Stomach Neoplasms
Conditions
Brief summary
The main purpose of this study is to evaluate the safety, tolerability, pharmacokinetics and antitumor response of ramucirumab in combination with platinum/fluoropyrimidine regimens in Japanese participants with advanced gastric/gastrooesophageal junction cancer who have not received chemotherapy.
Interventions
DRUGRamucirumab
Administered IV
DRUGCapecitabine
Administered orally
DRUGCisplatin
Administered IV
DRUGS-1
Administered orally
DRUGOxaliplatin
Administered IV
Sponsors
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* A histopathologically or cytologically confirmed diagnosis of gastric or gastroesophageal junction (GEJ) adenocarcinoma which is metastatic or locally advanced and unresectable. A participant with esophageal cancer is not eligible. * Not have received prior first-line systemic chemotherapy for locally advanced and unresectable and/or metastatic disease. Participants whose disease has progressed after \>6 months following the last dose of systemic treatment in the adjuvant/neoadjuvant setting are eligible. * Measurable or nonmeasurable, but evaluable, disease, determined using guidelines in Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. * Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 at the time of enrollment. * The participant has adequate organ function. * Resolution to Grade ≤1 by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; version \[v\]4.03) of all clinically significant toxic effects of prior locoregional therapy, surgery, or other anticancer. * Female participants of childbearing potential must have a negative serum or urinary pregnancy. Have an estimated life expectancy of ≥12 weeks in the judgment of the investigator.
Exclusion criteria
* A significant bleeding disorder, vasculitis, or had a significant bleeding episode from the gastrointestinal tract within 12 weeks prior to enrollment. * Uncontrolled arterial hypertension, despite standard medical management. * A serious or nonhealing wound or peptic ulcer or bone fracture at enrollment. * Undergone major surgery within 28 days prior to enrollment, or subcutaneous venous access device (reservoir) placement within 7 days prior to enrollment. * Radiation therapy within 14 days prior to enrollment. * Received any previous systemic therapy (including investigational agents) targeting vascular endothelial growth factor (VEGF) or the VEGF receptor signaling pathways. * Cirrhosis at a level of Child-Pugh B (or worse); or cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. * A serious illness or medical condition(s). * Pregnant or breastfeeding. * Dysphagia for oral medication. * Known allergy or hypersensitivity to any study treatment. * Human epidermal growth factor receptor (HER) 2 status of positive. * Received treatment within 28 days of the initial dose of study drug with an investigational product or non-approved use of a drug or device.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With One or More Serious Adverse Event(s) (SAEs) Considered by the Investigator to be Related to Study Drug Administration | First Dose to Study Completion Plus 30-Day Safety Follow-Up (Up To 22 Months) | Clinically significant events were defined as serious adverse events (SAE). A summary of other nonserious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Ramucirumab | Day 1, Day 8, Day 43, Day 50, Day 85 and Day 92: End of Infusion | Maximum Serum Concentration (Cmax) of Ramucirumab. |
| Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 8, Day 22, Day 29, Day 43, Day 50, Day 64, Day 71, Day 85, Day 92 and Day 106: Pre-Dose | Minimum Serum Concentration (Cmin) of Ramucirumab. |
| Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate) | First Dose to Date of Objective Progressive Disease or Death Due to Any Cause (Up To 22 Months) | Objective response rate (ORR) was defined as the percentage of randomized participants achieving a best confirmed overall response of CR or PR using Response Evaluation Criteria in Solid Tumors (RECIST v1). CR was defined as the disappearance of all target and non-target lesions. PR was defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions, taking as reference the baseline sum LD and no progression in non-target lesions. |
| Number of Participants With Treatment Emergent Anti-Ramucirumab Antibodies (TE-ADA) | First dose to study completion plus 30-day safety follow-up (Up To 22 Months) | Number of participants with positive treatment emergent anti-ramucirumab antibodies was summarized by treatment group. |
Countries
Japan
Participant flow
Pre-assignment details
Participants were considered completed if they either completed Cycle 1 of study drug or discontinued study drug due to a dose limiting toxicity (DLT) during Cycle 1.
Participants by arm
| Arm | Count |
|---|---|
| Ramucirumab + Capecitabine + Cisplatin Ramucirumab 8 mg/kg given intravenously (IV) on days 1 and 8 in combination with 1000 mg/square meter (m\^2) capecitabine given orally twice a day on days 1 through 14 and 80 mg/m\^2 cisplatin given IV on day 1 of each 21 day cycle (up to 6 cycles). Participants may continue to receive treatment until discontinuation criteria are met. | 6 |
| Ramucirumab + S-1 + Cisplatin Ramucirumab 8 mg/kg given IV on days 1 and 8 of 21 day in combination with 40 mg/m\^2 tegafur/gimeracil/oteracil (S-1) given orally twice a day on days 1 through 21 and 60 mg/m\^2 cisplatin given IV on day 8 of each 35 day cycle (up to 8 cycles). Participants may continue to receive treatment until discontinuation criteria are met. | 6 |
| Ramucirumab + S-1 + Oxaliplatin Ramucirumab 8 mg/kg given IV on days 1 and 8 in combination with 40 mg/m\^2 S-1 given orally twice a day on days 1 through 14 and 100 mg/m\^2 oxaliplatin given IV on day 1 of each 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met. | 6 |
| Total | 18 |
Baseline characteristics
| Characteristic | Ramucirumab + Capecitabine + Cisplatin | Total | Ramucirumab + S-1 + Oxaliplatin | Ramucirumab + S-1 + Cisplatin |
|---|---|---|---|---|
| Age, Continuous | 57.5 years STANDARD_DEVIATION 10.93 | 60.2 years STANDARD_DEVIATION 8.3 | 62.7 years STANDARD_DEVIATION 6.98 | 60.3 years STANDARD_DEVIATION 7.06 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 18 Participants | 6 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 18 Participants | 6 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Japan | 6 Participants | 18 Participants | 6 Participants | 6 Participants |
| Sex: Female, Male Female | 4 Participants | 10 Participants | 0 Participants | 6 Participants |
| Sex: Female, Male Male | 2 Participants | 8 Participants | 6 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 5 / 6 |
| serious Total, serious adverse events | 1 / 6 | 2 / 6 | 2 / 6 |
Outcome results
Primary
Number of Participants With One or More Serious Adverse Event(s) (SAEs) Considered by the Investigator to be Related to Study Drug Administration
Clinically significant events were defined as serious adverse events (SAE). A summary of other nonserious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section.
Time frame: First Dose to Study Completion Plus 30-Day Safety Follow-Up (Up To 22 Months)
Population: All enrolled participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ramucirumab + Capecitabine + Cisplatin | Number of Participants With One or More Serious Adverse Event(s) (SAEs) Considered by the Investigator to be Related to Study Drug Administration | 1 Participants |
| Ramucirumab + S-1 + Cisplatin | Number of Participants With One or More Serious Adverse Event(s) (SAEs) Considered by the Investigator to be Related to Study Drug Administration | 2 Participants |
| Ramucirumab + S-1 + Oxaliplatin | Number of Participants With One or More Serious Adverse Event(s) (SAEs) Considered by the Investigator to be Related to Study Drug Administration | 2 Participants |
Secondary
Number of Participants With Treatment Emergent Anti-Ramucirumab Antibodies (TE-ADA)
Number of participants with positive treatment emergent anti-ramucirumab antibodies was summarized by treatment group.
Time frame: First dose to study completion plus 30-day safety follow-up (Up To 22 Months)
Population: All enrolled participants who received at least one dose of the study drug and had evaluable immunogenicity data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ramucirumab + Capecitabine + Cisplatin | Number of Participants With Treatment Emergent Anti-Ramucirumab Antibodies (TE-ADA) | 0 Participants |
| Ramucirumab + S-1 + Cisplatin | Number of Participants With Treatment Emergent Anti-Ramucirumab Antibodies (TE-ADA) | 0 Participants |
| Ramucirumab + S-1 + Oxaliplatin | Number of Participants With Treatment Emergent Anti-Ramucirumab Antibodies (TE-ADA) | 0 Participants |
Secondary
Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate)
Objective response rate (ORR) was defined as the percentage of randomized participants achieving a best confirmed overall response of CR or PR using Response Evaluation Criteria in Solid Tumors (RECIST v1). CR was defined as the disappearance of all target and non-target lesions. PR was defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions, taking as reference the baseline sum LD and no progression in non-target lesions.
Time frame: First Dose to Date of Objective Progressive Disease or Death Due to Any Cause (Up To 22 Months)
Population: All enrolled participants who received at least one dose of study drug and with measurable disease.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ramucirumab + Capecitabine + Cisplatin | Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate) | 20 Percentage of participants |
| Ramucirumab + S-1 + Cisplatin | Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate) | 100 Percentage of participants |
| Ramucirumab + S-1 + Oxaliplatin | Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate) | 60 Percentage of participants |
| Total | Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate) | 45.5 Percentage of participants |
Secondary
Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Ramucirumab
Maximum Serum Concentration (Cmax) of Ramucirumab.
Time frame: Day 1, Day 8, Day 43, Day 50, Day 85 and Day 92: End of Infusion
Population: All enrolled participants who received at least one dose of the study drug and had evaluable ramucirumab PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ramucirumab + Capecitabine + Cisplatin | Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Ramucirumab | Day 1 | 149 microgram per milliliter (μg/mL) | Geometric Coefficient of Variation 21 |
| Ramucirumab + Capecitabine + Cisplatin | Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Ramucirumab | Day 8 | 229 microgram per milliliter (μg/mL) | Geometric Coefficient of Variation 24 |
| Ramucirumab + Capecitabine + Cisplatin | Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Ramucirumab | Day 43 | 205 microgram per milliliter (μg/mL) | Geometric Coefficient of Variation 24 |
| Ramucirumab + Capecitabine + Cisplatin | Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Ramucirumab | Day 50 | 273 microgram per milliliter (μg/mL) | Geometric Coefficient of Variation 24 |
| Ramucirumab + Capecitabine + Cisplatin | Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Ramucirumab | Day 85 | NA microgram per milliliter (μg/mL) | — |
| Ramucirumab + Capecitabine + Cisplatin | Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Ramucirumab | Day 92 | NA microgram per milliliter (μg/mL) | — |
| Ramucirumab + S-1 + Cisplatin | Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Ramucirumab | Day 92 | 289 microgram per milliliter (μg/mL) | Geometric Coefficient of Variation 22 |
| Ramucirumab + S-1 + Cisplatin | Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Ramucirumab | Day 1 | 139 microgram per milliliter (μg/mL) | Geometric Coefficient of Variation 23 |
| Ramucirumab + S-1 + Cisplatin | Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Ramucirumab | Day 50 | 249 microgram per milliliter (μg/mL) | Geometric Coefficient of Variation 24 |
| Ramucirumab + S-1 + Cisplatin | Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Ramucirumab | Day 85 | 272 microgram per milliliter (μg/mL) | Geometric Coefficient of Variation 29 |
| Ramucirumab + S-1 + Cisplatin | Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Ramucirumab | Day 8 | 200 microgram per milliliter (μg/mL) | Geometric Coefficient of Variation 21 |
| Ramucirumab + S-1 + Cisplatin | Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Ramucirumab | Day 43 | 253 microgram per milliliter (μg/mL) | Geometric Coefficient of Variation 11 |
| Ramucirumab + S-1 + Oxaliplatin | Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Ramucirumab | Day 8 | 211 microgram per milliliter (μg/mL) | Geometric Coefficient of Variation 11 |
| Ramucirumab + S-1 + Oxaliplatin | Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Ramucirumab | Day 43 | 180 microgram per milliliter (μg/mL) | Geometric Coefficient of Variation 28 |
| Ramucirumab + S-1 + Oxaliplatin | Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Ramucirumab | Day 92 | NA microgram per milliliter (μg/mL) | — |
| Ramucirumab + S-1 + Oxaliplatin | Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Ramucirumab | Day 50 | 207 microgram per milliliter (μg/mL) | Geometric Coefficient of Variation 12 |
| Ramucirumab + S-1 + Oxaliplatin | Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Ramucirumab | Day 1 | 137 microgram per milliliter (μg/mL) | Geometric Coefficient of Variation 20 |
| Ramucirumab + S-1 + Oxaliplatin | Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Ramucirumab | Day 85 | NA microgram per milliliter (μg/mL) | — |
Secondary
Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab
Minimum Serum Concentration (Cmin) of Ramucirumab.
Time frame: Day 8, Day 22, Day 29, Day 43, Day 50, Day 64, Day 71, Day 85, Day 92 and Day 106: Pre-Dose
Population: All enrolled participants who received at least one dose of the study drug and had evaluable ramucirumab PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ramucirumab + Capecitabine + Cisplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 85 | 55.5 μg/mL | Geometric Coefficient of Variation 34 |
| Ramucirumab + Capecitabine + Cisplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 43 | 60.8 μg/mL | Geometric Coefficient of Variation 27 |
| Ramucirumab + Capecitabine + Cisplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 106 | 68.6 μg/mL | Geometric Coefficient of Variation 52 |
| Ramucirumab + Capecitabine + Cisplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 64 | 47.7 μg/mL | Geometric Coefficient of Variation 31 |
| Ramucirumab + Capecitabine + Cisplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 50 | 91.7 μg/mL | Geometric Coefficient of Variation 32 |
| Ramucirumab + Capecitabine + Cisplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 71 | 71.1 μg/mL | Geometric Coefficient of Variation 34 |
| Ramucirumab + Capecitabine + Cisplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 8 | 43.8 μg/mL | Geometric Coefficient of Variation 16 |
| Ramucirumab + Capecitabine + Cisplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 92 | 97.6 μg/mL | Geometric Coefficient of Variation 24 |
| Ramucirumab + Capecitabine + Cisplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 29 | 84.6 μg/mL | Geometric Coefficient of Variation 24 |
| Ramucirumab + Capecitabine + Cisplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 22 | 40.9 μg/mL | Geometric Coefficient of Variation 21 |
| Ramucirumab + S-1 + Cisplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 50 | 91.3 μg/mL | Geometric Coefficient of Variation 28 |
| Ramucirumab + S-1 + Cisplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 71 | 109 μg/mL | Geometric Coefficient of Variation 13 |
| Ramucirumab + S-1 + Cisplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 8 | 51.6 μg/mL | Geometric Coefficient of Variation 28 |
| Ramucirumab + S-1 + Cisplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 22 | 63.9 μg/mL | Geometric Coefficient of Variation 33 |
| Ramucirumab + S-1 + Cisplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 29 | 105 μg/mL | Geometric Coefficient of Variation 19 |
| Ramucirumab + S-1 + Cisplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 43 | 87.6 μg/mL | Geometric Coefficient of Variation 34 |
| Ramucirumab + S-1 + Cisplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 64 | 85.4 μg/mL | Geometric Coefficient of Variation 34 |
| Ramucirumab + S-1 + Cisplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 85 | 102 μg/mL | Geometric Coefficient of Variation 18 |
| Ramucirumab + S-1 + Cisplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 92 | 119 μg/mL | Geometric Coefficient of Variation 14 |
| Ramucirumab + S-1 + Cisplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 106 | 118 μg/mL | Geometric Coefficient of Variation 12 |
| Ramucirumab + S-1 + Oxaliplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 71 | 124 μg/mL | Geometric Coefficient of Variation 5 |
| Ramucirumab + S-1 + Oxaliplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 29 | 81.6 μg/mL | Geometric Coefficient of Variation 28 |
| Ramucirumab + S-1 + Oxaliplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 8 | 43.2 μg/mL | Geometric Coefficient of Variation 30 |
| Ramucirumab + S-1 + Oxaliplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 85 | NA μg/mL | — |
| Ramucirumab + S-1 + Oxaliplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 22 | 41.8 μg/mL | Geometric Coefficient of Variation 37 |
| Ramucirumab + S-1 + Oxaliplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 106 | NA μg/mL | — |
| Ramucirumab + S-1 + Oxaliplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 50 | 86.2 μg/mL | Geometric Coefficient of Variation 17 |
| Ramucirumab + S-1 + Oxaliplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 43 | 68.5 μg/mL | Geometric Coefficient of Variation 41 |
| Ramucirumab + S-1 + Oxaliplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 92 | NA μg/mL | — |
| Ramucirumab + S-1 + Oxaliplatin | Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) of Ramucirumab | Day 64 | 81.5 μg/mL | Geometric Coefficient of Variation 11 |