants | 10 Participants |
| Sex: Female, Male Male | 29 Participants | 128 Participants | 32 Participants | 35 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 30 / 38 | 31 / 42 | 36 / 41 | 31 / 40 |
| serious Total, serious adverse events | 10 / 38 | 11 / 42 | 10 / 41 | 18 / 40 |
Outcome results
Primary
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab
The Cmin is the minimum observed serum concentration of ramucirumab.
Time frame: Day 29, 43, 71 and 85: predose
Population: All randomized participants who received at least one dose of ramucirumab and had evaluable ramucirumab PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ramucirumab Regimen 1 | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Day 29 | 32.9 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 51 |
| Ramucirumab Regimen 1 | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Day 43 | 47.6 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 36 |
| Ramucirumab Regimen 1 | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Day 71 | 60.4 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 34 |
| Ramucirumab Regimen 1 | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Day 85 | 64.3 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 40 |
| Ramucirumab Regimen 2 | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Day 43 | 71.0 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 58 |
| Ramucirumab Regimen 2 | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Day 71 | 65.0 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 60 |
| Ramucirumab Regimen 2 | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Day 85 | 79.4 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 46 |
| Ramucirumab Regimen 2 | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Day 29 | 59.5 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 60 |
| Ramucirumab Regimen 3 | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Day 71 | 122 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 65 |
| Ramucirumab Regimen 3 | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Day 43 | 83.0 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 57 |
| Ramucirumab Regimen 3 | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Day 85 | 125 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 56 |
| Ramucirumab Regimen 3 | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Day 29 | 69.3 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 45 |
| Ramucirumab Regimen 4 | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Day 85 | 81.6 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 50 |
| Ramucirumab Regimen 4 | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Day 43 | 57.4 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 44 |
| Ramucirumab Regimen 4 | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Day 29 | 71.6 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 37 |
| Ramucirumab Regimen 4 | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Day 71 | 97.1 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 46 |
Secondary
Immunogenicity: Number of Participants With Anti-Ramucirumab Antibodies
Number of participants with positive treatment emergent anti-ramucirumab antibodies was summarized by treatment group. A treatment-emergent anti-drug antibodies (TEADA) sample was defined as: a post treatment sample with at least a 4-fold increase in titer from pre treatment sample; or 1:20 post treatment titer for participants that had no detectable ADA titer at baseline.
Time frame: Predose Cycle 1 Through Short Term Follow Up (Up to 5 Months)
Population: All randomized participants who received at least 1 dose of ramucirumab and had evaluable anti-ramucirumab antibody measurement.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ramucirumab Regimen 1 | Immunogenicity: Number of Participants With Anti-Ramucirumab Antibodies | 0 Participants |
| Ramucirumab Regimen 2 | Immunogenicity: Number of Participants With Anti-Ramucirumab Antibodies | 0 Participants |
| Ramucirumab Regimen 3 | Immunogenicity: Number of Participants With Anti-Ramucirumab Antibodies | 0 Participants |
| Ramucirumab Regimen 4 | Immunogenicity: Number of Participants With Anti-Ramucirumab Antibodies | 0 Participants |
Secondary
Rate of Progression Free Survival (PFS) at the First 6-Week Tumor Assessment
PFS defined as the time from first day of therapy to first evidence of disease progression per response evaluation criteria in solid tumors version 1.1 (RECIST v1.1) or death from any cause up to the first 6-week tumor assessment. Progressive Disease (PD) is at least 20% increase in sum of diameters of target lesions,taking as reference smallest sum on study and absolute increase of at least 5 mm.Appearance of 1 or more new lesions was also considered progression. Nontarget PD is unequivocal progression of existing nontarget lesions.Appearance of 1 or more new nontarget lesions was also considered PD.Participants with no baseline disease assessment: PFS time was censored at the randomization date,regardless of whether or not objectively determined disease progression or death has been observed.
Time frame: Baseline until the first 6-week tumor assessment
Population: All randomized participants.Censored participants:Ramucirumab Regimen 1 = 8,Ramucirumab Regimen 2 =10,Ramucirumab Regimen 3=8 and Ramucirumab Regimen 4=12. PFS survival rate at the first 6-week assessment was estimated using the Kaplan-Meier method which takes into consideration who were censored prior to 6 weeks.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ramucirumab Regimen 1 | Rate of Progression Free Survival (PFS) at the First 6-Week Tumor Assessment | 43.9 Percentage of participants |
| Ramucirumab Regimen 2 | Rate of Progression Free Survival (PFS) at the First 6-Week Tumor Assessment | 61.9 Percentage of participants |
| Ramucirumab Regimen 3 | Rate of Progression Free Survival (PFS) at the First 6-Week Tumor Assessment | 53.0 Percentage of participants |
| Ramucirumab Regimen 4 | Rate of Progression Free Survival (PFS) at the First 6-Week Tumor Assessment | 51.2 Percentage of participants |