Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Ramucirumab · 43 trials · 52 indications
PFS defined as the time from the date of randomization to the first evidence of disease progression as defined by response evaluation criteria in solid tumors (RECIST) v1.1 or death from any cause. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. If a participant does not have a complete baseline disease assessment, then the PFS time was censored at the date of randomization, regardless of whether or not objectively determined disease progression or death has been observed for the participant. If a participant was not known to have died or have objective progression as of the data inclusion cutoff date for the analysis, the PFS time was censored at the last adequate tumor assessment date.
OS defined as the time from randomization to the date of death due to any cause. For each participant who is not known to have died as of the data-inclusion cutoff date for overall survival analysis, OS time was censored on the last date the participant is known to be alive.
PFS is defined as the time from the date of randomization to the date of radiographically documented progressive disease (PD) based on investigator assessment, or the date of death due to any cause, whichever is first assessed via Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new lesions is also considered progression.
A summary of other non-serious adverse events and all serious adverse events, regardless of causality, is located in the Reported Adverse Events Section.
PFS time was measured from the date of randomization to the date of radiographic(rgr) documentation of progression(by RECIST v.1.1) or the date of death due to any cause, whichever was earlier.If a participant did not have a complete baseline tumor assessment,then the PFS time was censored at the randomization date.If a participant was not known to have died or have rgr documented progression as of the data cutoff date for the analysis, the PFS time was censored at the last adequate tumor assessment date. If death or progressive disease(PD) occurred after 2 or more consecutive missing rgr visits,censoring occurred at the date of the last rgr visit prior to the missed visits.If death or PD occurred after postdiscontinuation(pdis) systemic anticancer therapy,censoring occurred at the date of last rgr visit prior to the start of pdis systemic anticancer therapy. PD was defined according to RECIST v.1.1.
Overall survival was the time from randomization until the date of death from any cause. Participants who were alive at the end of the follow-up period (or lost to follow-up) were censored on the last date the participant was known to be alive.
* ORR: percentage of participants with a complete or partial response * Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. * Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
ORR is defined as the number of patients with a complete response (CR) and a partial response (PR) by RECIST 1.1 criteria. A CR is defined as the disappearance of all target lesions, reduction in pathological lymph nodes to \<10 mm in short axis, and disappearance of all non-target lesions with normalization of tumor marker level. A PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Rate of patients alive
Derived from items 31,33 and 34of the ELD14 questionnaire. The score is from 0 to 100. The endpoint is defined as the difference of at least 10 points (clinical significance) between baseline score and 4-months score.
Derived from items 31,33 and 34of the ELD14 questionnaire. The score is from 0 to 100. The endpoint is defined as the difference of at least 10 points (clinical significance) between baseline score and 4-months score.
Derived from items 43 and 44of the ELD14 questionnaire. The score is from 0 to 100. The endpoint is defined as the difference of at least 10 points (clinical significance) between baseline score and 4-months score
PFS was defined as time from the date of randomization(RD) to date of radiographic documentation of progression(RDP) or the date of death due to any cause, whichever is earlier as defined by RECIST v.1.1. Participants with no tumor progression and no death were censored at date of last adequate radiological assessment (AST) or date of RD(whichever is later).PD is at least a 20% increase in sum of diameters of target lesions,taking as reference the smallest sum on study.In addition to the relative increase of 20%,the sum must also demonstrate an absolute increase of at least 5 mm.The appearance of 1 or more new lesions is also considered progression.Non-Target PD is unequivocal progression of existing nontarget lesions.A participant with incomplete baseline disease had PFS time censored at the enrollment date.A participant not known to have died or have RDP as of the data inclusion cutoff date for the analysis had PFS time censored at date of the last complete RDP-free disease AST.
The Cmin is the minimum observed serum concentration of ramucirumab.
The 12-week PFS rate is the probability of participants who survived during the first 12 weeks in the study without disease progression. It was estimated using the Kaplan-Meier method for the main analysis of the 12-week PFS rate.
Dose-normalized AUC(0-∞) was calculated from AUC(0-∞) divided by the dose. Data presented are Geometric Least Squares (Geo LS) means. Geo LS means were adjusted for cycle, participant and random error.
Dose-normalized AUC(0-∞) was calculated from AUC(0-∞) divided by the dose. Data presented are Geo LS means. Geo LS means were adjusted for cycle, participant and random error.
Dose-normalized Cmax was calculated from Cmax divided by the dose. Data presented are Geo LS means. Geo LS means were adjusted for cycle, participant and random error.
Dose-normalized Cmax was calculated from Cmax divided by the dose. Data presented are Geo LS means. Geo LS means were adjusted for cycle, participant and random error.
Dose-normalized AUC(0-∞) was calculated from AUC(0-∞) divided by the dose. Data presented are Geometric Least Squares (Geo LS) means. Geo LS means were adjusted for cycle, participant and random error.
Dose-normalized AUC(0-∞) was calculated from AUC(0-∞) divided by the dose. Data presented are Geometric Least Squares (Geo LS) means. Geo LS means were adjusted for cycle, participant and random error.
Dose-normalized Cmax was calculated from Cmax divided by the dose. Data presented are Geometric Least Squares (Geo LS) means. Geo LS means were adjusted for cycle, participant and random error.
Dose-normalized Cmax was calculated from Cmax divided by the dose. Data presented are Geometric Least Squares (Geo LS) means. Geo LS means were adjusted for cycle, participant and random error.
Dose-normalized AUC(0-∞) was calculated from AUC(0-∞) divided by the dose.
Data presented are the percentage of participants without disease progression or death at 6 months. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0). Progressive disease was defined as having at least a 20% increase in sum of longest diameter of target lesions or the appearance of one or more new lesions and/or unequivocal progression of existing nontarget lesions.
Data presented are the percentage of participants without progressive disease (PD) or death from any cause at 6 month after first dose. PD was determined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.0. PD is ≥20% increase in sum of longest diameter of target lesions and/or unequivocal progression of non-target lesion and/or new lesion.
Objective response is confirmed complete response (CR) + partial response (PR), as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.0. CR is disappearance of all target and non-target lesions; PR is ≥30% decrease in sum of longest diameter of target lesions without new lesion and progression of non-target lesion. ORR is calculated as a total number of participants with CR or PR from the start of study treatment until disease progression/recurrence or the start of new therapeutic anticancer treatment, whichever occurred first, divided by the total number of participants treated, then multiplied by 100.
PFS was defined as the time from the first day of therapy to the first evidence of disease progression or death from any cause. As classified according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria, disease progression was having at least a 20% increase in the sum of the longest diameter of target lesions and/or unequivocal progression of a non-target lesion and/or detection of a new lesion. Participants who were alive and without disease progression and participants who did not progress and were subsequently lost to follow-up were censored at the last objective tumor assessment.
The percentage of participants with a best overall response of confirmed complete response (CR) or partial response (PR) as classified according to Response Evaluation Criteria In Solid Tumors (RECIST, version 1.0) criteria. CR is the disappearance of all target and non-target lesions and normalization of tumor marker levels. PR is having at least a 30% decrease in the sum of the longest diameter of target lesions without new lesions and progression of non-target lesions. The percentage of participants with objective response=(number of participants whose best overall response during therapy is CR or PR/number of participants treated)\*100.
-The RP2D of ramucirumab is defined as the highest dose level at which fewer than 2 patients of a cohort of three patients experience a dose-limiting toxicity (DLT) during the first cycle.
* Overall tumor response rate = number of participants with complete response + partial response * Complete response (CR)=Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. * Partial response (PR)=At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
A Dose Limiting Toxicity (DLT) was defined as one of the following Adverse Events (AE) that is likely related to the study drug or combination, and fulfils any one of the following criteria, graded according to the NCI-CTCAE Version 4.0: 1. Any nonhematologic Grade ≥3 toxicity, except for toxicities such as liver or renal function abnormality, skin rash that resolves with appropriate therapy, transient hypersensitivity and injection site reactions, myalgia, fatigue, constipation, electrolyte imbalance, nausea, vomiting, diarrhea 2. Hematologic toxicity was considered a DLT as the following: 1. Grade 4 toxicity lasting ≥7 days, or 2. Grade 3 or 4 thrombocytopenia if associated with bleeding or requires platelet transfusion, or 3. Febrile neutropenia 3. Death if considered related to study treatment 4. Any other significant toxicity deemed by the primary investigator and Lilly clinical research personnel to be dose limiting
A DLT is defined as an Adverse Event (AE) that is likely related to the study medication or combination, and fulfills any one of the following criteria, graded according to the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0: 1\. Any death not clearly due to the underlying disease or extraneous causes 2. Neutropenic fever 2. Any Grade ≥3 non-hematologic toxicity 3. Grade ≥4 neutropenia or thrombocytopenia \>7 days 4. Grade ≥3 thrombocytopenia with bleeding 5. Grade ≥3 nausea/vomiting or diarrhea\>72 hours with adequate antiemetic and other supportive care 6. Grade ≥3 fatigue ≥1 week 7. Grade ≥3 electrolyte abnormality that lasts\>72 hours, unless the Participant has clinical symptoms, in which case all Grade 3+electrolyte abnormality regardless of duration should count as a DLT. 8\. Grade ≥3 prolongation of QT interval corrected using the Fridericia formula on 2 separate electrocardiogram readings approximately 5 min apart.
Population Pharmacokinetics (PK): Minimum observed plasma concentration of Ramucirumab.
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.
DLT is defined as an Adverse Event (AE) that is likely related to study medication or combination,and fulfills any one of following criteria:Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0): Grade (Gr) 3 and 4 nonlaboratory toxicity (tox),Any Gr 3 or 4 laboratory value if medical intervention is required to treat participant (pt) or abnormality persists for \>1 week;Hematologic tox:Gr 4 toxicity lasting ≥ 7 days,or Gr 3 thrombocytopenia if associated with bleeding and requires platelet transfusion,or Febrile neutropenia Gr 3 or Gr 4;GR 5 tox (death);Any toxicity that is possibly related to study treatment that requires withdrawal of pt from study during Cycle 1,A delay of \> 14 days due to persistent Grade ≥ 2 toxicities in initiating Cycle 2,with exception of Grade 2 fatigue;Any infusion or hypersensitivity reactions are NOT a DLT. A summary of other nonserious AEs and all Serious AEs,regardless of causality is located in Reported Adverse Event section.
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.
A summary of AEs and SAEs considered by the investigator to be drug-related is located in the Reported Adverse Events module. An AE is summarized if the onset date is on or after the first dose of study drug and within 30 days after the last dose, or it occurred before the first dose of study drug and worsened while on the therapy.
Cycle 1 analysis performed: Area Under the Concentration-Time Curve Zero to Infinity (AUC\[0-∞\]); Cycle 2 analysis performed: Area Under the Concentration-Time Curve Over the Dosing Interval at Steady State (AUC\[τ,ss\])
DLTs were adverse events (AEs) possibly related to study drug that met the National Cancer Institute's Common Terminology Criteria for AEs (NCI CTCAE, version 4.03): Grade 4 neutropenia ≥7 days or ≥Grade 3 with bacteremia or sepsis; Absolute neutrophil count \<1.0x10\^9/Liters with fever ≥38.3°Celsius requiring intravenous antibiotic therapy; Grade 4 thrombocytopenia or ≥Grade 3 with bleeding requiring platelet transfusion; ≥Grade 3 altered coagulation tests and no anticoagulation; ≥Grade 4 or uncontrolled hypertension; ≥Grade 3 non-hematologic toxicity (except non-clinically significant Grade 3 events like electrolyte abnormality, hypersensitivity, and arthralgia/myalgia); urine protein \>3 grams/24 hours; study drug-related toxicity causing Cycle 3, Day 1 treatment delay until Day 44 or later. Grade 3 or Grade 4 infusion-related reaction (hypersensitivity) due to ramucirumab or FOLFIRI, not a DLT.
Data are presented for the number of participants who experienced treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), Grade ≥3 TEAEs, or adverse events (AEs) leading to discontinuation of treatment that were considered to be related to ramucirumab. Events related to Irinotecan, Levofolinate, and 5-fluorouracil (5-FU) were reported separately. A summary of SAEs and other nonserious AEs, regardless of causality, is located in the Reported Adverse Events section.
Number participants with drug related dose-limiting toxicities (DLT) during Cycle 1; ramucirumab related: treatment-emergent adverse events (TEAE), serious adverse events (SAE), Grade 3 or higher TEAE, or TEAE leading to discontinuation or ramucirumab dose modification. DLT=G4 neutropenia \>7days; G ≥3 neutropenia with fever ≥38.5°C requiring IV antibiotics or bacteriemia or sepsis; G4 thrombocytopenia; G ≥3 thrombocytopenia with bleeding requiring platelets; G≥3 prothrombin time and/or partial thromboplastin time in absence of anticoagulants; G≥2 hyperbilirubinemia ≥5 days; QTc \>500 milliseconds (ms) or increase ≥100 ms or arrhythmia; G≥4 or uncontrollable hypertension; G≥3 nonhematologic toxicity (excluding G3: hypersensitivity, injection-site reaction, arthralgia/myalgia, asthenia/fatigue, diarrhea without loperamide therapy, nausea/vomiting without antiemetics, transient G3/4 elevation of aminotransferases); treatment delay \>2 weeks due to toxicity.
DLT based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE v4.02) in Cycle (Cy) 1 due to study drug (SD) with (w/): Grade (Gr) ≥3 neutropenia w/fever ≥38.5°C or w/bacteremia or sepsis, thrombocytopenia w/bleeding and platelet substitution, prothrombin and/or partial thromboplastin time w/no anticoagulation, hyperbilirubinemia; Gr 4: neutropenia \>5 days, thrombocytopenia, Gr 4 or uncontrollable hypertension QTc\>500 milliseconds (ms) or increase ≥100 ms increase in 24 hours after SD or significant arrhythmia in this period; Gr ≥3 nonhematologic toxicity (tox), excluding Gr 3 hypersensitivity, hypertension, injection-site reaction, arthralgia/myalgia, asthenia/fatigue, diarrhea w/out loperamide/nausea/vomiting w/out antiemetic and transient aminotransferase elevation. SD tox=delay \>1 week in ramucirumab (RAM) dose or omission of 1 dose of RAM or 2 paclitaxel doses due to tox in Cy 1 or delay \>2 weeks between Cy 1 and Cy 2 due to persistent tox.
The number of participants who experienced AEs of any grade, AEs of Grade ≥3 or AEs resulting in death that were considered to be related to ramucirumab \[RAM (IMC-1121B)\] or paclitaxel (PAC). A summary of serious adverse events (SAEs) and all other non-SAEs, regardless of causality, is located in the Reported Adverse Events module.
The number of participants who experienced SAEs that were considered to be related to ramucirumab \[RAM (IMC-1121B)\] or paclitaxel (PAC). A summary of SAEs and all other non-SAEs, regardless of causality, is located in the Reported Adverse Events module.
| Arm | Type | Description |
|---|---|---|
| 8 milligram/kilogram (mg/kg) Ramucirumab + 80 mg/square meter (mg/m²) Paclitaxel | EXPERIMENTAL | 8 mg/kg ramucirumab was administered as an intravenous infusion (IV) on days 1 and 15, in combination with 80 mg/m² paclitaxel administered by IV on days 1, 8, and 15 of every 28-day cycle. Participants may continue on treatment until discontinuation criteria were met. |
| Placebo + 80 mg/m² Paclitaxel | EXPERIMENTAL | Placebo was administered at a volume equivalent to a dose of 8 mg/kg by IV on Days 1 and 15, in combination with 80 mg/m² paclitaxel administered by IV on Days 1, 8, and 15 of a 28-day cycle. Participants may continue on treatment until discontinuation criteria were met. |
| Ramucirumab + Best Supportive Care (BSC) | EXPERIMENTAL | 8 milligrams per kilogram (mg/kg) ramucirumab administered as an intravenous (IV) injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. |
| Placebo + BSC | PLACEBO_COMPARATOR | Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. |
| Open Label Ramucirumab + BSC | EXPERIMENTAL | 8 mg/kg ramucirumab administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. |
| Ramucirumab MEE Cohort + BSC | EXPERIMENTAL | 8 mg/kg ramucirumab administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. |
| Placebo MEE Cohort + BSC | PLACEBO_COMPARATOR | Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. |
| Ramucirumab + Docetaxel | EXPERIMENTAL | Ramucirumab (10 milligram/kilogram \[mg/kg\]) intravenously (IV) plus docetaxel (75 milligram/square meter \[mg/m²\]) IV on day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| Placebo + Docetaxel | PLACEBO_COMPARATOR | Placebo IV plus docetaxel (75 mg/m²) IV on day 1 of each 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| Ramucirumab + Erlotinib | EXPERIMENTAL | Part A: 10 milligrams per kilogram (mg/kg) ramucirumab administered every 2 weeks intravenously (IV) in combination with 150 mg erlotinib daily orally. Participants may continue to receive treatment until discontinuation criteria are met. Part B: 10 mg/kg ramucirumab administered every 2 weeks IV in combination with 150 mg erlotinib daily orally. Participants may continue to receive treatment until discontinuation criteria are met. |
| Placebo + Erlotinib | PLACEBO_COMPARATOR | Part B: Placebo administered every 2 weeks IV in combination with 150 mg erlotinib daily orally. Participants may continue to receive treatment until discontinuation criteria are met. |
| Ramucirumab + Gefitinib or Osimertinib | EXPERIMENTAL | Part C: 10 mg/kg ramucirumab administered every 2 weeks intravenously (IV) + 250 mg Gefitinib or 80 mg Osimertinib daily orally. * Ramucirumab and gefitinib administered during period 1. * Ramucirumab and osimertinib administered during period 2. |
| Ramucirumab + Cisplatin + Capecitabine | EXPERIMENTAL | 8 milligrams/kilogram (mg/kg) ramucirumab given intravenously (IV) on days 1 and 8 in combination with 80 mg/square meter (m\^2) cisplatin given IV on day 1 of each 21-day cycle (for up to 6 cycles) and 1000 mg/m\^2 capecitabine given orally twice a day on days 1 through 14. Participants that were unable to take capecitabine will be given 800 mg/m\^2/day fluorouracil (5-FU) IV on days 1 to 5 of each 21-day cycle. |
| Placebo + Cisplatin + Capecitabine | ACTIVE_COMPARATOR | Placebo for blinding given IV on days 1 and 8 in combination with 80 mg/m\^2 cisplatin given IV on day 1 of each 21-day cycle (for up to 6 cycles) and 1000 mg/m\^2 capecitabine given orally twice a day on days 1 through 14. Participants that were unable to take capecitabine will be given 800 mg/m\^2/day 5-FU IV on days 1 to 5 of each 21-day cycle. |
| FOLFIRI + Ramucirumab | EXPERIMENTAL | - |
| FOLFIRI + Placebo | PLACEBO_COMPARATOR | - |
| ramucirumab | EXPERIMENTAL | Participants receive ramucirumab, administered via intravenous infusion every 2 weeks at a dose of 8 milligrams/kilogram (mg/kg), and best supportive care (BSC) as determined appropriate by the investigator(s). Treatment will continue until there is evidence of progressive disease (PD), the development of unacceptable toxicity, protocol noncompliance, or withdrawal of consent. |
| Placebo | PLACEBO_COMPARATOR | Participants receive injection for intravenous infusion every 2 weeks plus BSC as determined appropriate by the investigator(s). Because investigators and ancillary medical personnel will be blinded as to assignment to active therapy versus placebo, the volume of placebo to be administered will be calculated as if it were active product with a dose of 8 mg/kg. Treatment will continue until there is evidence of PD, the development of unacceptable toxicity, protocol noncompliance, or withdrawal of consent. |
| ramucirumab (IMC-1121B) + docetaxel | EXPERIMENTAL | - |
| Ramucirumab + Atezolizumab | EXPERIMENTAL | * Ramucirumab will be given intravenously over the course of an hour on an outpatient basis on Day 1 of each 21-day cycle at a dose of 10 mg/kg. * Atezolizumab will be given intravenously on an outpatient basis on Day 1 of each 21-day cycle at a dose of 1200 mg. |
| Arm 1: Ramucirumab and Pembrolizumab | EXPERIMENTAL | Patients receive ramucirumab IV and pembrolizumab IV every 3 weeks. Cycles are 21 days in length. Treatment will continue until progression or unacceptable toxicity for up to 35 cycles of treatment. |
| Arm 2: Pembrolizumab monotherapy | ACTIVE_COMPARATOR | Patients receive pembrolizumab IV every 3 weeks. Cycles are 21 days in length. Treatment will continue until progression or unacceptable toxicity for up to 35 cycles of treatment. |
| Ramucirumab + Cyclophosphamide + Vinorelbine (DSRCT ISA) | EXPERIMENTAL | Ramucirumab given intravenously (IV), cyclophosphamide given orally and vinorelbine given IV in 28-day cycles for desmoplastic small round cell tumor (DSRCT) intervention-specific appendix (ISA). |
| Cyclophosphamide + Vinorelbine (DSRCT ISA) | ACTIVE_COMPARATOR | Cyclophosphamide given orally and vinorelbine given IV in 28-day cycles for DSRCT ISA. |
| Ramucirumab + Gemcitabine + Docetaxel (SS ISA) | EXPERIMENTAL | Ramucirumab and gemcitabine given IV in 21-day cycles for synovial sarcoma (SS) ISA. |
| Gemcitabine + Docetaxel (SS ISA) | ACTIVE_COMPARATOR | Gemcitabine and docetaxel given IV in 21-day cycles for SS ISA. |
| Abemaciclib + Irinotecan + Temozolomide (ES ISA) | EXPERIMENTAL | Abemaciclib given orally, irinotecan given IV, and temozolomide given orally in 21-day cycles for Ewing's sarcoma (ES) ISA. |
| Irinotecan + Temozolomide (ES ISA) | ACTIVE_COMPARATOR | Irinotecan given IV and temozolomide given orally in 21-day cycles for ES ISA. |
| Ramucirumab + Paclitaxel | ACTIVE_COMPARATOR | IV ramucirumab at 8 mg/kg on D1 and D15 IV paclitaxel at 80 mg/m² on D1, D8 and D15 |
| 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | EXPERIMENTAL | Participants received 8 mg/kg ramucirumab plus 25 mg/square meter (mg/m²) cisplatin and 1000 mg/m² gemcitabine intravenously (IV) on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy). |
| Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | PLACEBO_COMPARATOR | Participants received placebo (indistinguishable and equivalent volume to ramucirumab) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy). |
| 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | EXPERIMENTAL | Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy). |
| Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | PLACEBO_COMPARATOR | Participants received placebo (indistinguishable to merestinib) orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days. Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy). |
| 12mg/kg Ramucirumab + 80 mg/m² Paclitaxel | EXPERIMENTAL | 12 milligram per kilogram (mg/kg) ramucirumab administered intravenously (IV) on day 1 and day 15 (28 day cycles) in combination with 80 milligram per square meter (mg/m²) paclitaxel administered IV on day 1, day 8 and day 15. |
| 8 mg/kg Ramucirumab + 80 mg/m² Paclitaxel | ACTIVE_COMPARATOR | 8 mg/kg ramucirumab administered IV on day 1 and day 15 (28 day cycles) in combination with 80 mg/m² paclitaxel administered IV on day 1, day 8 and day 15. |
| S-1/Oxaliplatin + Ramucirumab | EXPERIMENTAL | (Part A) Ramucirumab intravenously (IV) on day 1 and day 8 along with S-1 by mouth (PO) on days 1-14 and oxaliplatin IV on day 1 of each 21 day cycle. Participants may continue on study drug until disease progression, unacceptable toxicity, or other withdrawal criterion is met then move to Part B. (Part B) Ramucirumab IV on day 1 and day 15 along with paclitaxel IV on day 1, 8, and 15 of each 28 day cycle. Participants may continue on study drug until disease progression, unacceptable toxicity, or other withdrawal criterion is met. |
| S-1/Oxaliplatin + Placebo | ACTIVE_COMPARATOR | (Part A) Placebo IV on day 1 and day 8 along with S-1 PO on days 1-14 and oxaliplatin IV on day 1 of each 21 day cycle. Participants may continue on study drug until disease progression, unacceptable toxicity, or other withdrawal criterion is met then move to Part B. (Part B) Ramucirumab IV on day 1 and day 15 along with paclitaxel IV on day 1, 8, and 15 of each 28 day cycle. Participants may continue on study drug until disease progression, unacceptable toxicity, or other withdrawal criterion is met. |
| Ramucirumab Regimen 1 | EXPERIMENTAL | Standard dose of 8 milligram per kilogram (mg/kg) ramucirumab given intravenously (IV) on day 1 and day 15 of each cycle (28-day cycle) until discontinuation criteria are met. |
| Ramucirumab Regimen 2 | EXPERIMENTAL | Experimental dose of 12 mg/kg ramucirumab given IV on day 1 and day 15 of each cycle (28-day cycle) until discontinuation criteria are met. |
| Ramucirumab Regimen 3 | EXPERIMENTAL | Experimental dose of 6 mg/kg ramucirumab given IV on day 1, 8, 15 and 22 of each cycle (28-day cycle) until discontinuation criteria are met. |
| Ramucirumab Regimen 4 | EXPERIMENTAL | Experimental dose of 8 mg/kg ramucirumab given IV on day 1 and day 8 of each cycle (21-day cycle) until discontinuation criteria are met. |
| Ramucirumab plus Docetaxel | EXPERIMENTAL | Ramucirumab 10 milligram per kilogram (mg/kg) on Day 1 of every 21 day cycle, administered as an intravenous (IV) infusion over approximately 60 minutes. Docetaxel 60 milligram per square meter (mg/m2) on Day 1 of every 21 day cycle, administered as an IV infusion over approximately 60 minutes. |
| Placebo plus Docetaxel | PLACEBO_COMPARATOR | Placebo (administered at a volume equivalent to a dose of milligram per kilogram (mg/kg)) on Day 1 of every 21 day cycle, administered as an IV infusion over approximately 60 minutes. Docetaxel 60 mg/m2 on Day 1 of every 21 day cycle, administered as an IV infusion over approximately 60 minutes. |
| ramucirumab (IMC-1121B) and FOLFIRI | EXPERIMENTAL | Treatment is sequential, Ramucirumab (IMC-1121B) will be administered before FOLFIRI ((Irinotecan + Folinic acid + 5-Fluorouracil). FOLFIRI will be administered each cycle and Ramucirumab (IMC-1121B) will be administered beginning from Cycle 2 (2-week cycle). |
| Part A: ramucirumab (IMC-1121B) and paclitaxel | EXPERIMENTAL | Experimental: Part A: ramucirumab (IMC-1121B) and paclitaxel Cycle 1: paclitaxel administered on Day 1 of 2-week cycle. Cycle 2 and beyond : ramucirumab (IMC-1121B) administered on Day 1 and Day 15, paclitaxel administered on Day 1, Day 8 and Day 15 of 4-week cycle. |
| Part B: ramucirumab (IMC-1121B) and paclitaxel | EXPERIMENTAL | Cycle 1: ramucirumab (IMC-1121B) administered as monotherapy on Day 1 of 3-week cycle. Cycle 2 and beyond: ramucirumab (IMC-1121B) administered on Day 1 and Day 15, paclitaxel administered on Day 1, Day 8 and Day 15 of 4- week cycle. \*After Cycle 1 (mandatory pharmacokinetic phase) is completed, participants may continue to receive ramucirumab (IMC-1121B) monotherapy or combination therapy with paclitaxel as described in Part A. |
| ramucirumab (IMC-1121B) and docetaxel | EXPERIMENTAL | Cycle 1: docetaxel administered on Day 1 of 3-week cycle Cycle 2: ramucirumab and docetaxel administered on Day 1 of 3-week cycle Cycle 3 and beyond: ramucirumab and docetaxel administered on Day 1 of each 3-week cycle Extension Phase: ramucirumab and docetaxel administered on Day 1 of each 3-week cycle |
| Ramucirumab and Eribulin | EXPERIMENTAL | Ramucirumab 10 milligrams/kilogram (mg/kg) administered by intravenous (IV) infusion on Day 1 of each 3-week cycle Eribulin 1.4 milligrams/square meter (mg/m²) administered by IV bolus on Day 1 and Day 8 of each 3-week cycle |
| Eribulin Monotherapy | ACTIVE_COMPARATOR | Eribulin 1.4 mg/m² administered by IV bolus on Day 1 and Day 8 of each 3-week cycle |
| mFOLFOX-6 | ACTIVE_COMPARATOR | mFOLFOX-6 |
| mFOLFOX-6 + Ramucirumab | EXPERIMENTAL | mFOLFOX-6 + Ramucirumab |
| mFOLFOX-6 + Icrucumab | EXPERIMENTAL | mFOLFOX-6 + Icrucumab |
| ramucirumab + paclitaxel + carboplatin | EXPERIMENTAL | Participants will receive ramucirumab in combination with paclitaxel and carboplatin until disease progression, the development of an unacceptable toxicity, or other withdrawal criteria, for up to six cycles (3 weeks per cycle). In the absence of any withdrawal criteria, participants will continue to receive ramucirumab monotherapy every 3 weeks, provided there is ongoing evidence of benefit upon review every 6 weeks. |
| Ramucirumab (IMC-1121B) | EXPERIMENTAL | - |
| Phase I: Ramucirumab + Pembrolizumab | EXPERIMENTAL | -Ramucirumab will be administered IV over 1 hour on Day 1 of each 21-day cycle. Pembrolizumab will be administered as per standard of care (IV at a dose of 200 mg over 30 minutes on Day 1 of each 21-day cycle). On Day 1, pembrolizumab will be given after ramucirumab. |
| Phase II: Ramucirumab + Pembrolizumab | EXPERIMENTAL | -Patients will be treated with ramucirumab at the RP2D on Day 1 and SOC pembrolizumab (200 mg IV over 30 minutes) on Day 1 of each 21-day cycle. |
| Ramucirumab + Cyclophosphamide + Vinorelbine | EXPERIMENTAL | Participants received the following treatments in a 28-day cycle, continuing until disease progression or a criterion for discontinuation was met. * Ramucirumab administered intravenously at a dose of 12 milligrams per kilogram (mg/kg) as a one-hour infusion on days 1 and 15. * Cyclophosphamide administered orally at 25 milligrams per meter square (mg/m2) daily from days 1 to 28. * Vinorelbine administered intravenously at 25 mg/m² on days 1, 8, and 15. |
| Cyclophosphamide + Vinorelbine | ACTIVE_COMPARATOR | Participants received the following treatments in a 28-day cycle, continuing until disease progression or a criterion for discontinuation was met. * Cyclophosphamide administered orally at 25 mg/m² daily from days 1 to 28. * Vinorelbine administered intravenously at 25 mg/m² on days 1, 8, and 15. |
| Ramucirumab+Nab-paclitaxel+Gemcitabine | EXPERIMENTAL | Nab-paclitaxel and Gemcitabine will be administered on days 1, 8 and 15 every 4 weeks for a maximum of 8 cycles. |
| Arm A: Ramucirumab + Osimertinib | EXPERIMENTAL | Dose Finding: Participants received Ramucirumab 10 milligrams/kilogram (mg/kg) given intravenously (IV) on day 1 every 2 weeks and osimertinib 80 milligrams (mg) given orally daily during each 14-day cycle. |
| Arm B: Necitumumab + Osimertinib | EXPERIMENTAL | Dose Finding: Participants received Necitumumab 800 mg given IV on days 1 and 8 every 3 weeks and osimertinib 80 mg given orally daily during each 21 day cycle. |
| Cohort A: Ramucirumab + Osimertinib | EXPERIMENTAL | Dose Expansion: Participants received Ramucirumab 10 mg/kg given IV on day 1 every 2 weeks and osimertinib 80 mg given orally daily during each 14-day cycle. |
| Ramucirumab + Merestinib | EXPERIMENTAL | Ramucirumab intravenously (IV) on day 1 and day 15 in combination with merestinib orally once a day over a 28 day cycle. Participants receiving benefit may continue until disease progression. |
| Ramucirumab + Abemaciclib | EXPERIMENTAL | Ramucirumab IV on day 1 and day 15 in combination with abemaciclib orally twice a day over a 28 day cycle. Participants receiving benefit may continue until disease progression. On June 21st 2017 the Ramucirumab + Abemaciclib arm was cancelled with no participants enrolled. |
| Ramucirumab + MEDI4736 (NSCLC) | EXPERIMENTAL | In phase 1a (DLT phase), ramucirumab plus MEDI4736 given intravenously (IV) every 3 weeks (q3w) of a 21 day treatment cycle. Participants may continue to receive study treatment until discontinuation criteria are met. In phase 1b (expansion phase), ramucirumab plus MEDI4736 given IV q3w. Participants may continue to receive study treatment until discontinuation criteria are met. |
| Ramucirumab + MEDI4736 (Gastric/GEJ) | EXPERIMENTAL | In phase 1a (DLT phase), ramucirumab plus MEDI4736 given IV every 2 weeks (q2w) of a 28 day treatment cycle. Participants may continue to receive study treatment until discontinuation criteria are met. In phase 1b (expansion phase), ramucirumab plus MEDI4736 given IV q2w. Participants may continue to receive study treatment until discontinuation criteria are met. |
| Ramucirumab + MEDI4736 (HCC) | EXPERIMENTAL | In phase 1a (DLT phase), ramucirumab plus MEDI4736 given IV q2w of a 28 day treatment cycle. Participants may continue to receive study treatment until discontinuation criteria are met. In phase 1b (expansion phase), ramucirumab plus MEDI4736 given IV q2w. Participants may continue to receive study treatment until discontinuation criteria are met. |
| Cohort A | EXPERIMENTAL | Participants with gastroesophageal junction (GEJ) cancer \[Second-Third Line (L)\] received 8 milligrams per kilogram (mg/kg) ramucirumab given intravenously (IV) on day 1 and 8 in combination with 200 mg pembrolizumab given IV on day 1 for every 3 weeks (Q3W) of a 21-day cycle. |
| Cohort A1 | EXPERIMENTAL | Participants with BTC cancer (Second-Third L) received 8 mg/kg ramucirumab given IV on day 1 and 8 in combination with 200 mg pembrolizumab given IV on day 1 Q3W of a 21-day cycle. |
| Cohort A2 | EXPERIMENTAL | Participants with Gastric-GEJ cancer (First L) received 8 mg/kg ramucirumab given IV on day 1 and 8 in combination with 200 mg pembrolizumab given IV on day 1 Q3W of a 21-day cycle. |
| Cohort B | EXPERIMENTAL | Participants with Gastric-GEJ cancer (Second-Third L) received 10 mg/kg ramucirumab given IV on day 1 in combination with 200 mg pembrolizumab given IV on day 1 Q3W of a 21-day cycle. |
| Cohort C | EXPERIMENTAL | Participants with NSCLC (Second-Fourth L) received 10 mg/kg ramucirumab given IV on day 1 in combination with 200 mg pembrolizumab given IV on day 1 Q3W of a 21-day cycle. |
| Cohort D | EXPERIMENTAL | Participants with Urothelial cancer (Second-Fourth L) received 10 mg/kg ramucirumab given IV on day 1 in combination with 200 mg pembrolizumab given IV on day 1 Q3W of a 21-day cycle. |
| Cohort E | EXPERIMENTAL | Participants with NSCLC cancer (First L) received 10 mg/kg ramucirumab given IV on day 1 in combination with 200 mg pembrolizumab given IV on day 1 Q3W of a 21-day cycle. |
| Ramucirumab + Capecitabine + Cisplatin | OTHER | Ramucirumab (8 milligram per kilogram (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. |
| Ramucirumab + S-1 + Cisplatin | OTHER | 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. |
| Ramucirumab + S-1 + Oxaliplatin | OTHER | 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. |
| Ramucirumab + FOLFOX4 | EXPERIMENTAL | 8 milligram/kilogram (mg/kg) ramucirumab given intravenously (IV) on Day 1 followed by FOLFOX4 (folinic acid + fluorouracil + oxaliplatin chemotherapy regimen) given IV on Day 1 of 2 week cycles: FOLFOX4 every 2 weeks: 85 milligram per square meter (mg/m²) oxaliplatin IV on Day 1 200 mg/m² folinic acid(FA) IV on days 1 and 2 400 mg/m² 5-FU bolus on days 1 and 2 600 mg/m2 5-FU 22-h continuous infusion on Days 1 and 2 Participants may continue to receive treatment until discontinuation criteria are met. |
| FOLFIRI plus Ramucirumab (IMC-1121B) | EXPERIMENTAL | - |
| ramucirumab and docetaxel combination | EXPERIMENTAL | - |
| Ramucirumab (IMC-1121B ) and Pacitaxel | EXPERIMENTAL | Each treatment cycle is 4 weeks (28 days) |
| Name | Type | Description |
|---|---|---|
| Ramucirumab | DRUG | Administered IV |
| Paclitaxel | DRUG | Administered IV |
| Placebo | DRUG | Administered IV |
| Docetaxel | DRUG | Administered IV |
| Erlotinib | DRUG | Administered orally. |
| Gefitinib | DRUG | Administered orally. |
| Osimertinib | DRUG | Administered orally. |
| Capecitabine | DRUG | Administered orally |
| Cisplatin | DRUG | Administered IV |
| Fluorouracil | DRUG | Administered IV |
| Irinotecan | DRUG | 180 milligrams/square meter (mg/m\^2) administered intravenously every 2 weeks until disease progression, unacceptable toxicity, noncompliance or withdrawal of consent by the participant or investigator decision |
| Folinic Acid | DRUG | 400 mg/m\^2 administered intravenously every 2 weeks until disease progression, unacceptable toxicity, noncompliance or withdrawal of consent by the participant or investigator decision |
| 5-Fluorouracil | DRUG | 400 mg/m\^2 bolus immediately followed by 2400 mg/m\^2 continuous infusion every 2 weeks until disease progression, unacceptable toxicity, noncompliance or withdrawal of consent by the participant or investigator decision |
| Placebo (for Ramucirumab) | DRUG | Administered IV on Day 1 of 21-day cycle until disease progression, unacceptable toxicity, or another withdrawal criterion is met |
| Best Supportive Care (BSC) | OTHER | BSC as determined appropriate by the investigator(s). BSC may include but are not limited to antiemetic agents, opiate and nonopiate analgesic agents, appetite stimulants, and granulocyte and erythroid growth factors. |
| ramucirumab (IMC-1121B) | BIOLOGICAL | Ramucirumab (IMC-1121B) is administered at a dose of 10 milligrams per kilogram (mg/kg) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. |
| Atezolizumab | DRUG | The initial dose will be administered over 60 minutes (+/- 15 minutes). If the first infusion is tolerated without infusion-associated events, the second infusion may be delivered over 30 minutes (+/- 10 minutes). |
| Peripheral blood draw | PROCEDURE | -Baseline and Cycle 2 Day 1 |
| Biopsy | PROCEDURE | * If archival biopsy tissue not available, participant will undergo biopsy at baseline * When feasible, a repeated tumor biopsy will be obtained between Cycles 2 and 3 after the scheduled CT scan. |
| Pembrolizumab | DRUG | Pembrolizumab is administered at a flat dose of 200 mg over 30 minutes. |
| Cyclophosphamide | DRUG | Administered orally |
| Vinorelbine | DRUG | Administered IV |
| Gemcitabine | DRUG | Administered IV |
| Abemaciclib | DRUG | Administered orally |
| Temozolomide | DRUG | Administered orally |
| Merestinib | DRUG | Administered orally |
| Placebo Oral | DRUG | Administered orally |
| Placebo IV | DRUG | Administered IV |
| S-1 | DRUG | Administered PO |
| Oxaliplatin | DRUG | Administered IV |
| Eribulin | DRUG | Administered intravenously |
| Leucovorin | DRUG | Administered intravenously |
| Icrucumab | BIOLOGICAL | 15 mg/kg IV Q2W |
| mFOLFOX-6 | DRUG | Oxaliplatin: 85 milligram per square meter (mg/m²) IV every 2 weeks (Q2W) FA: 400 mg/m² IV Q2W (or LFA: 200 mg/m² Q2W if FA is unavailable). 5FU: 400 mg/m² bolus + 2400 mg/m² IV Q2W |
| Carboplatin | DRUG | Administered after paclitaxel, as an intravenous infusion (IV), over 30 minutes on day 1 of each 21-day cycle, for up to six cycles. The dose to be administered is calculated based on the participant's actual body weight at time of treatment and the area under the curve (AUC) dosing. The target AUC for carboplatin treatment is AUC=6. |
| EORTC QLQ-30 | OTHER | -Screening, start of cycle 2, start of cycle 5 |
| FACT H&N | OTHER | -Screening, start of cycle 2, start of cycle 5 |
| Peripheral blood | PROCEDURE | -Baseline |
| Necitumumab | DRUG | Administered IV |
| MEDI4736 | DRUG | Administered IV |
| FOLFOX4 | DRUG | Administered IV. |
| levofolinate | DRUG | IV infusion, 200 mg/m² every 2 weeks |
| 5-Fluorouracil (5-FU) | DRUG | 400 mg/m² bolus followed by a 2400 mg/m² continuous infusion, every 2 weeks |
| Ramucirumab (IMC-1121B ) | BIOLOGICAL | 8 milligrams/kilogram (mg/kg) intravenously on Days 1 and 15 of each 28-ay cycle |
Inclusion Criteria: * Have an Eastern Cooperative Oncology Group Performance Status (ECOGPS) of 0 or 1 at study entry. * Have a histopathologically or cytologically confirmed diagnosis of gastric or gastroesophageal junction (GEJ) adenocarcinoma. * Have metastatic disease or locally advanced, unres...
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