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Phase III Study of Docetaxel + Ramucirumab or Placebo in Breast Cancer

Sponsor
Eli Lilly and Company (Industry)
Overall Status
Completed
CT.gov ID
NCT00703326
Collaborator
(none)
1,144
Enrollment
233
Locations
2
Arms
147.4
Actual Duration (Months)
4.9
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The objective of this study is to compare the progression-free survival (PFS) of the drug combination ramucirumab plus docetaxel to placebo plus docetaxel in previously untreated participants with human epidermal growth factor receptor 2 (HER2)-negative, unresectable, locally-recurrent or metastatic breast cancer.

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

Female participants at least 18 years of age with histologically or cytologically confirmed, human epidermal growth factor receptor 2 (HER2) negative breast adenocarcinoma that is metastatic or locally-recurrent and inoperable with curative intent will be randomized. Participants may not have received chemotherapy for metastatic or locally-recurrent, inoperable breast cancer.

It is anticipated that 1113 participants will be randomized with 371 participants in the docetaxel plus placebo arm and 742 participants in the docetaxel plus ramucirumab (IMC-1121B) arm. There will be approximately 250 centers in North and South America, Europe, Asia, Middle East, Africa, Australia, and New Zealand.

On Day 1 of each 21-day cycle, participants will receive docetaxel 75 mg/m² as a one-hour I.V. infusion followed by either ramucirumab (IMC-1121B) 10 mg/kg or placebo 10 mg/kg as a one-hour I.V. infusion. Each cycle is repeated every 21 days.

Treatment will continue until there is evidence of progressive disease, unacceptable toxicity, or other withdrawal criteria are met. Participants who discontinue study treatment with either ramucirumab (IMC-1121B) or placebo may continue to receive docetaxel.

Study Design

Study Type:
Interventional
Actual Enrollment :
1144 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
A Multicenter, Multinational, Randomized, Double-Blind, Phase III Study of IMC-1121B Plus Docetaxel Versus Placebo Plus Docetaxel in Previously Untreated Patients With HER2-Negative, Unresectable, Locally-Recurrent or Metastatic Breast Cancer
Actual Study Start Date :
Aug 6, 2008
Actual Primary Completion Date :
Mar 31, 2013
Actual Study Completion Date :
Nov 19, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: ramucirumab (IMC-1121B) + docetaxel

Biological: ramucirumab (IMC-1121B)
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.
Other Names:
  • IMC-1121B
  • LY3009806

    • Drug: docetaxel
    Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.
    Placebo Comparator: placebo + docetaxel

    Drug: docetaxel
    Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.

    Other: Placebo
    Placebo comparator for ramucirumab (IMC-1121B) administered at a dose of 10 mg/kg as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.

    Outcome Measures

    Primary Outcome Measures

    1. Progression-Free Survival (PFS) [Randomization to disease progression or death or until data cutoff of 31 Mar 2013 (up to 56 months)]

      PFS was defined as time from randomization until the first evidence of progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.0) or death from any cause; by Investigator assessment. Progressive disease (PD) was defined as at least a 20% increase in sum of longest diameter of target lesions taking as reference the smallest sum longest diameter since baseline, progression in non-target lesions or the appearance of 1 or more new lesion(s). Participants who neither progressed nor died were censored the day of their last radiographic tumor assessment if available or date of randomization if no post initiation radiographic assessment was available. If death or PD occurred after ≥2 missing radiographic visits, censoring occurred at date of the last radiographic visit prior to the missed visits. The symptomatic/clinical disease progression (deterioration) without documented radiologic progression did not constitute progression.

    Secondary Outcome Measures

    1. Overall Survival (OS) [Randomization to death or until data cutoff of 29-May-2015 (up to 82 months)]

      OS was defined as the duration from randomization to death from any cause. Participants who were alive at data cut-off for the OS analysis or lost to follow-up were censored on the last date the participant was known to be alive.

    2. Time to Progression (TTP) [Randomization to disease progression or until data cutoff of 31-Mar-2013 (up to 56 months)]

      TTP was defined as the time from the date of randomization to the first documented date of disease progression using Response Evaluation Criteria in Solid Tumors (RECIST v1.0) criteria; by Investigator assessment. Progressive disease (PD) was defined as at least a 20% increase in sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD since baseline, progression in non-target lesions or the appearance of 1 or more new lesion(s). Participants who did not progress were censored at the last radiographic tumor assessment. If no post-baseline assessment was available censoring occurred at the date of randomization. If PD occurred after 2 or more missing radiographic visits, censoring occurred at the date of the last radiographic visit prior to the missed visits. The symptomatic/clinical disease progression (deterioration) without documented radiologic progression did not constitute progression.

    3. Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate) [Randomization to disease progression or until data cutoff of 31-Mar-2013 (up to 56 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 v1.0), based on the achievement of both measurement and confirmation criteria; by Investigator assessment. 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.

    4. Duration of Response [Date of first CR or PR to PD or death or until data cutoff date of 31-Mar-2013 (up to 56 months)]

      Duration of complete response (CR) or partial response (PR) measured from time criteria were first met for CR or PR until first date of progressive disease (PD) or death from any cause defined using Response Evaluation Criteria in Solid Tumor (RECIST 1.0); by Investigator assessment. CR defined as disappearance of all target and non-target lesions. PR defined as ≥30% decrease in sum of longest diameter (LD) of target lesions and no progression in non-target lesions. PD defined as ≥20% increase in LD sum of target lesions taking as reference the smallest sum LD since baseline, progression in non-target lesions or the appearance of ≥1 new lesion(s). Participants who did not relapse or die censored at day of last radiographic tumor assessment. If death or PD was after ≥2 missing radiographic visits, censoring was at date of last radiographic visit prior to missed visits. Symptomatic/clinical disease progression without documented radiologic progression did not constitute progression.

    5. Total Functional Assessment of Cancer Therapy-Breast (FACT-B): Change From Baseline to End of Therapy [Baseline, End of Therapy or until data cutoff of 31-Mar-2013 (up to 56 months)]

      FACT-B measures the following domains of health-related quality of life (HR-QoL): physical well-being (PWB), social/family well-being (SFWB), emotional well-being (EWB), functional well-being (FWB), and additional concerns of breast cancer subscale (BCS) each with 6 or more items developed to measure problems specific to breast cancer symptoms plus additional items related to global QoL. Participants respond to each of the 36 questions on a 5-point scale from 0 (not at all) to 4 (very much) with a total scores range of 0-144. Higher scores indicate fewer symptoms and better HR-QoL.

    6. Number of Participants With Adverse Events [First dose to study completion (up to 12.3 years)]

      Clinically significant events were defined as serious adverse events (SAE) and other treatment-emergent non-serious adverse events (NSAE). A summary of SAEs and other NSAEs is located in the Reported Adverse Event module.

    7. Immunogenicity: Percentage of Participants With Treatment Emergent Anti-Ramucirumab Antibodies Until Primary Data Cutoff of 31-Mar-2013 [Baseline, prior to cycle 3 infusion, prior to cycle 5 infusion, onset of infusion reaction, resolution of reaction and 30 days following the event up to 56 months]

      Percentage of participants with treatment-emergent positive for anti-ramucirumab (IMC-1121B) antibodies during the study. Participants were considered positive for anti-ramucirumab (IMC-1121B) antibodies if they exhibited a post-treatment antibody level that exceeded the positive upper cut point determined from the anti-ramucirumab (IMC-1121B) level seen in healthy untreated individuals.

    8. Immunogenicity: Percentage of Participants Available After 31-Mar-2013 With Treatment Emergent Anti-Ramucirumab Antibodies Until Data Cutoff From 01-Apr-2013 to 08-Sep-2016 [Follow-up from 01-Apr-2013 to 08-Sep-2016 (Up to 56 -97 months)]

      Percentage of participants with treatment-emergent positive for anti-ramucirumab (IMC-1121B) antibodies during the study. Participants were considered positive for anti-ramucirumab (IMC-1121B) antibodies if they exhibited a post-treatment antibody level that exceeded the positive upper cut point determined from the anti-ramucirumab (IMC-1121B) level seen in healthy untreated individuals.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    Female
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Participant is able to provide signed informed consent

    • Participant is female and ≥ 18 years of age or older if required by local laws or regulations

    • Participant has histologically or cytologically confirmed adenocarcinoma of the breast that is now metastatic or locally-recurrent and inoperable with curative intent. Every effort should be made to make paraffin-embedded tissue or slides from the diagnostic biopsy or surgical specimen available for confirmation of diagnosis

    • Participant has measurable and/or non-measurable disease

    • Participants' primary and/or metastatic tumor is human epidermal growth factor receptor 2 (HER2)-negative by fluorescence in-situ hybridization (FISH) or chromogenic in-situ hybridization (CISH) or 0, 1+ overexpression by immunohistochemistry (IHC)

    • Participant has not received prior chemotherapy for metastatic or locally-recurrent and inoperable breast cancer

    • Participant completed (neo) adjuvant taxane therapy at least 6 months prior to randomization

    • Participant completed (neo) adjuvant biologic therapy at least 6 weeks prior to randomization

    • Participant completed all prior radiotherapy with curative intent ≥ 3 weeks prior to randomization

    • Participant may have received prior hormonal therapy for breast cancer in the (neo) adjuvant and/or the metastatic setting ≥ 2 weeks prior to randomization

    • Participant's left ventricular ejection fraction is within normal institutional ranges

    • Participant has resolution to grade ≤ 1 by the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3 (NCI-CTCAE v 3.0) of all clinically significant toxic effects of prior chemotherapy, surgery, radiotherapy, or hormonal therapy with the exception of peripheral neuropathy which must have resolved to grade ≤ 2

    • Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

    • Participant is amenable to compliance with protocol schedules and testing

    • Participant has adequate hematological functions [absolute neutrophil count (ANC) ≥ 1500 cells/microliter (mcL), hemoglobin ≥ 9 grams/deciliter (g/dL), and platelets ≥ 100,000 cells/mcL and ≤ 850,000 cells/mcL]

    • Participant has adequate hepatic function [bilirubin within normal limits (WNL), aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 times the upper limit of normal (ULN), or ≤ 5.0 times the ULN if the transaminase elevation is due to liver metastases, and alkaline phosphatase ≤ 5.0 times the ULN]

    • Participant has serum creatinine ≤ 1.5 x ULN. If serum creatinine > 1.5 x ULN the calculated creatinine clearance should be > 40 milliliters/minute (mL/min)

    • Participant's urinary protein is ≤ 1+ on dipstick or routine urinalysis (UA); if urine protein ≥ 2+, a 24-hour urine collection must demonstrate < 1000 milligrams (mg) of protein in 24 hours to allow participation in the study

    • Participant must have adequate coagulation function as defined by international normalized ratio (INR) ≤ 1.5 and a partial thromboplastin time (PTT) ≤ 1.5 X ULN if not receiving anticoagulation therapy. Participants on full-dose anticoagulation must be on a stable dose of oral anticoagulant or low molecular weight heparin and if on warfarin must have a INR between 2 and 3 and have no active bleeding (defined as within 14 days of randomization) or pathological condition that carries a high risk of bleeding (such as, tumor involving major vessels or known varices)

    • Women of childbearing potential must implement adequate contraception in the opinion of the investigator

    • Participant has not received prior biologic therapy for metastatic or locally recurrent and inoperable breast cancer

    Exclusion Criteria:

    • Participant has a concurrent active malignancy other than breast adenocarcinoma, adequately treated non melanomatous skin cancer, or other non-invasive carcinoma or in situ neoplasm. A participant with previous history of malignancy is eligible, provided that she has been disease free for > 3 years

    • Participant has a known sensitivity to docetaxel or other drugs formulated with polysorbate 80

    • Participant has a known sensitivity to agents of similar biologic composition as ramucirumab or other agents that specifically target vascular endothelial growth factor (VEGF)

    • Participant has a history of chronic diarrheal disease within 6 months prior to randomization

    • Participant has received irradiation to a major bone marrow area as defined as > 25% of bone marrow (such as, pelvic or abdominal radiation) within 30 days prior to randomization

    • Participant has participated in clinical trials of experimental agents within 4 weeks prior to randomization

    • Participant has a history of uncontrolled hereditary or acquired bleeding or thrombotic disorders

    • Participant has active, high risk bleeding (such as, via gastric ulcers or gastric varices) within 14 days prior to randomization

    • Participant has an ongoing or active infection requiring parenteral antibiotic, antifungal, or antiviral therapy

    • Participant has uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, symptomatic or poorly controlled cardiac arrhythmia, psychiatric illness/social situations, or any other serious uncontrolled medical disorders in the opinion of the investigator

    • Participant has brain metastases, uncontrolled spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease

    • Participant has known human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness

    • Participant has pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring active treatment, including the use of oxygen.

    • Participant is pregnant or lactating

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 ImClone Investigational Site Birmingham Alabama United States 35202
    2 ImClone Investigational Site Mobile Alabama United States 36608
    3 ImClone Investigational Site Chandler Arizona United States 85224
    4 ImClone Investigational Site Gilbert Arizona United States 85297
    5 ImClone Investigational Site Mesa Arizona United States 85206
    6 ImClone Investigational Site Alhambra California United States 91801
    7 ImClone Investigational Site Bakersfield California United States 93309
    8 ImClone Investigational Site Chula Vista California United States 91911
    9 ImClone Investigational Site La Mesa California United States 91942
    10 ImClone Investigational Site Los Angeles California United States 90095
    11 ImClone Investigational Site Oceanside California United States 92056
    12 ImClone Investigational Site Pasadena California United States 01107
    13 ImClone Investigational Site Pasadena California United States 91105
    14 ImClone Investigational Site San Diego California United States 92123
    15 ImClone Investigational Site Santa Barbara California United States 93105
    16 ImClone Investigational Site Santa Maria California United States 93454
    17 ImClone Investigational Site Santa Monica California United States 90404
    18 ImClone Investigational Site Solvang California United States 93463
    19 ImClone Investigational Site Valencia California United States 91355
    20 ImClone Investigational Site Aurora Colorado United States 80045
    21 ImClone Investigational Site Fort Lauderdale Florida United States 33308
    22 ImClone Investigational Site Gainesville Florida United States 32605
    23 ImClone Investigational Site New Port Richey Florida United States 34655
    24 ImClone Investigational Site Atlanta Georgia United States 30341
    25 ImClone Investigational Site Atlanta Georgia United States 30342
    26 ImClone Investigational Site Macon Georgia United States 31217
    27 ImClone Investigational Site Marietta Georgia United States 30060
    28 ImClone Investigational Site Alton Illinois United States 62002
    29 ImClone Investigational Site Chicago Illinois United States 60076
    30 ImClone Investigational Site Chicago Illinois United States 60611
    31 ImClone Investigational Site Skokie Illinois United States 60076
    32 ImClone Investigational Site Elkhart Indiana United States 46514
    33 ImClone Investigational Site Mishawaka Indiana United States 46545
    34 ImClone Investigational Site South Bend Indiana United States 46601
    35 ImClone Investigational Site Westville Indiana United States 46891
    36 ImClone Investigational Site Lexington Kentucky United States 40604
    37 ImClone Investigational Site Lansing Michigan United States 48912
    38 ImClone Investigational Site Saint Joseph Michigan United States 49085
    39 ImClone Investigational Site Minneapolis Minnesota United States 55415
    40 ImClone Investigational Site Southaven Mississippi United States 38671
    41 ImClone Investigational Site Saint Louis Missouri United States 63136
    42 ImClone Investigational Site Grand Island Nebraska United States 68803
    43 ImClone Investigational Site Kearney Nebraska United States 68845
    44 ImClone Investigational Site Henderson Nevada United States 89052
    45 ImClone Investigational Site New York New York United States 10011
    46 ImClone Investigational Site Charlotte North Carolina United States 15830
    47 ImClone Investigational Site Charlotte North Carolina United States 28203
    48 ImClone Investigational Site Charlotte North Carolina United States 28210
    49 ImClone Investigational Site Charlotte North Carolina United States 28211
    50 ImClone Investigational Site Charlotte North Carolina United States 28262
    51 ImClone Investigational Site Charlotte North Carolina United States 28294
    52 ImClone Investigational Site Bismarck North Dakota United States 58501
    53 ImClone Investigational Site Oklahoma City Oklahoma United States 73120
    54 ImClone Investigational Site Portland Oregon United States 97239
    55 ImClone Investigational Site West Reading Pennsylvania United States 19611
    56 ImClone Investigational Site Bartlett Tennessee United States 38133
    57 ImClone Investigational Site Germantown Tennessee United States 38138
    58 ImClone Investigational Site Memphis Tennessee United States 38104
    59 ImClone Investigational Site Memphis Tennessee United States 38119
    60 ImClone Investigational Site Memphis Tennessee United States 38120
    61 ImClone Investigational Site Niles Tennessee United States 49120
    62 ImClone Investigational Site Oxford Tennessee United States 38655
    63 ImClone Investigational Site Lubbock Texas United States 79410
    64 ImClone Investigational Site Temple Texas United States 76508
    65 ImClone Investigational Site Salt Lake City Utah United States 84106
    66 ImClone Investigational Site Fitzroy Victoria Australia 3065
    67 ImClone Investigational Site Frankston Victoria Australia 3199
    68 ImClone Investigational Site Bankstown Australia NSW2200
    69 ImClone Investigational Site Bedford Park Australia SA 5042
    70 ImClone Investigational Site Box Hill Australia V1C 3128
    71 ImClone Investigational Site Darlinghurst Australia NSW 2010
    72 ImClone Investigational Site East Bentleigh Australia VIC 3165
    73 ImClone Investigational Site East Melbourne Australia 3002
    74 ImClone Investigational Site Herston Australia QLD 4029
    75 ImClone Investigational Site Hobart Australia 7000
    76 ImClone Investigational Site Milton Australia QLD 4064
    77 ImClone Investigational Site Nambour Australia QLD 4560
    78 ImClone Investigational Site New Lambton Heights Australia NSW 2305
    79 ImClone Investigational Site Perth Australia WA 6001
    80 ImClone Investigational Site Ringwood East Australia 3135
    81 ImClone Investigational Site Subiaco Australia 6008
    82 ImClone Investigational Site Sydney Australia NSW 2010
    83 ImClone Investigational Site Tweed Heads Australia NSW 2305
    84 ImClone Investigational Site Wendouree Australia VIC 3355
    85 ImClone Investigational Site Brasschaat Belgium 2930
    86 ImClone Investigational Site Charleroi Belgium 6000
    87 ImClone Investigational Site Edegem Belgium 2650
    88 ImClone Investigational Site Gent Belgium 9000
    89 ImClone Investigational Site Kortrijk Belgium 8500
    90 ImClone Investigational Site Liege Belgium 4000
    91 ImClone Investigational Site Namur Belgium 5000
    92 ImClone Investigational Site Yvoir Belgium 5530
    93 ImClone Investigational Site Ijui Brazil 98700-000
    94 ImClone Investigational Site Porto Alegre Brazil 90035-001
    95 ImClone Investigational Site Porto Alegre Brazil 90430-090
    96 ImClone Investigational Site Porto Alegre Brazil 906-000
    97 ImClone Investigational Site Rio de Janeiro Brazil 21941-913
    98 ImClone Investigational Site San Paulo Brazil 05651-901
    99 ImClone Investigational Site San Paulo Brazil 1246-000
    100 ImClone Investigational Site Santo Andre Brazil 09060-650
    101 ImClone Investigational Site Sao Paulo Brazil 01318-000
    102 ImClone Investigational Site Sao Paulo Brazil 05651-901
    103 ImClone Investigational Site Sao Paulo Brazil 08270-070
    104 ImClone Investigational Site Calgary Alberta Canada T2N4N2
    105 ImClone Investigational Site Edmonton Alberta Canada T6G 1Z2
    106 ImClone Investigational Site Vancouver British Columbia Canada V5Z 4E6
    107 ImClone Investigational Site Toronto Ontario Canada M4N 3M5
    108 ImClone Investigational Site Weston Ontario Canada M9N 1N8
    109 ImClone Investigational Site Greenfield Park Quebec Canada
    110 ImClone Investigational Site Quebec Canada G1S 4L8
    111 ImClone Investigational Site Osijek Croatia 3100
    112 ImClone Investigational Site Praha Motol Czechia 150 06
    113 ImClone Investigational Site Brno Czechia 62500
    114 ImClone Investigational Site Kutna Hora Czechia 28401
    115 ImClone Investigational Site Pardubice Czechia 532 03
    116 ImClone Investigational Site Prague Czechia 14059
    117 ImClone Investigational Site Prague Czechia 180 80
    118 ImClone Investigational Site Videnska Czechia 14059
    119 ImClone Investigational Site Alexandria Egypt 21526
    120 ImClone Investigational Site Cairo Egypt 11796
    121 ImClone Investigational Site Cairo Egypt 16114
    122 ImClone Investigational Site Chemnitz Germany 9116
    123 ImClone Investigational Site Hamburg Germany 20246
    124 ImClone Investigational Site Hamburg Germany 22081
    125 ImClone Investigational Site Kiel Germany 24105
    126 ImClone Investigational Site Lubeck Germany 23538
    127 ImClone Investigational Site Munchen Germany 81675
    128 ImClone Investigational Site Munich Germany 80637
    129 ImClone Investigational Site Oldenburg Germany 26133
    130 ImClone Investigational Site Saarbrucken Germany 66113
    131 ImClone Investigational Site Trier Germany 54290
    132 ImClone Investigational Site Tubingen Germany 72076
    133 ImClone Investigational Site Cork Ireland
    134 ImClone Investigational Site Dublin Ireland 7
    135 ImClone Investigational Site Dublin Ireland
    136 ImClone Investigational Site Erlangen Ireland
    137 ImClone Investigational Site Limerick Ireland
    138 ImClone Investigational Site Beersheva Israel 84101
    139 ImClone Investigational Site Jerusalem Israel 91129
    140 ImClone Investigational Site Petach-Tikva Israel 49100
    141 ImClone Investigational Site Rehovot Israel 76100
    142 ImClone Investigational Site Tel Aviv Israel 64239
    143 ImClone Investigational Site Incheon Korea, Republic of 400-711
    144 ImClone Investigational Site Seoul Korea, Republic of 110-744
    145 ImClone Investigational Site Seoul Korea, Republic of 120-752
    146 ImClone Investigational Site Seoul Korea, Republic of 135-710
    147 ImClone Investigational Site Beirut Lebanon
    148 ImClone Investigational Site Bsalim Lebanon
    149 ImClone Investigational Site Metn Lebanon
    150 ImClone Investigational Site Saïda Lebanon
    151 ImClone Investigational Site Zgharta Lebanon
    152 ImClone Investigational Site Auckland New Zealand 1023
    153 ImClone Investigational Site Auckland New Zealand
    154 ImClone Investigational Site Palmerston North New Zealand 4414
    155 ImClone Investigational Site Arequipa Peru 054
    156 ImClone Investigational Site Lima Peru Lima1
    157 ImClone Investigational Site Lima Peru Lima27
    158 ImClone Investigational Site Lima Peru Lima34
    159 ImClone Investigational Site Lima Peru Lima41
    160 ImClone Investigational Site Lima Peru Lime27
    161 ImClone Investigational Site Bytom Poland 41-902
    162 ImClone Investigational Site Olsztyn Poland 10-228
    163 ImClone Investigational Site Olsztyn Poland 10-513
    164 ImClone Investigational Site Engels Russian Federation 413115
    165 ImClone Investigational Site Kazan Russian Federation 420029
    166 ImClone Investigational Site Kursk Russian Federation 305035
    167 ImClone Investigational Site Leningrad Region Russian Federation
    168 ImClone Investigational Site Lipetsk Russian Federation 398005
    169 ImClone Investigational Site Magnitogorsk Russian Federation 455001
    170 ImClone Investigational Site Moscow Russian Federation 111033
    171 ImClone Investigational Site Moscow Russian Federation 115478
    172 ImClone Investigational Site Moscow Russian Federation 143423
    173 ImClone Investigational Site Novosibirsk Russian Federation 630090
    174 ImClone Investigational Site Omsk Russian Federation 644013
    175 ImClone Investigational Site Orenburg Russian Federation 460021
    176 ImClone Investigational Site Perm Russian Federation 614066
    177 ImClone Investigational Site Samara Russian Federation 443031
    178 ImClone Investigational Site Saratov Russian Federation 410004
    179 ImClone Investigational Site St. Petersburg Russian Federation 197022
    180 ImClone Investigational Site St. Petersburg Russian Federation 197758
    181 ImClone Investigational Site Tambov Russian Federation 392013
    182 ImClone Investigational Site Ufa Russian Federation 450054
    183 ImClone Investigational Site Kragujevac Serbia 34000
    184 ImClone Investigational Site Nis Serbia 18000
    185 ImClone Investigational Site Sremska Kamenica Serbia 21204
    186 ImClone Investigational Site Bratislava Slovakia 81250
    187 ImClone Investigational Site Trnava Slovakia 91775
    188 ImClone Investigational Site Zilina Slovakia
    189 ImClone Investigational Site Parktown Johannesburg South Africa 2193
    190 ImClone Investigational Site Amanzimtoti South Africa 4126
    191 ImClone Investigational Site Bloemfontein South Africa 9301
    192 ImClone Investigational Site Durban South Africa 4001
    193 ImClone Investigational Site Durban South Africa 4091
    194 ImClone Investigational Site Lynnwood South Africa 0081
    195 ImClone Investigational Site Port Elizabeth South Africa 6045
    196 ImClone Investigational Site Pretoria South Africa 0001
    197 ImClone Investigational Site Pretoria South Africa 0081
    198 ImClone Investigational Site Pretoria South Africa 0181
    199 ImClone Investigational Site Sandton South Africa 2199
    200 ImClone Investigational Site Alicante Spain 03010
    201 ImClone Investigational Site Badalona Spain 08916
    202 ImClone Investigational Site Barbastro Spain 22300
    203 ImClone Investigational Site Barcelona Spain 08003
    204 ImClone Investigational Site Barcelona Spain 08036
    205 ImClone Investigational Site Girona Spain 17007
    206 ImClone Investigational Site Jaen Spain 23007
    207 ImClone Investigational Site La Coruna Spain 15009
    208 ImClone Investigational Site La Laguna - Tenerife Spain 38205
    209 ImClone Investigational Site Lleida Spain 25198
    210 ImClone Investigational Site Madrid Spain 28007
    211 ImClone Investigational Site Madrid Spain 28033
    212 ImClone Investigational Site Madrid Spain 28034
    213 ImClone Investigational Site Madrid Spain 28040
    214 ImClone Investigational Site Madrid Spain 28222
    215 ImClone Investigational Site Malaga Spain 29010
    216 ImClone Investigational Site Palma de Mallorca Spain 07010
    217 ImClone Investigational Site Salamanca Spain 37007
    218 ImClone Investigational Site San Sebastian Spain 20014
    219 ImClone Investigational Site Santander Spain 39008
    220 ImClone Investigational Site Sevilla Spain 41013
    221 ImClone Investigational Site Toledo Spain 45004
    222 ImClone Investigational Site Valencia Spain 46009
    223 ImClone Investigational Site Valencia Spain
    224 ImClone Investigational Site Zaragoza Spain 50009
    225 ImClone Investigational Site Changhua Taiwan M20 4BX
    226 ImClone Investigational Site Taipei Taiwan
    227 ImClone Investigational Site Taoyuan County Taiwan 33305
    228 ImClone Investigational Site Bournemouth United Kingdom BH7 7DW
    229 ImClone Investigational Site Edinburgh United Kingdom EH4 2XU
    230 ImClone Investigational Site Huddersfield United Kingdom HD3 3EA
    231 ImClone Investigational Site Hull United Kingdom HU16 5JQ
    232 ImClone Investigational Site Manchester United Kingdom M20 4BX
    233 ImClone Investigational Site Nottingham United Kingdom NG5 1PB

    Sponsors and Collaborators

    • Eli Lilly and Company

    Investigators

    • Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Eli Lilly and Company
    ClinicalTrials.gov Identifier:
    NCT00703326
    Other Study ID Numbers:
    • 13892
    • 2008-001727-65
    • TRIO-012
    • TRIO-CIRG-012
    • CP12-0606
    • I4T-IE-JVBC
    First Posted:
    Jun 23, 2008
    Last Update Posted:
    Dec 6, 2021
    Last Verified:
    Nov 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Keywords provided by Eli Lilly and Company
    Metastatic breast cancer
    HER2 negative breast cancer
    locally recurrent breast cancer
    Additional relevant MeSH terms:
    Breast Neoplasms
    Docetaxel
    Ramucirumab

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail Participants who were alive and completed the follow-up period or who died were considered to have completed the study.
    Arm/Group Title Ramucirumab (IMC-1121B) + Docetaxel Placebo + Docetaxel
    Arm/Group Description 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. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Placebo comparator for ramucirumab (IMC-1121B) administered at a dose of 10 mg/kg as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.
    Period Title: Overall Study
    STARTED 759 385
    Received at Least 1 Dose of Study Drug 752 382
    COMPLETED 657 347
    NOT COMPLETED 102 38

    Baseline Characteristics

    Arm/Group Title Ramucirumab (IMC-1121B) + Docetaxel Placebo + Docetaxel Total
    Arm/Group Description 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. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Placebo comparator for ramucirumab (IMC-1121B) administered at a dose of 10 mg/kg as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Total of all reporting groups
    Overall Participants 759 385 1144
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    629
    82.9%
    325
    84.4%
    954
    83.4%
    >=65 years
    130
    17.1%
    60
    15.6%
    190
    16.6%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    53.9
    (10.5)
    54.2
    (10.0)
    54.0
    (10.4)
    Sex: Female, Male (Count of Participants)
    Female
    759
    100%
    385
    100%
    1144
    100%
    Male
    0
    0%
    0
    0%
    0
    0%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    69
    9.1%
    42
    10.9%
    111
    9.7%
    Not Hispanic or Latino
    690
    90.9%
    343
    89.1%
    1033
    90.3%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    1
    0.1%
    1
    0.3%
    2
    0.2%
    Asian
    31
    4.1%
    20
    5.2%
    51
    4.5%
    Native Hawaiian or Other Pacific Islander
    2
    0.3%
    0
    0%
    2
    0.2%
    Black or African American
    27
    3.6%
    14
    3.6%
    41
    3.6%
    White
    676
    89.1%
    341
    88.6%
    1017
    88.9%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    22
    2.9%
    9
    2.3%
    31
    2.7%
    Region of Enrollment (Count of Participants)
    Serbia
    0
    0%
    2
    0.5%
    2
    0.2%
    United States
    58
    7.6%
    21
    5.5%
    79
    6.9%
    Taiwan
    4
    0.5%
    2
    0.5%
    6
    0.5%
    Slovakia
    2
    0.3%
    2
    0.5%
    4
    0.3%
    Spain
    118
    15.5%
    64
    16.6%
    182
    15.9%
    Lebanon
    24
    3.2%
    14
    3.6%
    38
    3.3%
    Ireland
    8
    1.1%
    2
    0.5%
    10
    0.9%
    Russia
    210
    27.7%
    99
    25.7%
    309
    27%
    Israel
    16
    2.1%
    7
    1.8%
    23
    2%
    United Kingdom
    21
    2.8%
    10
    2.6%
    31
    2.7%
    Egypt
    9
    1.2%
    3
    0.8%
    12
    1%
    Czechia
    4
    0.5%
    3
    0.8%
    7
    0.6%
    Canada
    83
    10.9%
    46
    11.9%
    129
    11.3%
    Poland
    12
    1.6%
    5
    1.3%
    17
    1.5%
    Belgium
    48
    6.3%
    20
    5.2%
    68
    5.9%
    Brazil
    30
    4%
    20
    5.2%
    50
    4.4%
    Peru
    12
    1.6%
    4
    1%
    16
    1.4%
    Australia
    28
    3.7%
    21
    5.5%
    49
    4.3%
    South Africa
    41
    5.4%
    22
    5.7%
    63
    5.5%
    Germany
    12
    1.6%
    5
    1.3%
    17
    1.5%
    New Zealand
    5
    0.7%
    6
    1.6%
    11
    1%
    South Korea
    14
    1.8%
    7
    1.8%
    21
    1.8%

    Outcome Measures

    1. Primary Outcome
    Title Progression-Free Survival (PFS)
    Description PFS was defined as time from randomization until the first evidence of progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.0) or death from any cause; by Investigator assessment. Progressive disease (PD) was defined as at least a 20% increase in sum of longest diameter of target lesions taking as reference the smallest sum longest diameter since baseline, progression in non-target lesions or the appearance of 1 or more new lesion(s). Participants who neither progressed nor died were censored the day of their last radiographic tumor assessment if available or date of randomization if no post initiation radiographic assessment was available. If death or PD occurred after ≥2 missing radiographic visits, censoring occurred at date of the last radiographic visit prior to the missed visits. The symptomatic/clinical disease progression (deterioration) without documented radiologic progression did not constitute progression.
    Time Frame Randomization to disease progression or death or until data cutoff of 31 Mar 2013 (up to 56 months)

    Outcome Measure Data

    Analysis Population Description
    Intent-to-Treat (ITT) Population: All randomized participants. Censored participants: ramucirumab + docetaxel=231, placebo + docetaxel=94.
    Arm/Group Title Ramucirumab (IMC-1121B) + Docetaxel Placebo + Docetaxel
    Arm/Group Description 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. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Placebo comparator for ramucirumab (IMC-1121B) administered at a dose of 10 mg/kg as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.
    Measure Participants 759 385
    Median (95% Confidence Interval) [months]
    9.5
    8.2
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ramucirumab (IMC-1121B) + Docetaxel, Placebo + Docetaxel
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.077
    Comments
    Method Stratified Log Rank (SLR)
    Comments SLR used Interactive Web Response System (IWRS) factors: prior taxane therapy, visceral metastasis, hormone receptor status and geographical regions.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.88
    Confidence Interval (2-Sided) 95%
    0.75 to 1.01
    Parameter Dispersion Type:
    Value:
    Estimation Comments HR with 95% confidence interval (CI) was estimated using a stratified Cox proportional hazards regression model using the IWRS stratification factors.
    2. Secondary Outcome
    Title Overall Survival (OS)
    Description OS was defined as the duration from randomization to death from any cause. Participants who were alive at data cut-off for the OS analysis or lost to follow-up were censored on the last date the participant was known to be alive.
    Time Frame Randomization to death or until data cutoff of 29-May-2015 (up to 82 months)

    Outcome Measure Data

    Analysis Population Description
    Intent-to-Treat (ITT) Population: All randomized participants. Censored participants: ramucirumab + docetaxel=267, placebo + docetaxel=121.
    Arm/Group Title Ramucirumab (IMC-1121B) + Docetaxel Placebo + Docetaxel
    Arm/Group Description 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. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Placebo comparator for ramucirumab (IMC-1121B) administered at a dose of 10 mg/kg as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.
    Measure Participants 759 385
    Median (95% Confidence Interval) [months]
    30.3
    28.7
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ramucirumab (IMC-1121B) + Docetaxel, Placebo + Docetaxel
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.487
    Comments The gate-keeping strategy used to control overall type 1 error 0.05 (2-sided) or 0.025 (1-sided) to analyze progression-free survival (PFS) and OS. At final PFS analysis only if primary PFS test was significant would analysis of OS be inferential.
    Method Stratified Log Rank (SLR)
    Comments SLR used Interactive Web Response System (IWRS) factors: prior taxane therapy, visceral metastasis, hormone receptor status and geographical regions.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.95
    Confidence Interval (2-Sided) 95%
    0.81 to 1.10
    Parameter Dispersion Type:
    Value:
    Estimation Comments HR with 95% confidence interval (CI) was estimated using a stratified Cox proportional hazards regression model using the IWRS stratification factors.
    3. Secondary Outcome
    Title Time to Progression (TTP)
    Description TTP was defined as the time from the date of randomization to the first documented date of disease progression using Response Evaluation Criteria in Solid Tumors (RECIST v1.0) criteria; by Investigator assessment. Progressive disease (PD) was defined as at least a 20% increase in sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD since baseline, progression in non-target lesions or the appearance of 1 or more new lesion(s). Participants who did not progress were censored at the last radiographic tumor assessment. If no post-baseline assessment was available censoring occurred at the date of randomization. If PD occurred after 2 or more missing radiographic visits, censoring occurred at the date of the last radiographic visit prior to the missed visits. The symptomatic/clinical disease progression (deterioration) without documented radiologic progression did not constitute progression.
    Time Frame Randomization to disease progression or until data cutoff of 31-Mar-2013 (up to 56 months)

    Outcome Measure Data

    Analysis Population Description
    Intent-to-Treat (ITT) Population: All randomized participants. Censored participants: ramucirumab + docetaxel=263, placebo + docetaxel=104.
    Arm/Group Title Ramucirumab (IMC-1121B) + Docetaxel Placebo + Docetaxel
    Arm/Group Description 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. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Placebo comparator for ramucirumab (IMC-1121B) administered at a dose of 10 mg/kg as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.
    Measure Participants 759 385
    Median (95% Confidence Interval) [months]
    9.7
    8.2
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ramucirumab (IMC-1121B) + Docetaxel, Placebo + Docetaxel
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.033
    Comments
    Method Stratified Log Rank (SLR)
    Comments SLR used Interactive Web Response System (IWRS) factors: prior taxane therapy, visceral metastasis, hormone receptor status and geographical regions.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.85
    Confidence Interval (2-Sided) 95%
    0.73 to 0.99
    Parameter Dispersion Type:
    Value:
    Estimation Comments HR with 95% confidence interval (CI) was estimated using a stratified Cox proportional hazards regression model using the IWRS stratification factors.
    4. Secondary Outcome
    Title Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate)
    Description 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 v1.0), based on the achievement of both measurement and confirmation criteria; by Investigator assessment. 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 Randomization to disease progression or until data cutoff of 31-Mar-2013 (up to 56 months)

    Outcome Measure Data

    Analysis Population Description
    Intent-to-Treat (ITT) Population: All randomized participants.
    Arm/Group Title Ramucirumab (IMC-1121B) + Docetaxel Placebo + Docetaxel
    Arm/Group Description 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. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Placebo comparator for ramucirumab (IMC-1121B) administered at a dose of 10 mg/kg as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.
    Measure Participants 759 385
    Number (95% Confidence Interval) [percentage of participants]
    44.7
    5.9%
    37.9
    9.8%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ramucirumab (IMC-1121B) + Docetaxel, Placebo + Docetaxel
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.027
    Comments
    Method Stratified Cochran-Mantel-Haenszel(SCMH)
    Comments SCMH used Interactive Web Response System (IWRS) factors: prior taxane therapy, visceral metastasis, hormone receptor status and geographical regions.
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.33
    Confidence Interval (2-Sided) 95%
    1.03 to 1.71
    Parameter Dispersion Type:
    Value:
    Estimation Comments Stratified odds ratio was calculated considering the IWRS stratification factors.
    5. Secondary Outcome
    Title Duration of Response
    Description Duration of complete response (CR) or partial response (PR) measured from time criteria were first met for CR or PR until first date of progressive disease (PD) or death from any cause defined using Response Evaluation Criteria in Solid Tumor (RECIST 1.0); by Investigator assessment. CR defined as disappearance of all target and non-target lesions. PR defined as ≥30% decrease in sum of longest diameter (LD) of target lesions and no progression in non-target lesions. PD defined as ≥20% increase in LD sum of target lesions taking as reference the smallest sum LD since baseline, progression in non-target lesions or the appearance of ≥1 new lesion(s). Participants who did not relapse or die censored at day of last radiographic tumor assessment. If death or PD was after ≥2 missing radiographic visits, censoring was at date of last radiographic visit prior to missed visits. Symptomatic/clinical disease progression without documented radiologic progression did not constitute progression.
    Time Frame Date of first CR or PR to PD or death or until data cutoff date of 31-Mar-2013 (up to 56 months)

    Outcome Measure Data

    Analysis Population Description
    A subset of the Intent-to-Treat (ITT) Population: all randomized participants with CR or PR. Censored participants: ramucirumab + docetaxel=80, placebo + docetaxel=28.
    Arm/Group Title Ramucirumab (IMC-1121B) + Docetaxel Placebo + Docetaxel
    Arm/Group Description 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. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Placebo comparator for ramucirumab (IMC-1121B) administered at a dose of 10 mg/kg as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.
    Measure Participants 339 146
    Median (95% Confidence Interval) [months]
    8.4
    8.1
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ramucirumab (IMC-1121B) + Docetaxel, Placebo + Docetaxel
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.150
    Comments
    Method Stratified Log Rank (SLR)
    Comments SLR used Interactive Web Response System (IWRS) factors: prior taxane therapy, visceral metastasis, hormone receptor status and geographical regions.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.84
    Confidence Interval (2-Sided) 95%
    0.67 to 1.06
    Parameter Dispersion Type:
    Value:
    Estimation Comments HR with 95% confidence interval (CI) was estimated using a stratified Cox proportional hazards regression model using the IWRS stratification factors.
    6. Secondary Outcome
    Title Total Functional Assessment of Cancer Therapy-Breast (FACT-B): Change From Baseline to End of Therapy
    Description FACT-B measures the following domains of health-related quality of life (HR-QoL): physical well-being (PWB), social/family well-being (SFWB), emotional well-being (EWB), functional well-being (FWB), and additional concerns of breast cancer subscale (BCS) each with 6 or more items developed to measure problems specific to breast cancer symptoms plus additional items related to global QoL. Participants respond to each of the 36 questions on a 5-point scale from 0 (not at all) to 4 (very much) with a total scores range of 0-144. Higher scores indicate fewer symptoms and better HR-QoL.
    Time Frame Baseline, End of Therapy or until data cutoff of 31-Mar-2013 (up to 56 months)

    Outcome Measure Data

    Analysis Population Description
    A subset of Intent-to-Treat (ITT) Population: all randomized participants with a valid baseline and end of therapy assessments.
    Arm/Group Title Ramucirumab (IMC-1121B) + Docetaxel Placebo + Docetaxel
    Arm/Group Description 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. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Placebo comparator for ramucirumab (IMC-1121B) administered at a dose of 10 mg/kg as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.
    Measure Participants 494 251
    Mean (Standard Deviation) [units on a scale]
    -6.8
    (17.3)
    -7.0
    (16.8)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ramucirumab (IMC-1121B) + Docetaxel, Placebo + Docetaxel
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.539
    Comments P-value is for end of therapy. Analysis of covariance (ANCOVA) adjusted for baseline score was used to compare the 2 treatment arms.
    Method ANCOVA
    Comments
    7. Secondary Outcome
    Title Number of Participants With Adverse Events
    Description Clinically significant events were defined as serious adverse events (SAE) and other treatment-emergent non-serious adverse events (NSAE). A summary of SAEs and other NSAEs is located in the Reported Adverse Event module.
    Time Frame First dose to study completion (up to 12.3 years)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least 1 dose of study drug.
    Arm/Group Title Ramucirumab (IMC-1121B) + Docetaxel Placebo + Docetaxel
    Arm/Group Description 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. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Placebo comparator for ramucirumab (IMC-1121B) administered at a dose of 10 mg/kg as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.
    Measure Participants 752 382
    Participants with SAEs
    285
    37.5%
    117
    30.4%
    Participants with NSAEs
    737
    97.1%
    373
    96.9%
    8. Secondary Outcome
    Title Immunogenicity: Percentage of Participants With Treatment Emergent Anti-Ramucirumab Antibodies Until Primary Data Cutoff of 31-Mar-2013
    Description Percentage of participants with treatment-emergent positive for anti-ramucirumab (IMC-1121B) antibodies during the study. Participants were considered positive for anti-ramucirumab (IMC-1121B) antibodies if they exhibited a post-treatment antibody level that exceeded the positive upper cut point determined from the anti-ramucirumab (IMC-1121B) level seen in healthy untreated individuals.
    Time Frame Baseline, prior to cycle 3 infusion, prior to cycle 5 infusion, onset of infusion reaction, resolution of reaction and 30 days following the event up to 56 months

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least 1 dose of study drug with anti-IMC-1121B antibodies samples collected during the study.
    Arm/Group Title Ramucirumab (IMC-1121B) + Docetaxel Placebo + Docetaxel
    Arm/Group Description 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. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Placebo comparator for ramucirumab (IMC-1121B) administered at a dose of 10 mg/kg as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.
    Measure Participants 715 360
    Number [percentage of participants]
    0.8
    0.1%
    0.8
    0.2%
    9. Secondary Outcome
    Title Immunogenicity: Percentage of Participants Available After 31-Mar-2013 With Treatment Emergent Anti-Ramucirumab Antibodies Until Data Cutoff From 01-Apr-2013 to 08-Sep-2016
    Description Percentage of participants with treatment-emergent positive for anti-ramucirumab (IMC-1121B) antibodies during the study. Participants were considered positive for anti-ramucirumab (IMC-1121B) antibodies if they exhibited a post-treatment antibody level that exceeded the positive upper cut point determined from the anti-ramucirumab (IMC-1121B) level seen in healthy untreated individuals.
    Time Frame Follow-up from 01-Apr-2013 to 08-Sep-2016 (Up to 56 -97 months)

    Outcome Measure Data

    Analysis Population Description
    All follow-up participants (additional participants who were available after primary data cut off 31-Mar-13) who received at least 1 dose of study drug with anti-IMC-1121B antibodies samples collected during the study.
    Arm/Group Title Ramucirumab (IMC-1121B) + Docetaxel Placebo + Docetaxel
    Arm/Group Description 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. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Placebo comparator for ramucirumab (IMC-1121B) administered at a dose of 10 mg/kg as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.
    Measure Participants 35 22
    Number [percentage of participants]
    0
    0%
    0
    0%

    Adverse Events

    Time Frame First dose to study completion (up to 12.3 years)
    Adverse Event Reporting Description All randomized participants who received at least 1 dose of study drug. Disease progression without clinical manifestation or death related to progressive disease (PD) was not to be reported as an adverse event (AE). However, all deaths within 30 days of last dose were reported as a serious AE (SAE), regardless of causality. PD itself was reported as an SAE, if any of the SAE criteria were met.
    Arm/Group Title Ramucirumab (IMC-1121B) + Docetaxel Placebo + Docetaxel
    Arm/Group Description 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. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Placebo comparator for ramucirumab (IMC-1121B) administered at a dose of 10 mg/kg as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.
    All Cause Mortality
    Ramucirumab (IMC-1121B) + Docetaxel Placebo + Docetaxel
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    Ramucirumab (IMC-1121B) + Docetaxel Placebo + Docetaxel
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 285/752 (37.9%) 117/382 (30.6%)
    Blood and lymphatic system disorders
    Anaemia 2/752 (0.3%) 2 3/382 (0.8%) 4
    Disseminated intravascular coagulation 2/752 (0.3%) 2 0/382 (0%) 0
    Febrile neutropenia 51/752 (6.8%) 57 11/382 (2.9%) 12
    Neutropenia 47/752 (6.3%) 52 20/382 (5.2%) 23
    Thrombocytopenia 2/752 (0.3%) 2 0/382 (0%) 0
    Cardiac disorders
    Atrial fibrillation 1/752 (0.1%) 1 1/382 (0.3%) 1
    Atrial flutter 0/752 (0%) 0 1/382 (0.3%) 1
    Cardiac failure congestive 1/752 (0.1%) 1 0/382 (0%) 0
    Left ventricular dysfunction 0/752 (0%) 0 1/382 (0.3%) 1
    Myocardial infarction 2/752 (0.3%) 3 0/382 (0%) 0
    Pericarditis 1/752 (0.1%) 1 0/382 (0%) 0
    Pericarditis constrictive 0/752 (0%) 0 1/382 (0.3%) 1
    Right ventricular failure 1/752 (0.1%) 1 0/382 (0%) 0
    Supraventricular tachycardia 1/752 (0.1%) 1 0/382 (0%) 0
    Tachycardia 1/752 (0.1%) 1 2/382 (0.5%) 2
    Ear and labyrinth disorders
    Vertigo 1/752 (0.1%) 1 0/382 (0%) 0
    Eye disorders
    Dacryostenosis acquired 1/752 (0.1%) 1 0/382 (0%) 0
    Panophthalmitis 1/752 (0.1%) 1 0/382 (0%) 0
    Papilloedema 0/752 (0%) 0 1/382 (0.3%) 1
    Visual acuity reduced 0/752 (0%) 0 1/382 (0.3%) 1
    Gastrointestinal disorders
    Abdominal pain 4/752 (0.5%) 5 1/382 (0.3%) 1
    Anal fistula 0/752 (0%) 0 1/382 (0.3%) 1
    Ascites 1/752 (0.1%) 1 0/382 (0%) 0
    Colitis ischaemic 1/752 (0.1%) 1 0/382 (0%) 0
    Constipation 3/752 (0.4%) 3 1/382 (0.3%) 1
    Diarrhoea 9/752 (1.2%) 10 2/382 (0.5%) 2
    Diverticular perforation 4/752 (0.5%) 4 0/382 (0%) 0
    Duodenitis haemorrhagic 0/752 (0%) 0 1/382 (0.3%) 1
    Enterocolitis 1/752 (0.1%) 1 0/382 (0%) 0
    Faecaloma 1/752 (0.1%) 1 0/382 (0%) 0
    Gastric ulcer perforation 1/752 (0.1%) 1 0/382 (0%) 0
    Gastritis 1/752 (0.1%) 1 0/382 (0%) 0
    Haemorrhoids 2/752 (0.3%) 2 0/382 (0%) 0
    Ileus 1/752 (0.1%) 1 0/382 (0%) 0
    Ileus paralytic 0/752 (0%) 0 1/382 (0.3%) 1
    Intestinal pseudo-obstruction 0/752 (0%) 0 1/382 (0.3%) 1
    Large intestinal ulcer 1/752 (0.1%) 1 0/382 (0%) 0
    Large intestine perforation 3/752 (0.4%) 3 0/382 (0%) 0
    Mouth haemorrhage 1/752 (0.1%) 1 0/382 (0%) 0
    Nausea 5/752 (0.7%) 6 1/382 (0.3%) 1
    Oesophagitis 2/752 (0.3%) 2 0/382 (0%) 0
    Pancreatitis 0/752 (0%) 0 1/382 (0.3%) 1
    Rectal haemorrhage 1/752 (0.1%) 1 1/382 (0.3%) 1
    Retroperitoneal fibrosis 1/752 (0.1%) 1 0/382 (0%) 0
    Small intestinal haemorrhage 0/752 (0%) 0 1/382 (0.3%) 1
    Stomatitis 9/752 (1.2%) 11 0/382 (0%) 0
    Vomiting 7/752 (0.9%) 7 2/382 (0.5%) 2
    General disorders
    Asthenia 5/752 (0.7%) 5 1/382 (0.3%) 1
    Chills 3/752 (0.4%) 3 0/382 (0%) 0
    Complication associated with device 2/752 (0.3%) 2 2/382 (0.5%) 2
    Death 2/752 (0.3%) 2 0/382 (0%) 0
    Disease progression 8/752 (1.1%) 8 4/382 (1%) 4
    Extravasation 1/752 (0.1%) 1 0/382 (0%) 0
    Face oedema 2/752 (0.3%) 2 0/382 (0%) 0
    Fatigue 10/752 (1.3%) 10 1/382 (0.3%) 1
    General physical health deterioration 2/752 (0.3%) 2 1/382 (0.3%) 1
    Generalised oedema 2/752 (0.3%) 2 1/382 (0.3%) 1
    Inflammation 1/752 (0.1%) 1 0/382 (0%) 0
    Infusion site thrombosis 1/752 (0.1%) 1 0/382 (0%) 0
    Malaise 0/752 (0%) 0 1/382 (0.3%) 1
    Mucosal inflammation 1/752 (0.1%) 1 0/382 (0%) 0
    Multiple organ dysfunction syndrome 0/752 (0%) 0 1/382 (0.3%) 1
    Oedema 1/752 (0.1%) 1 0/382 (0%) 0
    Oedema peripheral 2/752 (0.3%) 2 0/382 (0%) 0
    Pyrexia 8/752 (1.1%) 9 2/382 (0.5%) 2
    Sudden death 2/752 (0.3%) 2 0/382 (0%) 0
    Hepatobiliary disorders
    Cholecystitis 1/752 (0.1%) 1 0/382 (0%) 0
    Cholelithiasis 1/752 (0.1%) 1 0/382 (0%) 0
    Hepatic failure 2/752 (0.3%) 2 1/382 (0.3%) 1
    Hepatic function abnormal 2/752 (0.3%) 2 0/382 (0%) 0
    Hepatic pain 1/752 (0.1%) 1 0/382 (0%) 0
    Hyperbilirubinaemia 0/752 (0%) 0 1/382 (0.3%) 1
    Liver disorder 2/752 (0.3%) 2 0/382 (0%) 0
    Immune system disorders
    Hypersensitivity 4/752 (0.5%) 5 3/382 (0.8%) 3
    Infections and infestations
    Abdominal infection 1/752 (0.1%) 1 0/382 (0%) 0
    Abdominal wall abscess 1/752 (0.1%) 1 0/382 (0%) 0
    Abscess intestinal 1/752 (0.1%) 1 0/382 (0%) 0
    Abscess limb 1/752 (0.1%) 1 1/382 (0.3%) 1
    Abscess soft tissue 1/752 (0.1%) 1 0/382 (0%) 0
    Anal abscess 1/752 (0.1%) 1 1/382 (0.3%) 1
    Anal infection 1/752 (0.1%) 1 0/382 (0%) 0
    Bronchitis 3/752 (0.4%) 3 0/382 (0%) 0
    Catheter site infection 1/752 (0.1%) 1 0/382 (0%) 0
    Cellulitis 8/752 (1.1%) 8 0/382 (0%) 0
    Clostridium difficile colitis 1/752 (0.1%) 1 0/382 (0%) 0
    Clostridium difficile infection 0/752 (0%) 0 1/382 (0.3%) 1
    Device related infection 2/752 (0.3%) 2 0/382 (0%) 0
    Diverticulitis 1/752 (0.1%) 3 1/382 (0.3%) 1
    Gastroenteritis 1/752 (0.1%) 1 0/382 (0%) 0
    Gastroenteritis viral 0/752 (0%) 0 1/382 (0.3%) 1
    Infection 4/752 (0.5%) 4 0/382 (0%) 0
    Lower respiratory tract infection 3/752 (0.4%) 3 1/382 (0.3%) 1
    Lymphangitis 0/752 (0%) 0 1/382 (0.3%) 1
    Mastitis 1/752 (0.1%) 1 0/382 (0%) 0
    Mucosal infection 1/752 (0.1%) 1 0/382 (0%) 0
    Neutropenic infection 19/752 (2.5%) 19 9/382 (2.4%) 10
    Neutropenic sepsis 7/752 (0.9%) 7 0/382 (0%) 0
    Oral herpes 1/752 (0.1%) 1 0/382 (0%) 0
    Osteomyelitis 1/752 (0.1%) 1 0/382 (0%) 0
    Pelvic abscess 1/752 (0.1%) 1 0/382 (0%) 0
    Peritonitis 2/752 (0.3%) 2 0/382 (0%) 0
    Pneumonia 15/752 (2%) 16 5/382 (1.3%) 5
    Pneumonia chlamydial 1/752 (0.1%) 1 0/382 (0%) 0
    Postoperative wound infection 1/752 (0.1%) 1 0/382 (0%) 0
    Rectal abscess 1/752 (0.1%) 1 0/382 (0%) 0
    Respiratory tract infection 1/752 (0.1%) 1 0/382 (0%) 0
    Retroperitoneal abscess 1/752 (0.1%) 1 0/382 (0%) 0
    Sepsis 7/752 (0.9%) 7 0/382 (0%) 0
    Sinusitis 1/752 (0.1%) 1 0/382 (0%) 0
    Skin infection 1/752 (0.1%) 1 0/382 (0%) 0
    Staphylococcal sepsis 1/752 (0.1%) 1 0/382 (0%) 0
    Streptococcal infection 0/752 (0%) 0 1/382 (0.3%) 1
    Tonsillitis 2/752 (0.3%) 2 0/382 (0%) 0
    Tooth abscess 1/752 (0.1%) 1 0/382 (0%) 0
    Upper respiratory tract infection 4/752 (0.5%) 5 1/382 (0.3%) 1
    Urinary tract infection 6/752 (0.8%) 7 3/382 (0.8%) 3
    Vascular device infection 4/752 (0.5%) 6 1/382 (0.3%) 1
    Viral upper respiratory tract infection 1/752 (0.1%) 1 1/382 (0.3%) 1
    Wound infection 1/752 (0.1%) 1 0/382 (0%) 0
    Injury, poisoning and procedural complications
    Ankle fracture 1/752 (0.1%) 1 0/382 (0%) 0
    Chemical burn of skin 1/752 (0.1%) 1 0/382 (0%) 0
    Expired product administered 1/752 (0.1%) 1 0/382 (0%) 0
    Facial bones fracture 1/752 (0.1%) 1 0/382 (0%) 0
    Femur fracture 0/752 (0%) 0 1/382 (0.3%) 1
    Hip fracture 1/752 (0.1%) 1 1/382 (0.3%) 1
    Humerus fracture 1/752 (0.1%) 1 0/382 (0%) 0
    Ilium fracture 1/752 (0.1%) 1 0/382 (0%) 0
    Incorrect dose administered 0/752 (0%) 0 1/382 (0.3%) 1
    Infusion related reaction 3/752 (0.4%) 3 0/382 (0%) 0
    Injury 1/752 (0.1%) 1 0/382 (0%) 0
    Medication error 9/752 (1.2%) 9 2/382 (0.5%) 2
    Overdose 7/752 (0.9%) 13 5/382 (1.3%) 11
    Procedural pneumothorax 1/752 (0.1%) 1 0/382 (0%) 0
    Product administration error 1/752 (0.1%) 1 0/382 (0%) 0
    Product dispensing error 3/752 (0.4%) 3 1/382 (0.3%) 2
    Product preparation issue 1/752 (0.1%) 1 0/382 (0%) 0
    Radiation oesophagitis 1/752 (0.1%) 1 0/382 (0%) 0
    Spinal fracture 1/752 (0.1%) 1 0/382 (0%) 0
    Stoma site haemorrhage 0/752 (0%) 0 1/382 (0.3%) 1
    Suture rupture 1/752 (0.1%) 1 0/382 (0%) 0
    Underdose 11/752 (1.5%) 34 12/382 (3.1%) 24
    Wound dehiscence 1/752 (0.1%) 1 0/382 (0%) 0
    Wrong product administered 1/752 (0.1%) 1 1/382 (0.3%) 1
    Investigations
    Blood calcium decreased 0/752 (0%) 0 1/382 (0.3%) 1
    Neutrophil count decreased 1/752 (0.1%) 1 0/382 (0%) 0
    Metabolism and nutrition disorders
    Dehydration 7/752 (0.9%) 7 0/382 (0%) 0
    Diabetes mellitus inadequate control 0/752 (0%) 0 1/382 (0.3%) 1
    Fluid overload 0/752 (0%) 0 1/382 (0.3%) 1
    Fluid retention 1/752 (0.1%) 1 0/382 (0%) 0
    Hypercalcaemia 4/752 (0.5%) 4 1/382 (0.3%) 1
    Hypocalcaemia 1/752 (0.1%) 1 0/382 (0%) 0
    Hypoglycaemia 2/752 (0.3%) 2 0/382 (0%) 0
    Hypokalaemia 3/752 (0.4%) 3 0/382 (0%) 0
    Hyponatraemia 1/752 (0.1%) 1 0/382 (0%) 0
    Lactic acidosis 1/752 (0.1%) 1 0/382 (0%) 0
    Musculoskeletal and connective tissue disorders
    Arthralgia 3/752 (0.4%) 3 1/382 (0.3%) 1
    Back pain 3/752 (0.4%) 3 1/382 (0.3%) 1
    Bone pain 3/752 (0.4%) 3 1/382 (0.3%) 1
    Muscular weakness 0/752 (0%) 0 1/382 (0.3%) 1
    Musculoskeletal chest pain 2/752 (0.3%) 2 0/382 (0%) 0
    Musculoskeletal pain 2/752 (0.3%) 2 0/382 (0%) 0
    Myalgia 1/752 (0.1%) 1 0/382 (0%) 0
    Myositis 1/752 (0.1%) 1 0/382 (0%) 0
    Osteonecrosis of jaw 2/752 (0.3%) 2 0/382 (0%) 0
    Pain in extremity 2/752 (0.3%) 2 0/382 (0%) 0
    Pathological fracture 2/752 (0.3%) 2 0/382 (0%) 0
    Spinal pain 1/752 (0.1%) 1 0/382 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia 1/752 (0.1%) 1 0/382 (0%) 0
    Breast cancer 0/752 (0%) 0 1/382 (0.3%) 1
    Colon cancer 1/752 (0.1%) 1 0/382 (0%) 0
    Haemangioma 1/752 (0.1%) 2 0/382 (0%) 0
    Malignant ascites 1/752 (0.1%) 1 0/382 (0%) 0
    Malignant neoplasm progression 0/752 (0%) 0 1/382 (0.3%) 1
    Malignant pleural effusion 1/752 (0.1%) 1 0/382 (0%) 0
    Metastases to central nervous system 3/752 (0.4%) 3 1/382 (0.3%) 1
    Metastases to meninges 1/752 (0.1%) 1 0/382 (0%) 0
    Neoplasm progression 4/752 (0.5%) 4 0/382 (0%) 0
    Tumour embolism 1/752 (0.1%) 1 0/382 (0%) 0
    Nervous system disorders
    Cerebral haemorrhage 1/752 (0.1%) 1 0/382 (0%) 0
    Cerebral ischaemia 1/752 (0.1%) 1 0/382 (0%) 0
    Cerebrovascular accident 1/752 (0.1%) 1 0/382 (0%) 0
    Demyelinating polyneuropathy 1/752 (0.1%) 1 0/382 (0%) 0
    Dizziness 1/752 (0.1%) 1 0/382 (0%) 0
    Encephalopathy 2/752 (0.3%) 2 0/382 (0%) 0
    Epilepsy 0/752 (0%) 0 1/382 (0.3%) 1
    Haemorrhagic stroke 0/752 (0%) 0 1/382 (0.3%) 1
    Headache 7/752 (0.9%) 8 0/382 (0%) 0
    Hepatic encephalopathy 1/752 (0.1%) 2 0/382 (0%) 0
    Hydrocephalus 0/752 (0%) 0 1/382 (0.3%) 1
    Loss of consciousness 1/752 (0.1%) 2 0/382 (0%) 0
    Migraine 1/752 (0.1%) 1 0/382 (0%) 0
    Nervous system disorder 1/752 (0.1%) 1 0/382 (0%) 0
    Neuropathy peripheral 0/752 (0%) 0 1/382 (0.3%) 1
    Paraplegia 0/752 (0%) 0 1/382 (0.3%) 1
    Peripheral motor neuropathy 1/752 (0.1%) 1 0/382 (0%) 0
    Peripheral sensory neuropathy 2/752 (0.3%) 2 0/382 (0%) 0
    Radiculopathy 1/752 (0.1%) 1 0/382 (0%) 0
    Seizure 2/752 (0.3%) 2 0/382 (0%) 0
    Subarachnoid haemorrhage 1/752 (0.1%) 1 0/382 (0%) 0
    Syncope 1/752 (0.1%) 1 1/382 (0.3%) 1
    Transient ischaemic attack 1/752 (0.1%) 1 1/382 (0.3%) 1
    Product Issues
    Thrombosis in device 0/752 (0%) 0 1/382 (0.3%) 1
    Psychiatric disorders
    Anxiety 1/752 (0.1%) 1 0/382 (0%) 0
    Confusional state 4/752 (0.5%) 4 1/382 (0.3%) 1
    Depression 0/752 (0%) 0 1/382 (0.3%) 1
    Mood altered 0/752 (0%) 0 2/382 (0.5%) 2
    Renal and urinary disorders
    Acute kidney injury 5/752 (0.7%) 5 0/382 (0%) 0
    Dysuria 0/752 (0%) 0 1/382 (0.3%) 1
    Proteinuria 2/752 (0.3%) 2 0/382 (0%) 0
    Renal failure 1/752 (0.1%) 1 0/382 (0%) 0
    Renal impairment 1/752 (0.1%) 1 0/382 (0%) 0
    Ureteric obstruction 1/752 (0.1%) 1 0/382 (0%) 0
    Urinary retention 1/752 (0.1%) 1 0/382 (0%) 0
    Reproductive system and breast disorders
    Menstruation irregular 1/752 (0.1%) 1 1/382 (0.3%) 1
    Uterine haemorrhage 0/752 (0%) 0 1/382 (0.3%) 1
    Uterine polyp 1/752 (0.1%) 1 0/382 (0%) 0
    Vaginal haemorrhage 1/752 (0.1%) 1 0/382 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Acute interstitial pneumonitis 0/752 (0%) 0 1/382 (0.3%) 1
    Dyspnoea 5/752 (0.7%) 6 5/382 (1.3%) 6
    Epistaxis 2/752 (0.3%) 2 0/382 (0%) 0
    Haemoptysis 1/752 (0.1%) 1 0/382 (0%) 0
    Interstitial lung disease 0/752 (0%) 0 1/382 (0.3%) 1
    Lung infiltration 0/752 (0%) 0 1/382 (0.3%) 1
    Pleural effusion 8/752 (1.1%) 8 6/382 (1.6%) 7
    Pneumonitis 0/752 (0%) 0 1/382 (0.3%) 1
    Pneumothorax 3/752 (0.4%) 3 0/382 (0%) 0
    Pulmonary embolism 3/752 (0.4%) 3 4/382 (1%) 4
    Respiratory failure 1/752 (0.1%) 1 0/382 (0%) 0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic 1/752 (0.1%) 1 0/382 (0%) 0
    Erythema nodosum 1/752 (0.1%) 1 0/382 (0%) 0
    Lichen sclerosus 1/752 (0.1%) 1 0/382 (0%) 0
    Palmar-plantar erythrodysaesthesia syndrome 1/752 (0.1%) 1 0/382 (0%) 0
    Rash 1/752 (0.1%) 1 0/382 (0%) 0
    Skin ulcer 1/752 (0.1%) 1 0/382 (0%) 0
    Subcutaneous emphysema 1/752 (0.1%) 1 0/382 (0%) 0
    Social circumstances
    Disability 0/752 (0%) 0 1/382 (0.3%) 1
    Surgical and medical procedures
    Therapy change 0/752 (0%) 0 1/382 (0.3%) 2
    Vascular disorders
    Deep vein thrombosis 2/752 (0.3%) 2 3/382 (0.8%) 3
    Embolism 0/752 (0%) 0 1/382 (0.3%) 1
    Hypertension 1/752 (0.1%) 1 0/382 (0%) 0
    Hypertensive crisis 1/752 (0.1%) 1 0/382 (0%) 0
    Hypotension 4/752 (0.5%) 4 2/382 (0.5%) 2
    Jugular vein thrombosis 1/752 (0.1%) 1 0/382 (0%) 0
    Lymphoedema 0/752 (0%) 0 1/382 (0.3%) 1
    Subclavian vein thrombosis 1/752 (0.1%) 1 0/382 (0%) 0
    Thrombosis 1/752 (0.1%) 1 1/382 (0.3%) 1
    Other (Not Including Serious) Adverse Events
    Ramucirumab (IMC-1121B) + Docetaxel Placebo + Docetaxel
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 737/752 (98%) 373/382 (97.6%)
    Blood and lymphatic system disorders
    Anaemia 77/752 (10.2%) 108 28/382 (7.3%) 39
    Neutropenia 96/752 (12.8%) 175 41/382 (10.7%) 56
    Cardiac disorders
    Tachycardia 50/752 (6.6%) 70 23/382 (6%) 36
    Eye disorders
    Lacrimation increased 233/752 (31%) 337 65/382 (17%) 90
    Gastrointestinal disorders
    Abdominal pain 95/752 (12.6%) 141 42/382 (11%) 59
    Abdominal pain upper 51/752 (6.8%) 71 24/382 (6.3%) 33
    Constipation 157/752 (20.9%) 293 74/382 (19.4%) 116
    Diarrhoea 326/752 (43.4%) 751 152/382 (39.8%) 338
    Dry mouth 29/752 (3.9%) 54 20/382 (5.2%) 33
    Dyspepsia 75/752 (10%) 110 40/382 (10.5%) 57
    Gingival bleeding 73/752 (9.7%) 144 2/382 (0.5%) 2
    Haemorrhoids 39/752 (5.2%) 50 8/382 (2.1%) 8
    Nausea 278/752 (37%) 766 156/382 (40.8%) 343
    Stomatitis 380/752 (50.5%) 833 118/382 (30.9%) 215
    Vomiting 155/752 (20.6%) 288 80/382 (20.9%) 127
    General disorders
    Asthenia 270/752 (35.9%) 549 127/382 (33.2%) 363
    Face oedema 73/752 (9.7%) 100 27/382 (7.1%) 30
    Fatigue 271/752 (36%) 481 135/382 (35.3%) 240
    Influenza like illness 39/752 (5.2%) 48 29/382 (7.6%) 40
    Non-cardiac chest pain 39/752 (5.2%) 43 19/382 (5%) 21
    Oedema 43/752 (5.7%) 48 18/382 (4.7%) 26
    Oedema peripheral 181/752 (24.1%) 274 101/382 (26.4%) 140
    Pyrexia 110/752 (14.6%) 168 44/382 (11.5%) 65
    Infections and infestations
    Conjunctivitis 38/752 (5.1%) 42 17/382 (4.5%) 25
    Nasopharyngitis 63/752 (8.4%) 79 20/382 (5.2%) 30
    Upper respiratory tract infection 39/752 (5.2%) 48 21/382 (5.5%) 29
    Urinary tract infection 71/752 (9.4%) 91 28/382 (7.3%) 32
    Injury, poisoning and procedural complications
    Infusion related reaction 41/752 (5.5%) 56 24/382 (6.3%) 43
    Investigations
    Weight decreased 173/752 (23%) 209 41/382 (10.7%) 50
    Weight increased 123/752 (16.4%) 152 92/382 (24.1%) 105
    Metabolism and nutrition disorders
    Decreased appetite 165/752 (21.9%) 293 62/382 (16.2%) 101
    Musculoskeletal and connective tissue disorders
    Arthralgia 173/752 (23%) 359 82/382 (21.5%) 167
    Back pain 114/752 (15.2%) 143 54/382 (14.1%) 74
    Bone pain 92/752 (12.2%) 192 41/382 (10.7%) 82
    Musculoskeletal pain 51/752 (6.8%) 105 18/382 (4.7%) 32
    Myalgia 153/752 (20.3%) 292 89/382 (23.3%) 209
    Pain in extremity 107/752 (14.2%) 195 47/382 (12.3%) 66
    Nervous system disorders
    Dizziness 64/752 (8.5%) 88 36/382 (9.4%) 45
    Dysgeusia 68/752 (9%) 120 32/382 (8.4%) 66
    Headache 171/752 (22.7%) 306 70/382 (18.3%) 98
    Neuropathy peripheral 101/752 (13.4%) 124 64/382 (16.8%) 78
    Paraesthesia 47/752 (6.3%) 59 31/382 (8.1%) 40
    Peripheral sensory neuropathy 136/752 (18.1%) 193 73/382 (19.1%) 90
    Taste disorder 105/752 (14%) 156 58/382 (15.2%) 89
    Psychiatric disorders
    Anxiety 49/752 (6.5%) 65 27/382 (7.1%) 27
    Insomnia 99/752 (13.2%) 127 33/382 (8.6%) 39
    Renal and urinary disorders
    Proteinuria 44/752 (5.9%) 75 5/382 (1.3%) 5
    Respiratory, thoracic and mediastinal disorders
    Cough 127/752 (16.9%) 179 69/382 (18.1%) 89
    Dyspnoea 163/752 (21.7%) 225 75/382 (19.6%) 90
    Epistaxis 300/752 (39.9%) 817 64/382 (16.8%) 149
    Oropharyngeal pain 65/752 (8.6%) 96 27/382 (7.1%) 36
    Pleural effusion 69/752 (9.2%) 74 28/382 (7.3%) 29
    Rhinorrhoea 56/752 (7.4%) 82 19/382 (5%) 23
    Skin and subcutaneous tissue disorders
    Alopecia 535/752 (71.1%) 550 279/382 (73%) 287
    Dry skin 55/752 (7.3%) 60 21/382 (5.5%) 21
    Nail disorder 231/752 (30.7%) 250 105/382 (27.5%) 114
    Palmar-plantar erythrodysaesthesia syndrome 106/752 (14.1%) 157 33/382 (8.6%) 36
    Pruritus 41/752 (5.5%) 44 21/382 (5.5%) 23
    Rash 109/752 (14.5%) 143 47/382 (12.3%) 63
    Vascular disorders
    Hot flush 34/752 (4.5%) 44 21/382 (5.5%) 22
    Hypertension 204/752 (27.1%) 405 44/382 (11.5%) 96

    Limitations/Caveats

    One participant assigned to placebo + docetaxel (doc) treatment and was given ramucirumab (ram) in Cycle 1. Considered ram + doc treatment arm for safety population, for ITT population the participant was analyzed according to assigned treatment.

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Investigators agreed to delay independently publishing or disclosing data, findings or conclusions from the study except as part of a multi-center publication. Upon study publication or if the draft publication is not produced within approximately 6 months of the final report of the study results, investigators may independently publish, subject to confidential information review/redaction by sponsor. The sponsor may request publication delay up to 90 days to seek patent protection.

    Results Point of Contact

    Name/Title Chief Medical Officer
    Organization Eli Lilly and Company
    Phone 800-545-5979
    Email ClinicalTrials.gov@lilly.com
    Responsible Party:
    Eli Lilly and Company
    ClinicalTrials.gov Identifier:
    NCT00703326
    Other Study ID Numbers:
    • 13892
    • 2008-001727-65
    • TRIO-012
    • TRIO-CIRG-012
    • CP12-0606
    • I4T-IE-JVBC
    First Posted:
    Jun 23, 2008
    Last Update Posted:
    Dec 6, 2021
    Last Verified:
    Nov 1, 2021