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A Study of Emibetuzumab in Combination With Ramucirumab (LY3009806) in Participants With Advanced Cancer

Sponsor
Eli Lilly and Company (Industry)
Overall Status
Completed
CT.gov ID
NCT02082210
Collaborator
(none)
97
Enrollment
4
Locations
2
Arms
46.6
Actual Duration (Months)
24.3
Patients Per Site
0.5
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to find a recommended schedule and dose range for Emibetuzumab when given with ramucirumab that may be safely given to participants with cancer. In Part A of this study, escalating doses of Emibetuzumab will be given in combination with a fixed dose of ramucirumab to evaluate the safety of the combination. After a recommended schedule and dose range of Emibetuzumab and ramucirumab has been established, Part B of the study will confirm safety and to see how well certain tumors respond to the combination of study drugs. The average amount of time on study is expected to be about 6 months.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
97 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 1b/2 Study of Ramucirumab in Combination With LY2875358 in Patients With Advanced Cancer
Actual Study Start Date :
Mar 7, 2014
Actual Primary Completion Date :
Dec 5, 2017
Actual Study Completion Date :
Jan 24, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: Emibetuzumab + Ramucirumab (Part A)

Part A: Dose escalation (750mg, 2000mg) of Emibetuzumab administered intravenously (IV), on days 1 and 15 every 28 day cycle in combination with a fixed dose of 8mg/kg ramucirumab administered IV on Days 1 and 15 every 28 day cycle.

Drug: Emibetuzumab
Administered Intravenously (IV)
Other Names:
  • LY2875358

    • Drug: Ramucirumab
    Administered Intravenously (IV)
    Other Names:
  • LY3009806
  • IMC-1121B

    		•
    Experimental: Emibetuzumab + Ramucirumab (Part B)

    Part B: Recommended 750mg Emibetuzumab dose from Part A to be administered IV, on days 1 and 15 every 28 day cycle in combination with a fixed dose of 8mg/kg ramucirumab administered IV on Days 1 and 15 every 28 day cycle.

    Drug: Emibetuzumab
    Administered Intravenously (IV)
    Other Names:
  • LY2875358

    • Drug: Ramucirumab
    Administered Intravenously (IV)
    Other Names:
  • LY3009806
  • IMC-1121B

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) [Baseline through Cycle 1 (28 day cycle)]

      DLT is defined as an adverse event during Cycle1 that is possibly, probably, or definitely related to treatment with Emibetuzumab in combination with fixed regimen of Ramucirumab & fulfills any 1 of the following criterion using NCI CTCAE Version 4.03: Grade 3 non-hematological toxicity. Exceptions will be made for:Nausea, vomiting, diarrhea, constipation, or skin rash that persists for ≤3 days following appropriate supportive care intervention. Grade 3 hypertension in which systolic BP ≥160 mmHg and/or diastolic BP ≥100 mmHg persist <7 days after intensified antihypertensive therapy is initiated. Grade 4 hematological toxicity of ≥7 days duration. ≥Grade 3 thrombocytopenia with ≥Grade 2 bleeding. Any febrile neutropenia. Any other significant toxicity deemed by the primary investigator & Lilly clinical research personnel to be dose-limiting (eg, any toxicity that is possibly related to the study medication that requires the withdrawal of participant from study Cycle1).

    2. Part B: Percentage of Participants Who Exhibit Complete Response (CR) or Partial Response (PR) [Overall Response Rate (ORR)] [Baseline through Measured Progressive Disease or Death (Up to 17 months)]

      ORR is the percentage of participants achieving a best overall response (BOR) of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR is defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR is 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), no progression of non-target lesions, and no appearance of new lesions. 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 5mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.

    Secondary Outcome Measures

    1. Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) of Emibetuzumab [Cycle 1: Day1 Predose, End of infusion, 3 Hours (h), 5h, 8h, 21h, 168h, 334h, 335h and 336h Post dose]

      Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) of Emibetuzumab.

    2. Part B: Percentage of Participants Who Exhibit Stable Disease (SD) or Confirmed Response (CR) or Partial Response (PR) (Disease Control Rate [DCR]) [Baseline through Measured Progressive Disease (Up to 17 months)]

      DCR is the proportion of participants who exhibit a SD or confirmed CR or PR relative to baseline. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD for target lesions, no progression of non-target lesions, and no appearance of new lesions. 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 5mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.

    3. Part B: Progression Free Survival (PFS) [Baseline to Measured Progressive Disease or Death (Up to 17 Months)]

      PFS was defined as the time from the date of first dose of study drug until first observation of objective (radiographically documented) PD as defined by RECIST v1.1 or death from any cause, whichever comes first. 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.

    4. Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) From Time Zero to Tlast of Emibetuzumab [Cycle 1: Day1 Predose, End of infusion, 3 Hours (h), 5h, 8h, 21h, 168h, 334h, 335h and 336h Post dose]

      Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) from time zero to tlast of Emibetuzumab.

    5. Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Ramucirumab [Cycle 1: Day1 Predose, End of infusion, 3 Hours (h), 5h, 8h, 21h, 168h and 336h Post dose]

      Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Ramucirumab.

    6. Number of Participants With Treatment Emergent Anti-Emibetuzumab Antibodies [Baseline through 46 Months]

      Participants were considered as treatment-emergent anti drug antibodies (TE ADA) positive if there is a ≥4-fold increase from baseline when ADAs were detected at baseline. If no ADAs were detected at baseline, TE ADA were defined as those with a titer 2 fold (1 dilution) greater than the minimum required dilution (MRD) of the screening assay (1:4 for anti-emibetuzumab antibodies).

    7. Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Ramucirumab [Cycle 1: Day1 Predose, End of infusion, 3 Hours (h), 5h, 8h, 21h, 168h and 336h Post dose]

      Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Ramucirumab.

    8. Number of Participants With Treatment Emergent Anti-Ramucirumab Antibodies [Baseline through 46 Months]

      Participants were considered as treatment-emergent anti drug antibodies (TE ADA) positive if there is a ≥4-fold increase from baseline when ADAs were detected at baseline. If no ADAs were detected at baseline, TE ADA were defined as those with a titer 2 fold (1 dilution) greater than the minimum required dilution (MRD) of the screening assay (1:10 for anti-ramucirumab antibodies).

    Eligibility Criteria

    Criteria

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

    • Participants must have histological or cytological confirmed diagnosis of the following tumor types that is advanced and/or metastatic cancer and must be, in the judgment of the investigator, an appropriate participant for experimental therapy

    • Part A: Any type of solid tumor ("all comer")

    • Part B1: Gastric or Gastroesophageal Junction (GEJ) adenocarcinoma

    • Part B2: Hepatocellular cancer (excluding fibrolamellar carcinoma)

    • Part B3: Renal cell carcinoma (any histology)

    • Part B4: Non-small cell lung cancer (squamous or non-squamous)

    • Have at least 1 measurable lesion outside of the central nervous system (CNS) whose presence is assessable using standard techniques by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

    • Availability of a tumor sample taken after progression on the most recent line of systemic tumor therapy or willing to undergo a tumor biopsy pre-study treatment.

    • Have a performance status of ≤ 2 on the Eastern Cooperative Oncology Group (ECOG) scale in Part A and ≤ 1 on the ECOG scale in Part B.

    • Have adequate organ function.

    • Routine urinalysis showing ≤1+ protein or protein/creatinine ratio <0.5. For proteinuria ≥2+ or urine protein/creatinine ratio ≥0.5, 24-hour urine must be collected and the level must be <1 gram of protein in 24 hours for subject enrollment.

    • Have discontinued all previous cancer therapies and any agents that have not received regulatory approval for any indication, for at least 21 days or 5 halflives prior to study enrollment, whichever is shorter, and recovered from the acute effects for therapy.

    • Have an estimated life expectancy, in the judgment of the investigator, that will permit the participant to complete 8 weeks (2 cycles) of treatment.

    • Males and females with reproductive potential: Must agree to use medically approved contraceptive precautions during the study and for at least 3 months following the last dose of study drug. Females with childbearing potential must have had a negative serum pregnancy test 7 days before the first dose of study drug and must not be breast-feeding.

    Exclusion Criteria:

    • Have serious pre-existing medical conditions (at the discretion of the investigator, such as severe acute or chronic medical condition or laboratory abnormality that may increase the risk associated with study participation).

    • Have a history of hypertensive crisis or hypertensive encephalopathy or current poorly controlled hypertension despite standard medical management.

    • Participant has experienced any arterial thromboembolic event (ATE), including myocardial infarction, unstable angina pectoris, cerebrovascular accident, or transient ischemic attack, within 6 months prior to receiving study drugs.

    • Have a history of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolic event during the 3 months prior to receiving study drugs.

    • Are receiving therapeutic anticoagulation with warfarin, low-molecular weight heparin, or similar agents. Participants receiving prophylactic, low-dose anticoagulation therapy are eligible provided that they are on low-molecular weight heparin or oral factor Xa inhibitors.

    • The participant is receiving chronic therapy with nonsteroidal anti-inflammatory drugs or other antiplatelet agents. Aspirin use at doses up to 325 mg/day is permitted.

    • Have significant bleeding disorders, vasculitis, or had a significant bleeding episode from the gastrointestinal (GI) tract within 3 months prior to receiving study drugs.

    • Have a history of GI perforation and/or fistulae within 6 months prior to receiving study drugs.

    • Have congestive heart failure (CHF) New York Heart Association class ≥3 or symptomatic or poorly controlled cardiac arrhythmia.

    • Have undergone major surgery within 28 days prior to receiving study drugs.

    • Have a serious or nonhealing wound, peptic ulcer, or bone fracture within 28 days prior to receiving study drugs.

    • Have a known active fungal, bacterial, and/or known viral infection. Hepatocellular cancer participants with chronic viral (B or C) hepatitis are eligible if they retain adequate liver function.

    • Have liver cirrhosis with a Child-Pugh Stage of B or C.

    • Have symptomatic CNS malignancy (with the exception of medulloblastoma) or metastasis.

    • Have corrected QT (QTc) interval of >470 milliseconds on screening electrocardiogram (ECG).

    • Have received previous treatment with ramucirumab or Emibetuzumab, except for participants enrolled in cohort B1 (Gastric or GEJ adenocarcinoma) and B4 (non- small cell lung cancer) who may have received previous ramucirumab treatment.

    • Known hypersensitivity to any of the treatment components of ramucirumab or Emibetuzumab.

    • Have a second primary malignancy that, in the judgment of the investigator and sponsor, may affect the interpretation of results.

    • Are pregnant or breastfeeding.

    • For Part B4 (non-small cell lung cancer) only:

    • The participant has radiologically documented evidence of major blood vessel invasion or encasement by cancer

    • Participants with a history of gross hemoptysis within 2 months prior to study treatment

    • The participant has radiographic evidence of intratumor cavitation, regardless of tumor histology

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Massachusetts General Hospital Boston Massachusetts United States 02114-3117
    2 Dana Farber Cancer Institute Boston Massachusetts United States 02115
    3 Memorial Sloan Kettering Cancer Center New York New York United States 10065
    4 Tennessee Oncology PLLC Nashville Tennessee United States 37203

    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)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Eli Lilly and Company
    ClinicalTrials.gov Identifier:
    NCT02082210
    Other Study ID Numbers:
    • 15246
    • I4C-MC-JTBF
    First Posted:
    Mar 10, 2014
    Last Update Posted:
    Dec 19, 2020
    Last Verified:
    Mar 1, 2018
    Additional relevant MeSH terms:
    Adenocarcinoma
    Carcinoma, Renal Cell
    Neoplasms
    Liver Neoplasms
    Carcinoma, Hepatocellular
    Ramucirumab

    Study Results

    Participant Flow

    Recruitment Details Part A: Completers are those who have completed one cycle of treatment. Part B: Completers are those who 1)Have measurable disease at baseline and at least one post-baseline tumor assessment; and 2) Were treated until PD or death, or discontinued due to an AE and completed the required follow-up.
    Pre-assignment Detail Two part study, Part A with 2 cohorts (750 milligram (mg), 2000mg) & Part B with four tumor specific cohorts (gastric, hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC)).
    Arm/Group Title Part A - 750 mg Emibetuzumab Part A - 2000 mg Emibetuzumab Part B - Gastric Part B - HCC Part B - RCC Part B - NSCLC
    Arm/Group Description Participants received 8 milligram per kilogram (mg/kg) Ramucirumab followed by 750 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 2000 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle.
    Period Title: Overall Study
    STARTED 3 3 16 45 15 15
    Received at Least One Dose of Study Drug 3 3 16 45 15 15
    COMPLETED 3 3 13 39 12 13
    NOT COMPLETED 0 0 3 6 3 2

    Baseline Characteristics

    Arm/Group Title Part A - 750 mg Emibetuzumab Part A - 2000 mg Emibetuzumab Part B - Gastric Part B - HCC Part B - RCC Part B - NSCLC Total
    Arm/Group Description Participants received 8 mg/kg Ramucirumab followed by 750 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 2000 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Total of all reporting groups
    Overall Participants 3 3 16 45 15 15 97
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    41.3
    (20.6)
    62.0
    (13.5)
    62.6
    (9.1)
    63.4
    (9.5)
    63.1
    (10.1)
    59.9
    (8.6)
    62.0
    (10.4)
    Sex: Female, Male (Count of Participants)
    Female
    3
    100%
    0
    0%
    4
    25%
    11
    24.4%
    3
    20%
    6
    40%
    27
    27.8%
    Male
    0
    0%
    3
    100%
    12
    75%
    34
    75.6%
    12
    80%
    9
    60%
    70
    72.2%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    0
    0%
    1
    6.3%
    3
    6.7%
    2
    13.3%
    0
    0%
    6
    6.2%
    Not Hispanic or Latino
    3
    100%
    3
    100%
    15
    93.8%
    36
    80%
    13
    86.7%
    14
    93.3%
    84
    86.6%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    1
    2.2%
    0
    0%
    0
    0%
    1
    1%
    Asian
    0
    0%
    0
    0%
    0
    0%
    7
    15.6%
    0
    0%
    2
    13.3%
    9
    9.3%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    1
    33.3%
    1
    6.3%
    3
    6.7%
    0
    0%
    1
    6.7%
    6
    6.2%
    White
    3
    100%
    2
    66.7%
    14
    87.5%
    32
    71.1%
    14
    93.3%
    11
    73.3%
    76
    78.4%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Region of Enrollment (Count of Participants)
    United States
    3
    100%
    3
    100%
    16
    100%
    45
    100%
    15
    100%
    15
    100%
    97
    100%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)
    Description DLT is defined as an adverse event during Cycle1 that is possibly, probably, or definitely related to treatment with Emibetuzumab in combination with fixed regimen of Ramucirumab & fulfills any 1 of the following criterion using NCI CTCAE Version 4.03: Grade 3 non-hematological toxicity. Exceptions will be made for:Nausea, vomiting, diarrhea, constipation, or skin rash that persists for ≤3 days following appropriate supportive care intervention. Grade 3 hypertension in which systolic BP ≥160 mmHg and/or diastolic BP ≥100 mmHg persist <7 days after intensified antihypertensive therapy is initiated. Grade 4 hematological toxicity of ≥7 days duration. ≥Grade 3 thrombocytopenia with ≥Grade 2 bleeding. Any febrile neutropenia. Any other significant toxicity deemed by the primary investigator & Lilly clinical research personnel to be dose-limiting (eg, any toxicity that is possibly related to the study medication that requires the withdrawal of participant from study Cycle1).
    Time Frame Baseline through Cycle 1 (28 day cycle)

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least one dose of Emibetuzumab in Part A & Part B.
    Arm/Group Title Part A - 750 mg Emibetuzumab Part A - 2000 mg Emibetuzumab Part B - Gastric Part B - HCC Part B - RCC Part B - NSCLC
    Arm/Group Description Participants received 8 mg/kg Ramucirumab followed by 750 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 2000 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle.
    Measure Participants 3 3 16 45 15 15
    Count of Participants [Participants]
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2. Primary Outcome
    Title Part B: Percentage of Participants Who Exhibit Complete Response (CR) or Partial Response (PR) [Overall Response Rate (ORR)]
    Description ORR is the percentage of participants achieving a best overall response (BOR) of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR is defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR is 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), no progression of non-target lesions, and no appearance of new lesions. 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 5mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.
    Time Frame Baseline through Measured Progressive Disease or Death (Up to 17 months)

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least one dose of Emibetuzumab in Part B.
    Arm/Group Title Part B - Gastric Part B - HCC Part B - RCC Part B - NSCLC
    Arm/Group Description Participants received 8 mg/kg Ramucirumab followed by 750mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle.
    Measure Participants 16 45 15 15
    Number (95% Confidence Interval) [percentage of participants]
    6.3
    210%
    6.7
    223.3%
    0
    0%
    6.7
    14.9%
    3. Secondary Outcome
    Title Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) of Emibetuzumab
    Description Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) of Emibetuzumab.
    Time Frame Cycle 1: Day1 Predose, End of infusion, 3 Hours (h), 5h, 8h, 21h, 168h, 334h, 335h and 336h Post dose

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least one dose of Emibetuzumab and had evaluable PK samples in Part A & Part B. Per protocol analysis was performed per each dose irrespective of the study parts.
    Arm/Group Title All Parts - 750 mg Emibetuzumab All Parts - 2000 mg Emibetuzumab
    Arm/Group Description Participants received 8 mg/kg Ramucirumab followed by 750 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 2000 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle.
    Measure Participants 24 3
    Geometric Mean (Geometric Coefficient of Variation) [Microgram per milliliter (µg/mL)]
    210
    (27)
    575
    (33)
    4. Secondary Outcome
    Title Part B: Percentage of Participants Who Exhibit Stable Disease (SD) or Confirmed Response (CR) or Partial Response (PR) (Disease Control Rate [DCR])
    Description DCR is the proportion of participants who exhibit a SD or confirmed CR or PR relative to baseline. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD for target lesions, no progression of non-target lesions, and no appearance of new lesions. 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 5mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.
    Time Frame Baseline through Measured Progressive Disease (Up to 17 months)

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least one dose of Emibetuzumab in Part B.
    Arm/Group Title Part B - Gastric Part B - HCC Part B - RCC Part B - NSCLC
    Arm/Group Description Participants received 8 mg/kg Ramucirumab followed by 750mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle.
    Measure Participants 16 45 15 15
    Number (95% Confidence Interval) [percentage of participants]
    50
    1666.7%
    60
    2000%
    46.7
    291.9%
    86.7
    192.7%
    5. Secondary Outcome
    Title Part B: Progression Free Survival (PFS)
    Description PFS was defined as the time from the date of first dose of study drug until first observation of objective (radiographically documented) PD as defined by RECIST v1.1 or death from any cause, whichever comes first. 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.
    Time Frame Baseline to Measured Progressive Disease or Death (Up to 17 Months)

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least one dose of Emibetuzumab in part B. Censored participants in Part B- Gastric = 4; Part B - HCC = 15; Part B - RCC = 7; Part - B NSCLC = 4;
    Arm/Group Title Part B - Gastric Part B - HCC Part B - RCC Part B - NSCLC
    Arm/Group Description Participants received 8 mg/kg Ramucirumab followed by 750mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle.
    Measure Participants 16 45 15 15
    Median (95% Confidence Interval) [months]
    1.64
    5.42
    2.92
    6.57
    6. Secondary Outcome
    Title Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) From Time Zero to Tlast of Emibetuzumab
    Description Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) from time zero to tlast of Emibetuzumab.
    Time Frame Cycle 1: Day1 Predose, End of infusion, 3 Hours (h), 5h, 8h, 21h, 168h, 334h, 335h and 336h Post dose

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least one dose of Emibetuzumab and had evaluable PK samples in Part A & Part B. Per protocol, analysis was performed per each dose irrespective of study parts.
    Arm/Group Title All Parts - 750 mg Emibetuzumab All Parts - 2000 mg Emibetuzumab
    Arm/Group Description Participants received 8 mg/kg Ramucirumab followed by 750 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 2000 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle.
    Measure Participants 24 3
    Geometric Mean (Geometric Coefficient of Variation) [Microgram * hour per milliliter(µg*h/mL)]
    29800
    (26)
    86500
    (25)
    7. Secondary Outcome
    Title Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Ramucirumab
    Description Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Ramucirumab.
    Time Frame Cycle 1: Day1 Predose, End of infusion, 3 Hours (h), 5h, 8h, 21h, 168h and 336h Post dose

    Outcome Measure Data

    Analysis Population Description
    Noncompartmental PK parameters were not generated for Ramucirumab due to inadequate PK sampling.
    Arm/Group Title All Parts - 750mg All Parts - 2000mg
    Arm/Group Description Participants received 8 mg/kg Ramucirumab followed by 750 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 2000 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle.
    Measure Participants 0 0
    8. Secondary Outcome
    Title Number of Participants With Treatment Emergent Anti-Emibetuzumab Antibodies
    Description Participants were considered as treatment-emergent anti drug antibodies (TE ADA) positive if there is a ≥4-fold increase from baseline when ADAs were detected at baseline. If no ADAs were detected at baseline, TE ADA were defined as those with a titer 2 fold (1 dilution) greater than the minimum required dilution (MRD) of the screening assay (1:4 for anti-emibetuzumab antibodies).
    Time Frame Baseline through 46 Months

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least one dose of Emibetuzumab and had evaluable immunogenicity samples.
    Arm/Group Title Part A - 750 mg Emibetuzumab Part A - 2000 mg Emibetuzumab Part B - Gastric Part B - HCC Part B - RCC Part B - NSCLC
    Arm/Group Description Participants received 8 mg/kg Ramucirumab followed by 750 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 2000 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle.
    Measure Participants 3 3 15 42 15 15
    Count of Participants [Participants]
    0
    0%
    0
    0%
    0
    0%
    3
    6.7%
    0
    0%
    0
    0%
    9. Secondary Outcome
    Title Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Ramucirumab
    Description Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Ramucirumab.
    Time Frame Cycle 1: Day1 Predose, End of infusion, 3 Hours (h), 5h, 8h, 21h, 168h and 336h Post dose

    Outcome Measure Data

    Analysis Population Description
    Noncompartmental PK parameters were not generated for Ramucirumab due to inadequate PK sampling.
    Arm/Group Title All Parts - 750mg All Parts - 2000mg
    Arm/Group Description Participants received 8 mg/kg Ramucirumab followed by 750 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 2000 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle.
    Measure Participants 0 0
    10. Secondary Outcome
    Title Number of Participants With Treatment Emergent Anti-Ramucirumab Antibodies
    Description Participants were considered as treatment-emergent anti drug antibodies (TE ADA) positive if there is a ≥4-fold increase from baseline when ADAs were detected at baseline. If no ADAs were detected at baseline, TE ADA were defined as those with a titer 2 fold (1 dilution) greater than the minimum required dilution (MRD) of the screening assay (1:10 for anti-ramucirumab antibodies).
    Time Frame Baseline through 46 Months

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least one dose of ramucirumab and had evaluable immunogenicity samples.
    Arm/Group Title Part A - 750 mg Emibetuzumab Part A - 2000 mg Emibetuzumab Part B - Gastric Part B - HCC Part B - RCC Part B - NSCLC
    Arm/Group Description Participants received 8 mg/kg Ramucirumab followed by 750 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 2000 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle.
    Measure Participants 3 3 16 44 15 15
    Count of Participants [Participants]
    1
    33.3%
    0
    0%
    0
    0%
    4
    8.9%
    1
    6.7%
    0
    0%

    Adverse Events

    Time Frame Up to 46 months
    Adverse Event Reporting Description All participants who received at least one dose of study drug. Gender specific events occurring only in male or female participants have had the number of participants At Risk adjusted accordingly.
    Arm/Group Title Part A - 750 mg Emibetuzumab Part A - 2000 mg Emibetuzumab Part B - Gastric Part B - HCC Part B - RCC Part B - NSCLC
    Arm/Group Description Participants received 8 milligram per kilogram (mg/kg) Ramucirumab followed by 750 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 2000 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle. Participants received 8 mg/kg Ramucirumab followed by 750 mg Emibetuzumab given as intravenous (IV) infusion on days 1 and 15 of 28 days cycle.
    All Cause Mortality
    Part A - 750 mg Emibetuzumab Part A - 2000 mg Emibetuzumab Part B - Gastric Part B - HCC Part B - RCC Part B - NSCLC
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/3 (0%) 0/3 (0%) 3/16 (18.8%) 4/45 (8.9%) 1/15 (6.7%) 1/15 (6.7%)
    Serious Adverse Events
    Part A - 750 mg Emibetuzumab Part A - 2000 mg Emibetuzumab Part B - Gastric Part B - HCC Part B - RCC Part B - NSCLC
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/3 (66.7%) 2/3 (66.7%) 4/16 (25%) 19/45 (42.2%) 5/15 (33.3%) 3/15 (20%)
    Cardiac disorders
    Atrial fibrillation 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 0/15 (0%) 0 0/15 (0%) 0
    Pericardial effusion 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 1/15 (6.7%) 1 1/15 (6.7%) 1
    Gastrointestinal disorders
    Abdominal distension 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0
    Abdominal pain 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 0/15 (0%) 0 0/15 (0%) 0
    Ascites 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 1/15 (6.7%) 1 0/15 (0%) 0
    Constipation 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 0/15 (0%) 0 0/15 (0%) 0
    Gastritis 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 0/15 (0%) 0 0/15 (0%) 0
    Nausea 1/3 (33.3%) 1 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Oesophageal stenosis 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 0/15 (0%) 0 0/15 (0%) 0
    Oesophagitis 1/3 (33.3%) 1 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Small intestinal obstruction 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 0/15 (0%) 0 0/15 (0%) 0
    Upper gastrointestinal haemorrhage 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 2/45 (4.4%) 2 0/15 (0%) 0 0/15 (0%) 0
    Vomiting 1/3 (33.3%) 1 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    General disorders
    Oedema peripheral 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 0/15 (0%) 0 0/15 (0%) 0
    Pain 1/3 (33.3%) 1 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Pyrexia 0/3 (0%) 0 1/3 (33.3%) 1 0/16 (0%) 0 2/45 (4.4%) 2 0/15 (0%) 0 0/15 (0%) 0
    Hepatobiliary disorders
    Cholecystitis 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 0/15 (0%) 0 0/15 (0%) 0
    Infections and infestations
    Clostridium difficile infection 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 0/15 (0%) 0 0/15 (0%) 0
    Endocarditis 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 0/15 (0%) 0 0/15 (0%) 0
    Enterocolitis infectious 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Influenza 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0
    Lung infection 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Pneumonia 1/3 (33.3%) 1 0/3 (0%) 0 2/16 (12.5%) 2 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Investigations
    Alanine aminotransferase increased 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0
    Aspartate aminotransferase increased 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0
    Metabolism and nutrition disorders
    Dehydration 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0
    Failure to thrive 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 1/45 (2.2%) 1 0/15 (0%) 0 0/15 (0%) 0
    Hyperkalaemia 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 0/15 (0%) 0 0/15 (0%) 0
    Hyponatraemia 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 0/15 (0%) 0 0/15 (0%) 0
    Musculoskeletal and connective tissue disorders
    Back pain 0/3 (0%) 0 1/3 (33.3%) 2 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Nervous system disorders
    Hepatic encephalopathy 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 0/15 (0%) 0 0/15 (0%) 0
    Psychiatric disorders
    Mental status changes 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 0/15 (0%) 0 0/15 (0%) 0
    Renal and urinary disorders
    Acute kidney injury 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 1/45 (2.2%) 1 0/15 (0%) 0 0/15 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 0/15 (0%) 0 1/15 (6.7%) 1
    Pleural effusion 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 1/15 (6.7%) 1 1/15 (6.7%) 1
    Pulmonary embolism 0/3 (0%) 0 1/3 (33.3%) 1 0/16 (0%) 0 0/45 (0%) 0 1/15 (6.7%) 1 1/15 (6.7%) 1
    Vascular disorders
    Hypotension 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 2/45 (4.4%) 2 0/15 (0%) 0 0/15 (0%) 0
    Other (Not Including Serious) Adverse Events
    Part A - 750 mg Emibetuzumab Part A - 2000 mg Emibetuzumab Part B - Gastric Part B - HCC Part B - RCC Part B - NSCLC
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/3 (100%) 3/3 (100%) 15/16 (93.8%) 45/45 (100%) 15/15 (100%) 14/15 (93.3%)
    Blood and lymphatic system disorders
    Anaemia 0/3 (0%) 0 0/3 (0%) 0 5/16 (31.3%) 5 7/45 (15.6%) 9 1/15 (6.7%) 1 2/15 (13.3%) 6
    Leukopenia 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 2/45 (4.4%) 3 1/15 (6.7%) 1 0/15 (0%) 0
    Neutropenia 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Thrombocytopenia 1/3 (33.3%) 3 0/3 (0%) 0 0/16 (0%) 0 7/45 (15.6%) 9 1/15 (6.7%) 1 0/15 (0%) 0
    Cardiac disorders
    Palpitations 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 1/45 (2.2%) 1 0/15 (0%) 0 1/15 (6.7%) 1
    Sinus bradycardia 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0
    Tachycardia 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Ear and labyrinth disorders
    Vertigo 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Endocrine disorders
    Hyperthyroidism 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0
    Hypothyroidism 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 2/45 (4.4%) 2 2/15 (13.3%) 2 2/15 (13.3%) 3
    Eye disorders
    Eye discharge 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Lacrimation increased 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Periorbital oedema 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Vision blurred 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0
    Gastrointestinal disorders
    Abdominal distension 0/3 (0%) 0 0/3 (0%) 0 2/16 (12.5%) 2 3/45 (6.7%) 3 1/15 (6.7%) 1 1/15 (6.7%) 1
    Abdominal pain 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 6/45 (13.3%) 8 2/15 (13.3%) 2 1/15 (6.7%) 1
    Ascites 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 9/45 (20%) 11 0/15 (0%) 0 0/15 (0%) 0
    Constipation 0/3 (0%) 0 0/3 (0%) 0 5/16 (31.3%) 6 12/45 (26.7%) 14 3/15 (20%) 3 5/15 (33.3%) 6
    Diarrhoea 0/3 (0%) 0 0/3 (0%) 0 3/16 (18.8%) 3 11/45 (24.4%) 12 2/15 (13.3%) 2 4/15 (26.7%) 6
    Dry mouth 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 2/45 (4.4%) 2 0/15 (0%) 0 1/15 (6.7%) 1
    Dyspepsia 0/3 (0%) 0 0/3 (0%) 0 3/16 (18.8%) 3 1/45 (2.2%) 1 0/15 (0%) 0 0/15 (0%) 0
    Dysphagia 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Gastrointestinal haemorrhage 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Gastrooesophageal reflux disease 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0
    Gingival bleeding 1/3 (33.3%) 1 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 1/15 (6.7%) 1 1/15 (6.7%) 1
    Gingival swelling 1/3 (33.3%) 1 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Haematemesis 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 0/15 (0%) 0 1/15 (6.7%) 1
    Intra-abdominal haemorrhage 0/3 (0%) 0 1/3 (33.3%) 1 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Lip dry 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Nausea 1/3 (33.3%) 1 0/3 (0%) 0 8/16 (50%) 15 12/45 (26.7%) 16 4/15 (26.7%) 5 4/15 (26.7%) 6
    Proctalgia 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Retching 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Stomatitis 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 2/45 (4.4%) 2 1/15 (6.7%) 1 3/15 (20%) 4
    Toothache 1/3 (33.3%) 1 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 0/15 (0%) 0 0/15 (0%) 0
    Vomiting 1/3 (33.3%) 1 0/3 (0%) 0 6/16 (37.5%) 11 7/45 (15.6%) 8 1/15 (6.7%) 1 5/15 (33.3%) 7
    General disorders
    Asthenia 1/3 (33.3%) 1 1/3 (33.3%) 1 5/16 (31.3%) 5 3/45 (6.7%) 4 1/15 (6.7%) 1 2/15 (13.3%) 2
    Breakthrough pain 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Chills 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 4/45 (8.9%) 4 0/15 (0%) 0 0/15 (0%) 0
    Fatigue 1/3 (33.3%) 1 1/3 (33.3%) 3 11/16 (68.8%) 20 25/45 (55.6%) 34 6/15 (40%) 7 9/15 (60%) 13
    Gait disturbance 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Malaise 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 0/15 (0%) 0 1/15 (6.7%) 1
    Non-cardiac chest pain 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 4/45 (8.9%) 4 0/15 (0%) 0 0/15 (0%) 0
    Oedema 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 4 1/45 (2.2%) 1 1/15 (6.7%) 1 0/15 (0%) 0
    Oedema peripheral 3/3 (100%) 3 0/3 (0%) 0 6/16 (37.5%) 15 26/45 (57.8%) 38 5/15 (33.3%) 9 5/15 (33.3%) 9
    Pain 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 2/45 (4.4%) 2 0/15 (0%) 0 1/15 (6.7%) 1
    Pyrexia 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 3/45 (6.7%) 3 2/15 (13.3%) 2 1/15 (6.7%) 1
    Swelling 1/3 (33.3%) 1 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Hepatobiliary disorders
    Bile duct obstruction 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Hyperbilirubinaemia 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 3/45 (6.7%) 5 0/15 (0%) 0 0/15 (0%) 0
    Immune system disorders
    Rubber sensitivity 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0
    Seasonal allergy 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Infections and infestations
    Conjunctivitis 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Infected cyst 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Lung infection 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Mucosal infection 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 0/15 (0%) 0 1/15 (6.7%) 1
    Oral candidiasis 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 1/45 (2.2%) 1 0/15 (0%) 0 1/15 (6.7%) 1
    Pneumonia 1/3 (33.3%) 1 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Rash pustular 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Sinusitis 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 3/45 (6.7%) 3 0/15 (0%) 0 2/15 (13.3%) 2
    Tooth abscess 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0
    Tooth infection 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 2/45 (4.4%) 2 0/15 (0%) 0 1/15 (6.7%) 1
    Urinary tract infection 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 4/45 (8.9%) 4 0/15 (0%) 0 0/15 (0%) 0
    Viral upper respiratory tract infection 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 0/15 (0%) 0 2/15 (13.3%) 2
    Injury, poisoning and procedural complications
    Infusion related reaction 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 2/45 (4.4%) 3 2/15 (13.3%) 2 2/15 (13.3%) 2
    Wound 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Investigations
    Activated partial thromboplastin time prolonged 0/3 (0%) 0 0/3 (0%) 0 4/16 (25%) 5 1/45 (2.2%) 1 0/15 (0%) 0 1/15 (6.7%) 2
    Alanine aminotransferase increased 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 3 5/45 (11.1%) 5 2/15 (13.3%) 3 0/15 (0%) 0
    Aspartate aminotransferase increased 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 3 6/45 (13.3%) 7 1/15 (6.7%) 2 1/15 (6.7%) 1
    Blood albumin decreased 0/3 (0%) 0 0/3 (0%) 0 2/16 (12.5%) 3 2/45 (4.4%) 4 0/15 (0%) 0 0/15 (0%) 0
    Blood alkaline phosphatase increased 0/3 (0%) 0 0/3 (0%) 0 2/16 (12.5%) 5 5/45 (11.1%) 5 1/15 (6.7%) 2 0/15 (0%) 0
    Blood bilirubin increased 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 3/45 (6.7%) 7 1/15 (6.7%) 1 0/15 (0%) 0
    Blood calcium decreased 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Blood creatinine increased 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Blood glucose increased 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 1/45 (2.2%) 3 0/15 (0%) 0 0/15 (0%) 0
    Haemoglobin decreased 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    International normalised ratio increased 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 4/45 (8.9%) 6 0/15 (0%) 0 1/15 (6.7%) 3
    Paracentesis 1/3 (33.3%) 1 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Platelet count decreased 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 5/45 (11.1%) 7 0/15 (0%) 0 0/15 (0%) 0
    Weight decreased 0/3 (0%) 0 1/3 (33.3%) 1 0/16 (0%) 0 2/45 (4.4%) 2 3/15 (20%) 3 0/15 (0%) 0
    White blood cell count decreased 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 3/45 (6.7%) 8 0/15 (0%) 0 0/15 (0%) 0
    Metabolism and nutrition disorders
    Decreased appetite 2/3 (66.7%) 2 0/3 (0%) 0 8/16 (50%) 8 11/45 (24.4%) 13 3/15 (20%) 4 3/15 (20%) 3
    Dehydration 0/3 (0%) 0 0/3 (0%) 0 2/16 (12.5%) 2 2/45 (4.4%) 2 0/15 (0%) 0 1/15 (6.7%) 1
    Hyperglycaemia 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 6/45 (13.3%) 11 0/15 (0%) 0 2/15 (13.3%) 4
    Hyperkalaemia 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 2/45 (4.4%) 2 1/15 (6.7%) 1 0/15 (0%) 0
    Hyperuricaemia 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0
    Hypoalbuminaemia 0/3 (0%) 0 0/3 (0%) 0 3/16 (18.8%) 5 13/45 (28.9%) 21 0/15 (0%) 0 2/15 (13.3%) 2
    Hypocalcaemia 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 7/45 (15.6%) 11 0/15 (0%) 0 2/15 (13.3%) 3
    Hypokalaemia 0/3 (0%) 0 0/3 (0%) 0 2/16 (12.5%) 3 1/45 (2.2%) 1 0/15 (0%) 0 0/15 (0%) 0
    Hypomagnesaemia 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 3/45 (6.7%) 6 0/15 (0%) 0 0/15 (0%) 0
    Hyponatraemia 0/3 (0%) 0 0/3 (0%) 0 3/16 (18.8%) 5 9/45 (20%) 15 2/15 (13.3%) 2 1/15 (6.7%) 1
    Hypophosphataemia 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 4/45 (8.9%) 4 0/15 (0%) 0 0/15 (0%) 0
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/3 (0%) 0 1/3 (33.3%) 1 0/16 (0%) 0 4/45 (8.9%) 4 3/15 (20%) 3 3/15 (20%) 5
    Back pain 0/3 (0%) 0 1/3 (33.3%) 2 1/16 (6.3%) 1 5/45 (11.1%) 5 2/15 (13.3%) 2 3/15 (20%) 4
    Bone pain 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0
    Flank pain 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 1/45 (2.2%) 1 0/15 (0%) 0 0/15 (0%) 0
    Joint swelling 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Muscular weakness 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 2/45 (4.4%) 2 1/15 (6.7%) 1 0/15 (0%) 0
    Musculoskeletal chest pain 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 2/45 (4.4%) 3 1/15 (6.7%) 1 1/15 (6.7%) 1
    Musculoskeletal disorder 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Musculoskeletal pain 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 2/45 (4.4%) 2 2/15 (13.3%) 2 1/15 (6.7%) 1
    Myalgia 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 4/45 (8.9%) 4 1/15 (6.7%) 1 1/15 (6.7%) 1
    Pain in extremity 0/3 (0%) 0 1/3 (33.3%) 1 3/16 (18.8%) 4 2/45 (4.4%) 2 1/15 (6.7%) 1 0/15 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Nervous system disorders
    Dizziness 1/3 (33.3%) 1 1/3 (33.3%) 1 1/16 (6.3%) 1 3/45 (6.7%) 4 1/15 (6.7%) 1 1/15 (6.7%) 1
    Dysgeusia 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 1/45 (2.2%) 1 0/15 (0%) 0 1/15 (6.7%) 1
    Headache 0/3 (0%) 0 0/3 (0%) 0 5/16 (31.3%) 5 2/45 (4.4%) 2 4/15 (26.7%) 5 4/15 (26.7%) 4
    Hypoaesthesia 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 0/45 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0
    Memory impairment 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 0/15 (0%) 0 1/15 (6.7%) 1
    Paraesthesia 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0
    Peripheral sensory neuropathy 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 1/15 (6.7%) 1 0/15 (0%) 0
    Presyncope 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0
    Sciatica 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Psychiatric disorders
    Confusional state 0/3 (0%) 0 0/3 (0%) 0 2/16 (12.5%) 2 1/45 (2.2%) 1 0/15 (0%) 0 0/15 (0%) 0
    Depression 0/3 (0%) 0 1/3 (33.3%) 1 2/16 (12.5%) 2 2/45 (4.4%) 3 0/15 (0%) 0 0/15 (0%) 0
    Hallucination 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Insomnia 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 3/45 (6.7%) 3 1/15 (6.7%) 1 2/15 (13.3%) 2
    Mental status changes 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0
    Renal and urinary disorders
    Dysuria 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Haematuria 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 2/45 (4.4%) 2 1/15 (6.7%) 1 0/15 (0%) 0
    Micturition urgency 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 1/45 (2.2%) 1 0/15 (0%) 0 0/15 (0%) 0
    Nocturia 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Proteinuria 0/3 (0%) 0 0/3 (0%) 0 2/16 (12.5%) 2 2/45 (4.4%) 3 0/15 (0%) 0 0/15 (0%) 0
    Urinary retention 1/3 (33.3%) 1 0/3 (0%) 0 0/16 (0%) 0 2/45 (4.4%) 2 0/15 (0%) 0 0/15 (0%) 0
    Urinary tract pain 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 1/15 (6.7%) 1 0/15 (0%) 0
    Reproductive system and breast disorders
    Breast mass 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 1/15 (6.7%) 1 0/15 (0%) 0
    Erectile dysfunction 0/3 (0%) 0 0/3 (0%) 0 0/12 (0%) 0 0/34 (0%) 0 0/12 (0%) 0 1/9 (11.1%) 1
    Menorrhagia 0/3 (0%) 0 0/3 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0
    Penile oedema 0/3 (0%) 0 0/3 (0%) 0 1/12 (8.3%) 1 0/34 (0%) 0 0/12 (0%) 0 0/9 (0%) 0
    Scrotal oedema 0/3 (0%) 0 0/3 (0%) 0 1/12 (8.3%) 1 0/34 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Cough 0/3 (0%) 0 1/3 (33.3%) 2 3/16 (18.8%) 6 11/45 (24.4%) 12 4/15 (26.7%) 4 2/15 (13.3%) 2
    Dysphonia 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 2/45 (4.4%) 2 1/15 (6.7%) 1 2/15 (13.3%) 2
    Dyspnoea 1/3 (33.3%) 1 1/3 (33.3%) 2 2/16 (12.5%) 5 12/45 (26.7%) 21 8/15 (53.3%) 9 2/15 (13.3%) 2
    Dyspnoea exertional 0/3 (0%) 0 0/3 (0%) 0 2/16 (12.5%) 3 2/45 (4.4%) 2 2/15 (13.3%) 2 1/15 (6.7%) 1
    Epistaxis 0/3 (0%) 0 0/3 (0%) 0 2/16 (12.5%) 2 3/45 (6.7%) 3 0/15 (0%) 0 0/15 (0%) 0
    Haemoptysis 1/3 (33.3%) 1 0/3 (0%) 0 0/16 (0%) 0 2/45 (4.4%) 2 0/15 (0%) 0 0/15 (0%) 0
    Nasal congestion 0/3 (0%) 0 0/3 (0%) 0 2/16 (12.5%) 3 7/45 (15.6%) 7 1/15 (6.7%) 1 1/15 (6.7%) 1
    Oropharyngeal pain 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Pleural effusion 1/3 (33.3%) 1 0/3 (0%) 0 1/16 (6.3%) 1 1/45 (2.2%) 1 1/15 (6.7%) 1 0/15 (0%) 0
    Pulmonary embolism 0/3 (0%) 0 0/3 (0%) 0 2/16 (12.5%) 2 1/45 (2.2%) 1 0/15 (0%) 0 1/15 (6.7%) 1
    Respiratory tract congestion 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Rhinorrhoea 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Sinus congestion 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Upper-airway cough syndrome 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 1/15 (6.7%) 1 0/15 (0%) 0
    Wheezing 1/3 (33.3%) 1 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 2
    Skin and subcutaneous tissue disorders
    Alopecia 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 0/45 (0%) 0 1/15 (6.7%) 1 1/15 (6.7%) 1
    Dermatitis acneiform 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 2/45 (4.4%) 3 0/15 (0%) 0 1/15 (6.7%) 1
    Dry skin 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 3/45 (6.7%) 3 2/15 (13.3%) 2 0/15 (0%) 0
    Erythema 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0
    Erythema multiforme 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Hyperhidrosis 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Nail ridging 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Palmar-plantar erythrodysaesthesia syndrome 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0
    Photosensitivity reaction 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Pruritus 0/3 (0%) 0 0/3 (0%) 0 2/16 (12.5%) 2 5/45 (11.1%) 5 0/15 (0%) 0 1/15 (6.7%) 1
    Purpura 1/3 (33.3%) 1 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Rash 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 1/15 (6.7%) 1 1/15 (6.7%) 1
    Rash erythematous 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 1/15 (6.7%) 1 1/15 (6.7%) 2
    Rash maculo-papular 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 3/45 (6.7%) 3 0/15 (0%) 0 1/15 (6.7%) 1
    Rash pruritic 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 1/45 (2.2%) 1 0/15 (0%) 0 1/15 (6.7%) 1
    Skin disorder 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Skin ulcer 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Vascular disorders
    Deep vein thrombosis 0/3 (0%) 0 0/3 (0%) 0 2/16 (12.5%) 2 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Embolism 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Hypertension 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 11/45 (24.4%) 30 2/15 (13.3%) 2 2/15 (13.3%) 3
    Hypotension 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 0/15 (0%) 0 1/15 (6.7%) 1
    Jugular vein thrombosis 0/3 (0%) 0 0/3 (0%) 0 1/16 (6.3%) 1 0/45 (0%) 0 0/15 (0%) 0 0/15 (0%) 0
    Lymphoedema 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 1/45 (2.2%) 1 1/15 (6.7%) 1 0/15 (0%) 0
    Thrombophlebitis superficial 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1
    Venous thrombosis 0/3 (0%) 0 0/3 (0%) 0 0/16 (0%) 0 0/45 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release & can embargo communications regarding trial results for a period that is less than or equal to 30 days from the time submitted to sponsor for review. Sponsor can extend disclosure restriction for additional 60 days to protect intellectual property interests. If PI is unwilling to delay then PI shall remove the information that sponsor believes would jeopardize its IP interests

    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:
    NCT02082210
    Other Study ID Numbers:
    • 15246
    • I4C-MC-JTBF
    First Posted:
    Mar 10, 2014
    Last Update Posted:
    Dec 19, 2020
    Last Verified:
    Mar 1, 2018