Breast Cancer
Conditions
Keywords
Breast Cancer
Brief summary
An open-label, multicenter, randomized, Phase 2 trial in which participant with unresectable, locally advanced or metastatic breast cancer who have been previously treated with anthracycline and taxane therapy receive ramucirumab DP or Icrucumab (IMC-18F1) administered on an every-21-day cycle (in combination with oral capecitabine therapy; capecitabine is administered twice a day on Days 1-14 of each cycle). Approximately 150 participants will be randomized in a 1:1:1 ratio to either ramucirumab DP or Icrucumab (IMC-18F1) in combination with capecitabine (Arm A and Arm B, respectively) or capecitabine monotherapy (Arm C). Randomization will be stratified by triple-negative receptor status (estrogen receptor-negative, progesterone receptor-negative, and human epidermal growth factor receptor-2 \[HER2/neu\]-negative) (yes/no) and receipt of prior antiangiogenic therapy. Treatment with the study medication(s) will continue until disease progression, the development of unacceptable toxicity, noncompliance or withdrawal of consent by the participant, or investigator decision. Capecitabine dose reductions in the setting of significant myelosuppression, hand-and-foot syndrome, or diarrhea will be required.
Interventions
BIOLOGICALRamucirumab DP
10 mg/kg I.V. Day 1 of every-21-day cycle
BIOLOGICALIMC-18F1
12 mg/kg I.V. Days 1 and 8 of every-21-day cycle
DRUGCapecitabine
1000 mg/m\^2 orally Twice a day for 14 days
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 histologically or cytologically confirmed breast cancer which at the time of study entry is either Stage III disease not amenable to curative therapy or Stage IV disease * Has measurable or nonmeasurable disease * Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 * Has received prior anthracycline therapy * Has received prior taxane therapy * Participants with human epidermal growth factor receptor-2 (HER2) positive disease must have progressed on or following trastuzumab * Participants with hormone receptor-positive disease must have progressed on or following hormone therapy * Has received ≤ 3 prior chemotherapy regimens in any setting (a regimen is defined as any agent\[s\] that has been administered for more than 1 cycle; sequential neoadjuvant/adjuvant treatment is considered 1 regimen) * Has completed any prior radiotherapy ≥ 4 weeks prior to randomization * Has completed any prior hormonal therapy ≥ 2 weeks prior to randomization * Has adverse events (AEs) that have resolved to Grade ≤ 1 by the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI-CTCAE v 4.0) from all clinically significant toxic effects of prior chemotherapy, surgery, radiotherapy,or hormonal therapy * Has adequate hematologic, coagulation, hepatic and renal function * Does not have: * cirrhosis at a level of Child-Pugh B (or worse) or * cirrhosis (any degree) and a history of hepatic encephalopathy or ascites resulting from cirrhosis and requiring ongoing treatment with diuretics and/or paracentesis * Has urinary protein is ≤ 1+ on dipstick or routine urinalysis; if urine protein ≥ 2+, a 24-hour urine collection must demonstrate \< 1000 mg of protein in 24 hours to allow participation in the study * Agrees to use adequate contraception during the study period and for 12 weeks after the last dose of study medication
Exclusion criteria
* Has a concurrent active malignancy other than adequately treated nonmelanomatous skin cancer, curatively treated cervical carcinoma in situ, or other noninvasive carcinoma or in situ neoplasm. A participant with previous history of malignancy is eligible, provided that there has been a disease-free interval for \> 3 years * Has a known sensitivity to capecitabine, any of its components, or other drugs formulated with polysorbate 80 * Has a known sensitivity to 5-fluorouracil (5-FU) * Has a known dihydropyrimidine dehydrogenase deficiency * Has received prior capecitabine treatment for advanced breast cancer * Has received investigational therapy within 2 weeks prior to randomization * Has received bevacizumab within 4 weeks prior to randomization * Has received more than 1 prior antiangiogenic agent for breast cancer * Has a known sensitivity to agents of similar biologic composition as ramucirumab DP or Icrucumab (IMC-18F1), or other agents that specifically target vascular endothelial growth factor (VEGF) * Has an acute/subacute bowel obstruction or history of chronic diarrhea requiring ongoing medical intervention * Has a history of uncontrolled hereditary or acquired bleeding or thrombotic disorders * Has experienced a Grade ≥ 3 bleeding event within 3 months prior to randomization * Is receiving prophylactic or therapeutic anticoagulation with warfarin or any other oral anticoagulant * Has an uncontrolled intercurrent illness, including, but not limited to uncontrolled hypertension, symptomatic anemia, symptomatic congestive heart failure, unstable angina pectoris, symptomatic or poorly controlled cardiac arrhythmia, psychiatric illness/social situations, or any other serious uncontrolled medical disorder in the opinion of the investigator * Has experienced any arterial thrombotic or thromboembolic events, including, but not limited to myocardial infarction, transient ischemic attack, or cerebrovascular accident within 6 months prior to randomization * Has brain metastases, uncontrolled spinal cord compression, or leptomeningeal disease * Has an ongoing or active infection requiring parenteral antibiotic, antifungal, or antiviral therapy * Has received a prior allogeneic organ or tissue transplantation * Has undergone major surgery within 4 weeks prior to randomization, or subcutaneous venous access device placement within 7 days prior to randomization * Has had a serious nonhealing wound, ulcer, or bone fracture within 4 weeks prior to randomization * Has known HIV or AIDS infection * Has an elective or planned major surgery to be performed during the course of the trial * Participant is pregnant or lactating
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | From Date of Randomization until Disease Progression or Death Due to Any Cause (Up To 97 weeks) | PFS is defined as the time from the date of randomization until the date of objectively determined progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) or death from any cause, whichever is first. Disease progression is defined as ≥20% increase in the sum of diameters of target lesions, taking as reference smallest sum on study (included baseline sum if that was the smallest on study); sum must have demonstrated an absolute increase of ≥5 millimeter (mm) and the appearance of ≥1 new lesions was progression. Participants who did not progress, were lost to follow-up, or had missed 2 or more scheduled tumor assessments were censored at the day of their last adequate tumor assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Objective Response Rate (ORR) | From Date of Randomization until Disease Progression/Recurrence (Up to 97 weeks) | The ORR is the number of all participants with Partial Response (PR) or Complete Response (CR) according to RECIST v1.1 from the start of the treatment until disease progression/recurrence. CR was defined as the disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes reduced to \<10 mm. PR was defined as ≥30% decrease in the sum of the diameters of target lesions (including the short axes of any target lymph nodes), taking as reference the baseline sum diameter. Disease progression is defined as ≥20% increase in the sum of diameters of target lesions, taking as reference smallest sum on study (included baseline sum if that was the smallest on study); sum must have demonstrated an absolute increase of ≥5 mm and the appearance of ≥1 new lesions was progression. |
| Duration of Response | From Date of CR, PR until Disease Progression or Death Due to Any Cause (Up To 97 weeks) | Duration of response is measured from the time measurement criteria are first met for CR/PR (whichever is first recorded) until the first date that the criteria for progressive disease (PD) is met (taking as a reference for PD that smallest measurement recorded since the treatment started), or death, is objectively documented.CR was defined as the disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes reduced to \<10 mm. PR was defined as ≥30% decrease in the sum of the diameters of target lesions (including the short axes of any target lymph nodes), taking as reference the baseline sum diameter.PD defined as ≥20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). Sum must also have demonstrated an absolute increase of ≥5 mm, or the appearance of 1 or more new lesions was considered progression. |
| Number of Participants With Adverse Events (AEs) | Up To 160 Weeks | Adverse event (AE) will be regarded as treatment-emergent if onset date occurs any time on or after the administration of the first dose of study treatment up to 30 days after the last dose of study treatment (or up to any time if related to study treatment); or it occurs prior to first dose date and worsens while on therapy or up to 30 days after the last dose of study treatment (or up to any time if related to study treatment). A summary of other nonserious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section. |
| Number of Participants With Serious Adverse Events (SAEs) | Up To 160 Weeks | SAE was defined as any untoward medical occurrence that at any dose: Resulted in death; Was life-threatening; Required inpatient hospitalization or caused prolongation of existing hospitalization; Resulted in persistent or significant disability/incapacity; Was a congenital anomaly/birth defect; Required intervention to prevent permanent impairment/damage; Was an important medical event (defined as a medical event that may not have been immediately life-threatening or resulted in death or hospitalization but, based upon appropriate medical and scientific judgment, may jeopardize the participant or may require intervention to prevent one of the other serious outcomes listed in the definition above). A summary of other nonserious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section. |
| Maximum Concentration (Cmax) Ramucirumab Drug Product (DP) or Icrucumab | Cycle 1: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion | — |
| Overall Survival (OS) | From Date of Randomization until Death Due to Any Cause (Up To 160 weeks) | Overall survival is defined as the time from the date of randomization to the date of death from any cause. If the participant is alive at the end of the follow-up period or is lost to follow-up, OS will be censored on the last date the participant is known to be alive. |
| Area Under the Concentration Versus Time Curve From Time Zero to Infinity of Ramucirumab or Icrucumab | Cycle 1: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion | Area Under the Concentration (AUC) Versus Time Curve From Time Zero to Infinity of Ramucirumab and Icrucumab. |
| Terminal Half-life (t½) of Ramucirumab or Icrucumab | Cycle 1: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion | Terminal half-life (t½) of Ramucirumab and Icrucumab. |
| Clearance (Cl) of Ramucirumab or Icrucumab | Cycle 1: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion | Clearance (Cl) of Ramucirumab and Icrucumab. |
| Volume of Distribution at Steady State (Vss) of Ramucirumab or Icrucumab | Cycle 1: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion | Volume of Distribution at Steady State (Vss) of Ramucirumab and Icrucumab. |
| Number of Participants With Anti-Ramucirumab and Anti-Icrucumab Antibodies | Cycle 1: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion | — |
| Minimum Concentration (Cmin) Ramucirumab Drug Product (DP) or Icrucumab | Cycle 2,4,6,8,0,12,14,16,18,22: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion | Minimum Concentration (Cmin) Ramucirumab Drug Product (DP) or Icrucumab. |
Countries
Canada, United States
Participant flow
Recruitment details
Participants in Capecitabine arm were allowed to cross-over to ramucirumab or icrucumab in combination with capecitabine, after radiographic disease progression while on capecitabine.
Pre-assignment details
Completers are those participants who died or alive and on study at conclusion but off treatment.
Participants by arm
| Arm | Count |
|---|---|
| Ramucirumab + Capecitabine Participants received 10 mg/kg Ramucirumab intravenously on day 1 of 21 days cycle along with 1000 mg/m\^2 of Capecitabine twice daily orally on days 1 to 14 of 21 days cycle. | 52 |
| Icrucumab + Capecitabine Participants received 12 mg/kg Icrucumab intravenously on day 1 and day 8 of 21 day cycle along with 1000 mg/m\^2 of Capecitabine twice daily orally on days 1 to 14 of 21 days cycle. | 49 |
| Capecitabine Participants received 1000 mg/m\^2 of Capecitabine twice daily orally on days 1 to 14 of 21 days cycle.
After radiographic diseases progression while on Capecitabine, participants were crossed-over to either Ramucirumab or Icrucumab;
Participants crossed-over to Ramucirumab + Capecitabine had received 10 mg/kg Ramucirumab intravenously on day 1 of 21 days cycle along with 1000 mg/m\^2 of Capecitabine twice daily orally on days 1 to 14 of 21 days cycle.
Participants crossed-over to Icrucumab + Capecitabine received 12 mg/kg Icrucumab intravenously on day 1 and day 8 of 21 day cycle along with 1000 mg/m\^2 of Capecitabine twice daily orally on days 1 to 14 of 21 days cycle. | 49 |
| Total | 150 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 | 3 |
| Overall Study | Never treated: Death | 0 | 0 | 1 |
| Overall Study | Never treated: Insurance Denied Xeloda | 0 | 1 | 0 |
| Overall Study | Never treated: Withdrawal By Subject | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 3 | 4 |
Baseline characteristics
| Characteristic | Ramucirumab + Capecitabine | Total | Capecitabine | Icrucumab + Capecitabine |
|---|---|---|---|---|
| Age, Continuous | 55.2 years STANDARD_DEVIATION 10.75 | 53.3 years STANDARD_DEVIATION 11.19 | 53.5 years STANDARD_DEVIATION 11.12 | 51.1 years STANDARD_DEVIATION 11.54 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 6 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 49 Participants | 138 Participants | 45 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 6 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native,White | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 4 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 13 Participants | 25 Participants | 4 Participants | 8 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 5 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 36 Participants | 112 Participants | 39 Participants | 37 Participants |
| Race/Ethnicity, Customized White, Other | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Female | 52 Participants | 149 Participants | 49 Participants | 48 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 51 / 52 | 49 / 49 | 48 / 49 | 29 / 29 | 1 / 1 |
| serious Total, serious adverse events | 20 / 52 | 25 / 49 | 6 / 49 | 5 / 29 | 0 / 1 |
Outcome results
Primary
Progression-Free Survival (PFS)
PFS is defined as the time from the date of randomization until the date of objectively determined progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) or death from any cause, whichever is first. Disease progression is defined as ≥20% increase in the sum of diameters of target lesions, taking as reference smallest sum on study (included baseline sum if that was the smallest on study); sum must have demonstrated an absolute increase of ≥5 millimeter (mm) and the appearance of ≥1 new lesions was progression. Participants who did not progress, were lost to follow-up, or had missed 2 or more scheduled tumor assessments were censored at the day of their last adequate tumor assessment.
Time frame: From Date of Randomization until Disease Progression or Death Due to Any Cause (Up To 97 weeks)
Population: All randomized participants who received at least one dose of study drug; Censored participants: Ramucirumab + Capecitabine = 12; Icrucumab + Capecitabine = 11; Capecitabine = 7
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ramucirumab + Capecitabine | Progression-Free Survival (PFS) | 22.1 Weeks |
| Icrucumab + Capecitabine | Progression-Free Survival (PFS) | 7.3 Weeks |
| Capecitabine | Progression-Free Survival (PFS) | 19.0 Weeks |
Comparison: Kaplan-Meier methodology estimated median PFSp-value: 0.131595% CI: [0.429, 1.114]Log Rank
Comparison: Kaplan-Meier methodology estimated median PFSp-value: 0.085195% CI: [0.938, 2.335]Log Rank
Secondary
Area Under the Concentration Versus Time Curve From Time Zero to Infinity of Ramucirumab or Icrucumab
Area Under the Concentration (AUC) Versus Time Curve From Time Zero to Infinity of Ramucirumab and Icrucumab.
Time frame: Cycle 1: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion
Population: For ramucirumab, all randomized participants who received at least one dose of study drug \& had evaluable pharmacokinetic (PK) samples.~For icrucumab, zero participants analyzed as reliable PK parameters could not be estimated using non-compartmental PK analysis due to insufficient number of samples.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ramucirumab + Capecitabine | Area Under the Concentration Versus Time Curve From Time Zero to Infinity of Ramucirumab or Icrucumab | 54400 microgram*hour/mL | Geometric Coefficient of Variation 42 |
Secondary
Clearance (Cl) of Ramucirumab or Icrucumab
Clearance (Cl) of Ramucirumab and Icrucumab.
Time frame: Cycle 1: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion
Population: For ramucirumab, all randomized participants who received at least one dose of study drug \& had evaluable pharmacokinetic (PK) samples.~For icrucumab, zero participants analyzed as reliable PK parameters could not be estimated using non-compartmental PK analysis due to insufficient number of samples.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ramucirumab + Capecitabine | Clearance (Cl) of Ramucirumab or Icrucumab | 0.0141 Liters per hour | Geometric Coefficient of Variation 34 |
Secondary
Duration of Response
Duration of response is measured from the time measurement criteria are first met for CR/PR (whichever is first recorded) until the first date that the criteria for progressive disease (PD) is met (taking as a reference for PD that smallest measurement recorded since the treatment started), or death, is objectively documented.CR was defined as the disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes reduced to \<10 mm. PR was defined as ≥30% decrease in the sum of the diameters of target lesions (including the short axes of any target lymph nodes), taking as reference the baseline sum diameter.PD defined as ≥20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). Sum must also have demonstrated an absolute increase of ≥5 mm, or the appearance of 1 or more new lesions was considered progression.
Time frame: From Date of CR, PR until Disease Progression or Death Due to Any Cause (Up To 97 weeks)
Population: All randomized participants who received at least one dose of study drug and had CR/PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ramucirumab + Capecitabine | Duration of Response | 43.1 weeks |
| Icrucumab + Capecitabine | Duration of Response | 20.1 weeks |
| Capecitabine | Duration of Response | 17.1 weeks |
Secondary
Maximum Concentration (Cmax) Ramucirumab Drug Product (DP) or Icrucumab
Time frame: Cycle 1: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion
Population: For ramucirumab, all randomized participants who received at least one dose of study drug \& had evaluable pharmacokinetic (PK) samples.~For icrucumab, zero participants analyzed as reliable PK parameters could not be estimated using non-compartmental PK analysis due to insufficient number of samples.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ramucirumab + Capecitabine | Maximum Concentration (Cmax) Ramucirumab Drug Product (DP) or Icrucumab | 308 Microgram per milliliter | Geometric Coefficient of Variation 25 |
Secondary
Minimum Concentration (Cmin) Ramucirumab Drug Product (DP) or Icrucumab
Minimum Concentration (Cmin) Ramucirumab Drug Product (DP) or Icrucumab.
Time frame: Cycle 2,4,6,8,0,12,14,16,18,22: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion
Population: For ramucirumab, all randomized participants who received at least one dose of study drug \& had evaluable pharmacokinetic (PK) samples.~For icrucumab, zero participants analyzed as reliable PK parameters could not be estimated using non-compartmental PK analysis due to insufficient number of samples.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ramucirumab + Capecitabine | Minimum Concentration (Cmin) Ramucirumab Drug Product (DP) or Icrucumab | Cycle 2 | 23.7 Micro gram per milliliter | Geometric Coefficient of Variation 58 |
| Ramucirumab + Capecitabine | Minimum Concentration (Cmin) Ramucirumab Drug Product (DP) or Icrucumab | Cycle 4 | 80.6 Micro gram per milliliter | Geometric Coefficient of Variation 67 |
| Ramucirumab + Capecitabine | Minimum Concentration (Cmin) Ramucirumab Drug Product (DP) or Icrucumab | Cycle 6 | 44.7 Micro gram per milliliter | Geometric Coefficient of Variation 83 |
| Ramucirumab + Capecitabine | Minimum Concentration (Cmin) Ramucirumab Drug Product (DP) or Icrucumab | Cycle 8 | 65.8 Micro gram per milliliter | Geometric Coefficient of Variation 43 |
| Ramucirumab + Capecitabine | Minimum Concentration (Cmin) Ramucirumab Drug Product (DP) or Icrucumab | Cycle 10 | 66.8 Micro gram per milliliter | Geometric Coefficient of Variation 37 |
| Ramucirumab + Capecitabine | Minimum Concentration (Cmin) Ramucirumab Drug Product (DP) or Icrucumab | Cycle 12 | 74.3 Micro gram per milliliter | Geometric Coefficient of Variation 38 |
| Ramucirumab + Capecitabine | Minimum Concentration (Cmin) Ramucirumab Drug Product (DP) or Icrucumab | Cycle 14 | 62.5 Micro gram per milliliter | — |
| Ramucirumab + Capecitabine | Minimum Concentration (Cmin) Ramucirumab Drug Product (DP) or Icrucumab | Cycle 16 | 50.5 Micro gram per milliliter | — |
| Ramucirumab + Capecitabine | Minimum Concentration (Cmin) Ramucirumab Drug Product (DP) or Icrucumab | Cycle 18 | 50.5 Micro gram per milliliter | — |
| Ramucirumab + Capecitabine | Minimum Concentration (Cmin) Ramucirumab Drug Product (DP) or Icrucumab | Cycle 22 | 55.0 Micro gram per milliliter | — |
Secondary
Number of Participants With Adverse Events (AEs)
Adverse event (AE) will be regarded as treatment-emergent if onset date occurs any time on or after the administration of the first dose of study treatment up to 30 days after the last dose of study treatment (or up to any time if related to study treatment); or it occurs prior to first dose date and worsens while on therapy or up to 30 days after the last dose of study treatment (or up to any time if related to study treatment). A summary of other nonserious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section.
Time frame: Up To 160 Weeks
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ramucirumab + Capecitabine | Number of Participants With Adverse Events (AEs) | 52 Participants |
| Icrucumab + Capecitabine | Number of Participants With Adverse Events (AEs) | 49 Participants |
| Capecitabine | Number of Participants With Adverse Events (AEs) | 48 Participants |
Secondary
Number of Participants With Anti-Ramucirumab and Anti-Icrucumab Antibodies
Time frame: Cycle 1: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion
Population: For ramucirumab, Aall randomized participants who received at least one dose of study drug and had evaluable serum samples for antibody assessment.~For icrucumab, zero participants analyzed as antibody assessment data was not collected for Icrucumab.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ramucirumab + Capecitabine | Number of Participants With Anti-Ramucirumab and Anti-Icrucumab Antibodies | Neutralizing antibody | 0 Participants |
| Ramucirumab + Capecitabine | Number of Participants With Anti-Ramucirumab and Anti-Icrucumab Antibodies | Treatment emergent antibody | 0 Participants |
Secondary
Number of Participants With Serious Adverse Events (SAEs)
SAE was defined as any untoward medical occurrence that at any dose: Resulted in death; Was life-threatening; Required inpatient hospitalization or caused prolongation of existing hospitalization; Resulted in persistent or significant disability/incapacity; Was a congenital anomaly/birth defect; Required intervention to prevent permanent impairment/damage; Was an important medical event (defined as a medical event that may not have been immediately life-threatening or resulted in death or hospitalization but, based upon appropriate medical and scientific judgment, may jeopardize the participant or may require intervention to prevent one of the other serious outcomes listed in the definition above). A summary of other nonserious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section.
Time frame: Up To 160 Weeks
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ramucirumab + Capecitabine | Number of Participants With Serious Adverse Events (SAEs) | 20 Participants |
| Icrucumab + Capecitabine | Number of Participants With Serious Adverse Events (SAEs) | 25 Participants |
| Capecitabine | Number of Participants With Serious Adverse Events (SAEs) | 6 Participants |
Secondary
Overall Survival (OS)
Overall survival is defined as the time from the date of randomization to the date of death from any cause. If the participant is alive at the end of the follow-up period or is lost to follow-up, OS will be censored on the last date the participant is known to be alive.
Time frame: From Date of Randomization until Death Due to Any Cause (Up To 160 weeks)
Population: All randomized participants who received at least one dose of study drug; censored participants: Ramucirumab + Capecitabine = 21; Icrucumab + Capecitabine = 17; Capecitabine = 22 Participants were analyzed as per the randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ramucirumab + Capecitabine | Overall Survival (OS) | 67.4 Weeks |
| Icrucumab + Capecitabine | Overall Survival (OS) | 62.1 Weeks |
| Capecitabine | Overall Survival (OS) | 71.6 Weeks |
p-value: 0.028395% CI: [1.06, 3.169]Log Rank
p-value: 0.15595% CI: [0.862, 2.501]Log Rank
Secondary
Percentage of Participants With Objective Response Rate (ORR)
The ORR is the number of all participants with Partial Response (PR) or Complete Response (CR) according to RECIST v1.1 from the start of the treatment until disease progression/recurrence. CR was defined as the disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes reduced to \<10 mm. PR was defined as ≥30% decrease in the sum of the diameters of target lesions (including the short axes of any target lymph nodes), taking as reference the baseline sum diameter. Disease progression is defined as ≥20% increase in the sum of diameters of target lesions, taking as reference smallest sum on study (included baseline sum if that was the smallest on study); sum must have demonstrated an absolute increase of ≥5 mm and the appearance of ≥1 new lesions was progression.
Time frame: From Date of Randomization until Disease Progression/Recurrence (Up to 97 weeks)
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ramucirumab + Capecitabine | Percentage of Participants With Objective Response Rate (ORR) | 28.8 Percentage of Participants |
| Icrucumab + Capecitabine | Percentage of Participants With Objective Response Rate (ORR) | 20.4 Percentage of Participants |
| Capecitabine | Percentage of Participants With Objective Response Rate (ORR) | 34.7 Percentage of Participants |
p-value: 0.6691Fisher Exact
p-value: 0.1743Fisher Exact
Secondary
Terminal Half-life (t½) of Ramucirumab or Icrucumab
Terminal half-life (t½) of Ramucirumab and Icrucumab.
Time frame: Cycle 1: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion
Population: For ramucirumab, all randomized participants who received at least one dose of study drug \& had evaluable pharmacokinetic (PK) samples.~For icrucumab, zero participants analyzed as reliable PK parameters could not be estimated using non-compartmental PK analysis due to insufficient number of samples.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Ramucirumab + Capecitabine | Terminal Half-life (t½) of Ramucirumab or Icrucumab | 6.80 Days |
Secondary
Volume of Distribution at Steady State (Vss) of Ramucirumab or Icrucumab
Volume of Distribution at Steady State (Vss) of Ramucirumab and Icrucumab.
Time frame: Cycle 1: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion
Population: For ramucirumab, all randomized participants who received at least one dose of study drug \& had evaluable pharmacokinetic (PK) samples.~For icrucumab, zero participants analyzed as reliable PK parameters could not be estimated using non-compartmental PK analysis due to insufficient number of samples.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ramucirumab + Capecitabine | Volume of Distribution at Steady State (Vss) of Ramucirumab or Icrucumab | 3.17 Liters | Geometric Coefficient of Variation 18 |