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A Study of Necitumumab in the First-Line Treatment of Stage IV Squamous Non-Small Cell Lung Cancer (NSCLC)

Sponsor
Eli Lilly and Company (Industry)
Overall Status
Completed
CT.gov ID
NCT01763788
Collaborator
(none)
192
Enrollment
20
Locations
2
Arms
65.3
Actual Duration (Months)
9.6
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of the Phase 1b portion of the study is to investigate how the body tolerates necitumumab, in combination with gemcitabine and cisplatin chemotherapy as first line treatment in participants with Stage IV squamous NSCLC and to determine the recommended dose for the subsequent Phase 2 portion of the study.

The purpose of the Phase 2 portion of the study is to evaluate the efficacy of necitumumab in combination with gemcitabine and cisplatin chemotherapy in participants with Stage IV squamous NSCLC in a first-line setting.

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

Study Design

Study Type:
Interventional
Actual Enrollment :
192 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
An Open-Label, Multicenter, Phase 1b/2 Study to Evaluate Necitumumab in Combination With Gemcitabine and Cisplatin in the First-Line Treatment of Patients With Advanced (Stage IV) Squamous Non-Small Cell Lung Cancer (NSCLC)
Actual Study Start Date :
May 7, 2013
Actual Primary Completion Date :
Jun 28, 2017
Actual Study Completion Date :
Oct 17, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: Necitumumab + Gem and Cis

Phase 1b Dose Escalation: Necitumumab 800 milligram (mg) on Days 1 and 8 of every 21 day cycle, administered as an intravenous (IV) infusion. Gemcitabine (Gem) dose escalation of 1000 or 1250 milligram per square meter (mg/m^2) on Days 1 and 8 of every 21 day cycle, administered as an IV infusion for a maximum of 4 cycles. Cisplatin (Cis) 75 mg/m^2 on Day 1 of every 21 day cycle, administered as an IV infusion for a maximum of 4 cycles. Phase 2 Randomized: Necitumumab 800 mg on Days 1 and 8 of every 21 day cycle, administered as an IV infusion. Gemcitabine at fixed dose determined in Phase 1b (1000 or 1250 mg/m^2) on Days 1 and 8 of every 21 day cycle, administered as an IV infusion for a maximum of 4 cycles. Cisplatin 75 mg/m^2 on Day 1 of every 21 day cycle, administered as an IV infusion for a maximum of 4 cycles.

Drug: Necitumumab
Administered IV
Other Names:
  • IMC-11F8
  • LY3012211

    • Drug: Gemcitabine
    Administered IV
    Other Names:
  • LY188011

    • Drug: Cisplatin
    Administered IV
    Active Comparator: Gemcitabine + Cisplatin

    Phase 2 Randomized: Gemcitabine at fixed dose determined in Phase 1b (1000 to 1250 mg/m^2) on Day 1 and Day 8 of every 21 day cycle,administered as an IV infusion over approximately 30 minutes for a maximum of 4 cycles. Cisplatin 75 mg/m^2 on Day 1 of every 21 day cycle, administered as an IV infusion over approximately 120 minutes for a maximum of 4 cycles .

    Drug: Gemcitabine
    Administered IV
    Other Names:
  • LY188011

    • Drug: Cisplatin
    Administered IV

    Outcome Measures

    Primary Outcome Measures

    1. Phase 1b: Number of Participants With Dose Limiting Toxicities (DLTs) [Day 1 to Day 21 in Cycle 1 (Up To 21 days)]

      DLT was defined as any of the following events graded according to the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, when the event occurred within 21 days from Day 1 in Cycle 1 and was considered to be definitely or probably related to necitumumab and/or gemcitabine-cisplatin chemotherapy: Grade 4 neutropenia ≥ 7 days, Grade ≥ 3 febrile neutropenia except for transient febrile neutropenia (Grade 3 neutropenia with fever ≥ 38.5 degrees Celsius (°C) for ≤ 24 hours), Grade 3 thrombocytopenia requiring platelet substitution, Grade 4 thrombocytopenia, ≥Grade 3 nonhematologic toxicity (excluding nausea, vomiting, arthralgia, myalgia, asthenia, fatigue, diarrhea, constipation, anorexia), any toxicity leading to the omission of necitumumab on Day 8 or 15 (for participants for whom necitumumab was delayed from Days 8 to 15) during the Cycle 1.

    2. Phase 2: Overall Survival (OS) [From Date of Randomization until Death Due to Any Cause (Up To 39 Months)]

      OS defined as the time from the date of randomization to the date of death due to any cause. Participants who are alive at the time of study completion or are lost to follow-up will be censored at the time they were last known to be alive.

    Secondary Outcome Measures

    1. Phase 2: Progression Free Survival (PFS) [From Date of Randomization to Measured Progressive Disease or Death Due to Any Cause (Up To 39 Months)]

      PFS defined as time from date of randomization until first radiographic documentation of measured progressive disease(PD) defined by response evaluation criteria in solid tumors (RECIST) v1.1 or death from any cause. PD was at least 20% increase in sum of diameters of target lesions with reference being smallest sum on study and an absolute increase of at least 5 mm,or unequivocal progression of non-target lesions,or 1 or more new lesions.If participant does not have complete baseline disease assessment,PFS time censored at date of randomization,regardless of whether or not objectively determined disease progression or death observed for participant.If participant was not known to have died or have objective progression as of data inclusion cutoff date for analysis,the PFS time censored at last adequate tumor assessment date.The use of new anticancer therapy prior to occurrence of PD resulted in censoring at the date of last radiographic assessment prior to initiation of new therapy.

    2. Phase 1b: Percentage of Participants Who Achieve Best Overall Tumor Response of Complete Response or Partial Response (Objective Tumor Response Rate [ORR]) [Baseline to Measured Progressive Disease (Up To 39 Months)]

      ORR was the percentage of participants achieving a best overall response of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 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 longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of nontarget 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 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.

    3. Phase 2: Percentage of Participants Who Achieve Best Overall Tumor Response of Complete Response or Partial Response (Objective Tumor Response Rate [ORR]) [Baseline to Measured Progressive Disease (Up To 39 Months)]

      ORR was the percentage of participants achieving a best overall response of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 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 longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of nontarget 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 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.

    4. Phase 2: Time to Treatment Failure (TTF) [From Date of Randomization to Measured Progressive Disease, Death Due to Any Cause, Discontinuation of Treatment or Initiation of New Anticancer Therapy (Up To 39 Months)]

      TTF was time from the date of randomization until the date of the first observation of radiographically documented progressive disease (PD), death due to any cause, discontinuation of treatment for any reason, or initiation of new anticancer therapy. 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 to treatment failure was censored at the date of the last follow-up visit for participants who did not discontinue early, who were still alive, and who have not progressed.

    5. Phase 2: Change From Baseline in EuroQol 5-Dimensional 3 Level (EuroQol-5D-3L) Index Score [Baseline, Cycle 4 (Cycle = 3 weeks)]

      EQ-5D measures mobility, self-care, usual activities, pain/discomfort, anxiety/depression. 3 severity levels: no, some, severe problems. The index score was calculated from a set of item weights to derive a score on a theoretical scale of 0 to 1, with 1 representing the best health status and zero representing death based on item weights for the Japanese population. One Cycle = 3 weeks and it can be delayed up to 6 weeks.

    6. Phase 2: Change From Baseline in EuroQol 5-Dimensional 3 Level (EuroQol-5D-3L) Visual Analog Scale (VAS) [Baseline, Cycle 4 (Cycle = 3 weeks)]

      EQ-5D VAS allowed participants to rate their present health condition. Possible scores ranged from 0 (worst imaginable health state) to 100 (best imaginable health state). One Cycle = 3 weeks and it can be delayed up to 6 weeks.

    7. Phase 2: Change From Baseline in Lung Cancer Symptom Scale (LCSS) [Baseline, Cycle 4 (Cycle = 3 weeks)]

      The LCSS is a validated and reliable instrument to assess lung cancer-specific symptoms and their impact on QOL.The LCSS total score was defined as the mean of the 9 items of the scale and the average symptom burden index (ASBI) is defined as the mean of 6 symptom-specific lung cancer questions. Each of the 9 symptom or summary items is assessed on a 100-mm visual analogue scale (VAS), with 0 representing no symptoms or better QOL.

    8. Phase 1b: Pharmacokinetics (PK): Maximum Concentration (Cmax) of Necitumumab [Cycle 1 (C1) Day 1 (D1) and C3 D1: Predose, End-of-infusion and 1, 3, 6, 24, 96, 168 h post-end-of-infusion]

      The Cmax is observed maximum serum concentration, taken directly from the serum concentration-time profile.

    9. Phase 1b: PK: Cmax of Gemcitabine and Cisplatin [Gemcitabine: Cycle 1(C1) Day1(D1): Predose, End-of-infusion and 0.5, 1, 2 h post-end-of-infusion; Cisplatin:C1 D1: Predose, End-of-infusion and 3, 21, 93, 165 h post-end-of-infusion]

      The Cmax is observed maximum plasma concentration, taken directly from the plasma concentration-time profile.

    10. Phase 1b: PK: Area Under the Serum Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Necitumumab [Cycle 1 (C1) Day 1 (D1) and C3 D1: Predose, End-of-infusion and 1, 3, 6, 24, 96, 168 h post-end-of-infusion]

      The AUC(0-infinity) is area under the serum concentration-time curve from time zero to infinite time.

    11. Phase 1b: PK: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Gemcitabine and Cisplatin [Gemcitabine: C1D1: Predose, End-of-infusion and 0.5, 1, 2 h post-end-of-infusion; Cisplatin:C1D1: Predose, End-of-infusion and 3, 21, 93, 165 h post-end-of-infusion]

      The AUC(0-infinity) is area under the plasma concentration-time curve from time zero to infinite time.

    12. Phase 2: PK: Minimum Concentration (Ctrough) of Necitumumab [Predose Day 1 of Cycle 1, 2, 3, 4, and every 2 cycles after Cycle 5]

      The minimum observed serum concentration (Ctrough) of Necitumumab was evaluated.

    13. Phase 2: Number of Participants With Serum Anti-Necitumumab Antibody Assessment (Immunogenicity) [Baseline up to 30 Days Post Last Infusion (estimated up to 39 months)]

      A participant was considered to have an anti-Necitumumab antibody response if anti-drug antibodies (ADA) were detected at any time point.

    Eligibility Criteria

    Criteria

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

    • Squamous Non-Small Cell Lung Cancer Disease (NSCLC)

    • Clinical Stage IV NSCLC

    • Measurable or nonmeasurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

    • Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1

    • No prior systematic chemotherapy, targeted therapy, surgery and chest radiotherapy

    • Ha resolution to Grade less than or equal to (≤) 1 by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0, of all clinically significant toxic effects of prior therapy for other than NSCLC

    • Adequate-organ function defined as:

    • Total bilirubin ≤1.5 x the upper limit of normal value (ULN)

    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN

    • Serum creatinine ≤ 1.2 x ULN or calculated creatinine clearance (CrCL)>50 milliliter per minute (mL/min) (per the Cockcroft Gault formula or equivalent and/or 24-hour urine collection)

    • Absolute neutrophil count (ANC) greater than or equal to ≥1.5 x 10^3/μL(microliter)

    • Hemoglobin ≥10.0 g/dL(gram per deciliter)

    • Platelets ≥100 x 10^3/μL

    • At least 20 years of age

    • Estimated life expectancy of at least 12 weeks

    • A formalin-fixed, paraffin-embedded tumor tissue block or a minimum of 5 unstained slides of tumor sample prior to randomization for the evaluation of epidermal growth factor receptor (EGFR) protein expression (IHC).

    • If women: surgically sterile, postmenopausal, or compliant with a highly effective contraceptive method (failure rate <1%) during and for 6 months after the treatment period (oral hormonal contraception alone is not considered highly effective and must be used in combination with a barrier method). If men: surgically sterile or compliant with a highly effective contraceptive regimen during and for 6 months after the treatment period.

    • Has provided signed informed consent

    Exclusion Criteria:

    • Has enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use of a drug or device

    • Participant has undergone major surgery within 28 days prior to enrollment or have planned major surgery, subcutaneous venous access device placement within 7 days prior to enrollment Phase 1b) or randomization (Phase 2).

    • Has undergone any prior radiation therapy, except for Gamma Knife radiation and palliative radiation treatment at least 14 days have elapsed from last radiation treatment prior to enrollment (Phase 1b) or randomization (Phase 2)

    • Has brain metastases that are symptomatic or require surgery, medication and radiotherapy except for stereotactic irradiation

    • Has superior vena cava syndrome

    • Has clinically relevant coronary artery disease or uncontrolled congestive - heart failure

    • Participant has uncontrolled hypertension defined as systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥90 mmHg despite standard medical management.

    • Has diabetes requiring insulin

    • Has an angina or has experienced myocardial infarction within 6 months prior to enrollment (Phase 1b) or randomization (Phase 2)

    • Has an Acquired Immunodeficiency Syndrome (AIDS)-related illness or have evidence of or test positive test results for human immunodeficiency virus (HIV)

    • Has evidence of or test positive test results for hepatitis B, or hepatitis C virus antibodies

    • Has a known allergy and history of hypersensitivity reaction to any of the treatment components, including any ingredient used in the formulation of necitumumab, or any other contraindication to one of the administered treatments

    • Has significant third-space fluid retention requiring drainage

    • Has history of interstitial pneumonitis

    • Has an ongoing or active infection

    • Has a history of significant neurological or psychiatric disorders

    • Has a Grade 2 peripheral neuropathy

    • Pregnant (confirmed within 7 days prior to enrollment [Phase 1b] or randomization [Phase 2]), or breastfeeding

    • Has known history of drug abuse

    • Assessed as inadequate for the study by the investigator or sub investigator

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Aichi Japan 464-8681
    2 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Chiba Japan 277 8577
    3 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Ehime Japan 791-0280
    4 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Fukuoka Japan 830-0011
    5 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Hokkaido Japan 070-8644
    6 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Hyogo Japan 650-0047
    7 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Ishikawa Japan 920-8641
    8 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Kanagawa Japan 240-0062
    9 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Koto-ku Japan 135-8550
    10 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Miyagi Japan 980-8574
    11 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Nagasaki Japan 852-8501
    12 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Niigata Japan 951-8566
    13 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Oita Japan 8795593
    14 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Okayama Japan 700-8558
    15 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Osaka Japan 573-1191
    16 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Saitama Japan 362-0806
    17 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Sendai Japan 980-0873
    18 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Shizuoka Japan 411-8777
    19 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Wakayama Japan 641-8510
    20 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Yamaguchi Japan 755-0241

    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

    Publications

    None provided.
    Responsible Party:
    Eli Lilly and Company
    ClinicalTrials.gov Identifier:
    NCT01763788
    Other Study ID Numbers:
    • 14461
    • I4X-JE-JFCM
    First Posted:
    Jan 9, 2013
    Last Update Posted:
    Oct 25, 2019
    Last Verified:
    Dec 1, 2018
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Additional relevant MeSH terms:
    Lung Neoplasms
    Carcinoma, Non-Small-Cell Lung
    Gemcitabine
    Necitumumab

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail Completers included participants who died from any cause and participants who were alive and on study (but off treatment) at study conclusion.
    Arm/Group Title Phase 1b: Cohort 1 Phase 1b: Cohort 2 Phase 2: GC+N (Gemcitabine, Cisplatin + Necitumumab) Phase 2: GC (Gemcitabine, Cisplatin)
    Arm/Group Description Gemcitabine at a dose of 1000 mg/m^2 (milligrams per square meter) was administered over approximately 30 minutes intravenously (IV) on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle. Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle. Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle. Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles.
    Period Title: Overall Study
    STARTED 3 6 91 92
    Received at Least 1dose of Study Drug 3 6 90 91
    COMPLETED 3 6 90 92
    NOT COMPLETED 0 0 1 0

    Baseline Characteristics

    Arm/Group Title Phase 1b: Cohort 1 Phase 1b: Cohort 2 Phase 2: GC+N (Gemcitabine, Cisplatin + Necitumumab) Phase 2: GC (Gemcitabine, Cisplatin) Total
    Arm/Group Description Gemcitabine at a dose of 1000 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle. Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle. Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle. Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Total of all reporting groups
    Overall Participants 3 6 90 91 190
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    71.0
    66.0
    66.5
    65.0
    66.0
    Sex: Female, Male (Count of Participants)
    Female
    0
    0%
    1
    16.7%
    11
    12.2%
    10
    11%
    22
    11.6%
    Male
    3
    100%
    5
    83.3%
    79
    87.8%
    81
    89%
    168
    88.4%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    3
    100%
    6
    100%
    90
    100%
    89
    97.8%
    188
    98.9%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    White
    0
    0%
    0
    0%
    0
    0%
    1
    1.1%
    1
    0.5%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    1
    1.1%
    1
    0.5%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%

    Outcome Measures

    1. Primary Outcome
    Title Phase 1b: Number of Participants With Dose Limiting Toxicities (DLTs)
    Description DLT was defined as any of the following events graded according to the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, when the event occurred within 21 days from Day 1 in Cycle 1 and was considered to be definitely or probably related to necitumumab and/or gemcitabine-cisplatin chemotherapy: Grade 4 neutropenia ≥ 7 days, Grade ≥ 3 febrile neutropenia except for transient febrile neutropenia (Grade 3 neutropenia with fever ≥ 38.5 degrees Celsius (°C) for ≤ 24 hours), Grade 3 thrombocytopenia requiring platelet substitution, Grade 4 thrombocytopenia, ≥Grade 3 nonhematologic toxicity (excluding nausea, vomiting, arthralgia, myalgia, asthenia, fatigue, diarrhea, constipation, anorexia), any toxicity leading to the omission of necitumumab on Day 8 or 15 (for participants for whom necitumumab was delayed from Days 8 to 15) during the Cycle 1.
    Time Frame Day 1 to Day 21 in Cycle 1 (Up To 21 days)

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants who received at least one dose of study drug during study Phase 1b.
    Arm/Group Title Phase 1b: Cohort 1 Phase 1b: Cohort 2
    Arm/Group Description Gemcitabine at a dose of 1000 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle. Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle.
    Measure Participants 3 6
    Count of Participants [Participants]
    0
    0%
    0
    0%
    2. Primary Outcome
    Title Phase 2: Overall Survival (OS)
    Description OS defined as the time from the date of randomization to the date of death due to any cause. Participants who are alive at the time of study completion or are lost to follow-up will be censored at the time they were last known to be alive.
    Time Frame From Date of Randomization until Death Due to Any Cause (Up To 39 Months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug during study Phase 2. Censored participants in the GC+N Arm = 27 and in the GC Arm = 17.
    Arm/Group Title Phase 2: GC+N (Gemcitabine, Cisplatin + Necitumumab) Phase 2: GC (Gemcitabine, Cisplatin)
    Arm/Group Description Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle. Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles.
    Measure Participants 90 91
    Median (95% Confidence Interval) [Months]
    14.92
    10.84
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 1b: Cohort 1, Phase 1b: Cohort 2
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0161
    Comments
    Method Stratified Log Rank
    Comments
    Method of Estimation Estimation Parameter Stratified Hazard Ratio
    Estimated Value 0.656
    Confidence Interval (2-Sided) 95%
    0.465 to 0.926
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title Phase 2: Progression Free Survival (PFS)
    Description PFS defined as time from date of randomization until first radiographic documentation of measured progressive disease(PD) defined by response evaluation criteria in solid tumors (RECIST) v1.1 or death from any cause. PD was at least 20% increase in sum of diameters of target lesions with reference being smallest sum on study and an absolute increase of at least 5 mm,or unequivocal progression of non-target lesions,or 1 or more new lesions.If participant does not have complete baseline disease assessment,PFS time censored at date of randomization,regardless of whether or not objectively determined disease progression or death observed for participant.If participant was not known to have died or have objective progression as of data inclusion cutoff date for analysis,the PFS time censored at last adequate tumor assessment date.The use of new anticancer therapy prior to occurrence of PD resulted in censoring at the date of last radiographic assessment prior to initiation of new therapy.
    Time Frame From Date of Randomization to Measured Progressive Disease or Death Due to Any Cause (Up To 39 Months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study during study Phase 2. Censored participants in the GC+N Arm = 6 and in the GC Arm = 10.
    Arm/Group Title Phase 2: GC+N (Gemcitabine, Cisplatin + Necitumumab) Phase 2: GC (Gemcitabine, Cisplatin)
    Arm/Group Description Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle. Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles.
    Measure Participants 90 91
    Median (95% Confidence Interval) [Months]
    4.21
    4.01
    4. Secondary Outcome
    Title Phase 1b: Percentage of Participants Who Achieve Best Overall Tumor Response of Complete Response or Partial Response (Objective Tumor Response Rate [ORR])
    Description ORR was the percentage of participants achieving a best overall response of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 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 longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of nontarget 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 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.
    Time Frame Baseline to Measured Progressive Disease (Up To 39 Months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug during study Phase 1b.
    Arm/Group Title Phase 1b: Cohort 1 Phase 1b: Cohort 2
    Arm/Group Description Gemcitabine at a dose of 1000 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle. Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle.
    Measure Participants 3 6
    Number (95% Confidence Interval) [percentage of participants]
    0.0
    0%
    83.3
    1388.3%
    5. Secondary Outcome
    Title Phase 2: Percentage of Participants Who Achieve Best Overall Tumor Response of Complete Response or Partial Response (Objective Tumor Response Rate [ORR])
    Description ORR was the percentage of participants achieving a best overall response of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 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 longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of nontarget 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 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.
    Time Frame Baseline to Measured Progressive Disease (Up To 39 Months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug during study Phase 2.
    Arm/Group Title Phase 2: GC+N (Gemcitabine, Cisplatin + Necitumumab) Phase 2: GC (Gemcitabine, Cisplatin)
    Arm/Group Description Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle. Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles.
    Measure Participants 90 91
    Number (95% Confidence Interval) [percentage of participants]
    51.1
    1703.3%
    20.9
    348.3%
    6. Secondary Outcome
    Title Phase 2: Time to Treatment Failure (TTF)
    Description TTF was time from the date of randomization until the date of the first observation of radiographically documented progressive disease (PD), death due to any cause, discontinuation of treatment for any reason, or initiation of new anticancer therapy. 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 to treatment failure was censored at the date of the last follow-up visit for participants who did not discontinue early, who were still alive, and who have not progressed.
    Time Frame From Date of Randomization to Measured Progressive Disease, Death Due to Any Cause, Discontinuation of Treatment or Initiation of New Anticancer Therapy (Up To 39 Months)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug during study Phase 2. Censored participants in the GC+N Arm = 1 and in the GC Arm = 0.
    Arm/Group Title Phase 2: GC+N (Gemcitabine, Cisplatin + Necitumumab) Phase 2: GC (Gemcitabine, Cisplatin)
    Arm/Group Description Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle. Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles.
    Measure Participants 90 91
    Median (95% Confidence Interval) [Months]
    4.16
    3.75
    7. Secondary Outcome
    Title Phase 2: Change From Baseline in EuroQol 5-Dimensional 3 Level (EuroQol-5D-3L) Index Score
    Description EQ-5D measures mobility, self-care, usual activities, pain/discomfort, anxiety/depression. 3 severity levels: no, some, severe problems. The index score was calculated from a set of item weights to derive a score on a theoretical scale of 0 to 1, with 1 representing the best health status and zero representing death based on item weights for the Japanese population. One Cycle = 3 weeks and it can be delayed up to 6 weeks.
    Time Frame Baseline, Cycle 4 (Cycle = 3 weeks)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug and had evaluable baseline and post-baseline EQ-5D data during study Phase 2.
    Arm/Group Title Phase 2: GC+N (Gemcitabine, Cisplatin + Necitumumab) Phase 2: GC (Gemcitabine, Cisplatin)
    Arm/Group Description Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle. Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles.
    Measure Participants 77 61
    Mean (Standard Deviation) [Score on a scale]
    0.04
    (0.16)
    0.03
    (0.17)
    8. Secondary Outcome
    Title Phase 2: Change From Baseline in EuroQol 5-Dimensional 3 Level (EuroQol-5D-3L) Visual Analog Scale (VAS)
    Description EQ-5D VAS allowed participants to rate their present health condition. Possible scores ranged from 0 (worst imaginable health state) to 100 (best imaginable health state). One Cycle = 3 weeks and it can be delayed up to 6 weeks.
    Time Frame Baseline, Cycle 4 (Cycle = 3 weeks)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug and had had evaluable baseline and post-baseline EQ-5D data during study Phase 2.
    Arm/Group Title Phase 2: GC+N (Gemcitabine, Cisplatin + Necitumumab) Phase 2: GC (Gemcitabine, Cisplatin)
    Arm/Group Description Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle. Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles.
    Measure Participants 77 61
    Mean (Standard Deviation) [units on a scale]
    7.81
    (18.90)
    11.10
    (18.03)
    9. Secondary Outcome
    Title Phase 2: Change From Baseline in Lung Cancer Symptom Scale (LCSS)
    Description The LCSS is a validated and reliable instrument to assess lung cancer-specific symptoms and their impact on QOL.The LCSS total score was defined as the mean of the 9 items of the scale and the average symptom burden index (ASBI) is defined as the mean of 6 symptom-specific lung cancer questions. Each of the 9 symptom or summary items is assessed on a 100-mm visual analogue scale (VAS), with 0 representing no symptoms or better QOL.
    Time Frame Baseline, Cycle 4 (Cycle = 3 weeks)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug had evaluable baseline and post-baseline LCSS data. One Cycle = 3 weeks and it can be delayed up to 6 weeks.
    Arm/Group Title Phase 2: GC+N (Gemcitabine, Cisplatin + Necitumumab) Phase 2: GC (Gemcitabine, Cisplatin)
    Arm/Group Description Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle. Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles.
    Measure Participants 90 91
    Loss of Appetite
    -4.48
    (26.20)
    -9.03
    (29.32)
    Fatigue
    -5.42
    (26.63)
    -4.02
    (26.47)
    Cough
    -18.00
    (24.17)
    -15.82
    (30.59)
    Dyspnea
    -5.14
    (22.51)
    -5.08
    (24.51)
    Hemoptysis
    -4.75
    (21.75)
    -4.10
    (16.46)
    Pain
    -10.68
    (22.07)
    -12.38
    (26.99)
    Overall Symptoms
    -11.62
    (23.20)
    -9.56
    (24.61)
    Interference
    -6.92
    (26.70)
    -5.93
    (29.78)
    Quality of Life
    -5.10
    (23.83)
    -15.43
    (28.46)
    Average Symptom Burden Index (ASBI)
    -8.08
    (12.81)
    -8.40
    (16.24)
    LCSS Total Score
    -8.01
    (13.64)
    -9.04
    (16.32)
    10. Secondary Outcome
    Title Phase 1b: Pharmacokinetics (PK): Maximum Concentration (Cmax) of Necitumumab
    Description The Cmax is observed maximum serum concentration, taken directly from the serum concentration-time profile.
    Time Frame Cycle 1 (C1) Day 1 (D1) and C3 D1: Predose, End-of-infusion and 1, 3, 6, 24, 96, 168 h post-end-of-infusion

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants who had adequate data to calculate at least 1 PK parameter during study Phase 1b. In cohort 1 (cycle 3), zero participants were analyzed because no data was collected for the outcome measure.
    Arm/Group Title Phase 1b: Cohort 1 Phase 1b: Cohort 2
    Arm/Group Description Gemcitabine at a dose of 1000 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle. Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle.
    Measure Participants 3 6
    Cycle 1
    454
    (6)
    371
    (32)
    Cycle 3
    372
    (15)
    11. Secondary Outcome
    Title Phase 1b: PK: Cmax of Gemcitabine and Cisplatin
    Description The Cmax is observed maximum plasma concentration, taken directly from the plasma concentration-time profile.
    Time Frame Gemcitabine: Cycle 1(C1) Day1(D1): Predose, End-of-infusion and 0.5, 1, 2 h post-end-of-infusion; Cisplatin:C1 D1: Predose, End-of-infusion and 3, 21, 93, 165 h post-end-of-infusion

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants who had adequate data to calculate at least 1 PK parameter during study Phase 1b.
    Arm/Group Title Phase 1b: Cohort 1 Phase 1b: Cohort 2
    Arm/Group Description Gemcitabine at a dose of 1000 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle. Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle.
    Measure Participants 3 6
    Gemcitabine
    17400
    (8)
    26000
    (16)
    Cisplatin
    3740
    (14)
    3980
    (10)
    12. Secondary Outcome
    Title Phase 1b: PK: Area Under the Serum Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Necitumumab
    Description The AUC(0-infinity) is area under the serum concentration-time curve from time zero to infinite time.
    Time Frame Cycle 1 (C1) Day 1 (D1) and C3 D1: Predose, End-of-infusion and 1, 3, 6, 24, 96, 168 h post-end-of-infusion

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants who had adequate data to calculate at least 1 PK parameter during study Phase 1b. In cohort 1 and 2 (cycle 3), zero participants were analyzed because no data was collected for the outcome measure.
    Arm/Group Title Phase 1b: Cohort 1 Phase 1b: Cohort 2
    Arm/Group Description Gemcitabine at a dose of 1000 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle. Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle.
    Measure Participants 3 6
    Cycle 1
    NA
    (NA)
    38900
    (28)
    13. Secondary Outcome
    Title Phase 1b: PK: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Gemcitabine and Cisplatin
    Description The AUC(0-infinity) is area under the plasma concentration-time curve from time zero to infinite time.
    Time Frame Gemcitabine: C1D1: Predose, End-of-infusion and 0.5, 1, 2 h post-end-of-infusion; Cisplatin:C1D1: Predose, End-of-infusion and 3, 21, 93, 165 h post-end-of-infusion

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants who had adequate data to calculate at least 1 PK parameter during study Phase 1b. In cohort 1 (cisplatin), zero participants were analyzed because no data was collected for the outcome measure.
    Arm/Group Title Phase 1b: Cohort 1 Phase 1b: Cohort 2
    Arm/Group Description Gemcitabine at a dose of 1000 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle. Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle.
    Measure Participants 3 6
    Gemcitabine
    8710
    (7)
    13300
    (19)
    Cisplatin
    NA
    (NA)
    14. Secondary Outcome
    Title Phase 2: PK: Minimum Concentration (Ctrough) of Necitumumab
    Description The minimum observed serum concentration (Ctrough) of Necitumumab was evaluated.
    Time Frame Predose Day 1 of Cycle 1, 2, 3, 4, and every 2 cycles after Cycle 5

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants who had adequate data to calculate at least 1 PK parameter during study Phase 2.
    Arm/Group Title Phase 2: GC+N (Gemcitabine, Cisplatin + Necitumumab)
    Arm/Group Description Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle.
    Measure Participants 90
    Dose 3
    77.9
    (30)
    Dose 5
    110
    (32)
    Dose 7
    130
    (36)
    Dose 9
    137
    (41)
    Dose 13
    145
    (48)
    Dose 17
    120
    (59)
    Dose 21
    194
    (44)
    15. Secondary Outcome
    Title Phase 2: Number of Participants With Serum Anti-Necitumumab Antibody Assessment (Immunogenicity)
    Description A participant was considered to have an anti-Necitumumab antibody response if anti-drug antibodies (ADA) were detected at any time point.
    Time Frame Baseline up to 30 Days Post Last Infusion (estimated up to 39 months)

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants who received at least 1 dose of drug and had evaluable data for antibodies during study Phase 2.
    Arm/Group Title Phase 2: GC+N (Gemcitabine, Cisplatin + Necitumumab)
    Arm/Group Description Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle.
    Measure Participants 90
    Count of Participants [Participants]
    4
    133.3%

    Adverse Events

    Time Frame Up To 39 Months
    Adverse Event Reporting Description All enrolled participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants at risk adjusted accordingly.
    Arm/Group Title Phase 1b: Cohort 1 Phase 1b: Cohort 2 Phase 2: GC+N (Gemcitabine, Cisplatin + Necitumumab) Phase 2: GC (Gemcitabine, Cisplatin)
    Arm/Group Description Gemcitabine at a dose of 1000 mg/m^2 (milligrams per square meter) was administered over approximately 30 minutes intravenously (IV) on Days 1 and 8 of each cycle for a maximum of 4 cycles. Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles. Necitumumab at a dose of 800 mg was administered over approximately 50 minutes intravenously IV on Days 1 and 8 of each 3-week cycle. Gemcitabine at a dose of 1250 mg/m^2 was administered over approximately 30 minutes IV on Days 1 and 8 of each cycle for a maximum of 4 cycles. Cisplatin at a dose of 75 mg/m^2 was administered over approximately 120 minutes IV on Day 1 for a maximum of 4 cycles.
    All Cause Mortality
    Phase 1b: Cohort 1 Phase 1b: Cohort 2 Phase 2: GC+N (Gemcitabine, Cisplatin + Necitumumab) Phase 2: GC (Gemcitabine, Cisplatin)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/3 (0%) 0/6 (0%) 63/90 (70%) 74/91 (81.3%)
    Serious Adverse Events
    Phase 1b: Cohort 1 Phase 1b: Cohort 2 Phase 2: GC+N (Gemcitabine, Cisplatin + Necitumumab) Phase 2: GC (Gemcitabine, Cisplatin)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/3 (33.3%) 0/6 (0%) 32/90 (35.6%) 22/91 (24.2%)
    Blood and lymphatic system disorders
    Bone marrow toxicity 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Febrile neutropenia 0/3 (0%) 0 0/6 (0%) 0 6/90 (6.7%) 6 0/91 (0%) 0
    Thrombocytopenia 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Gastrointestinal disorders
    Abdominal hernia 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Diarrhoea 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Diverticular perforation 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 1/91 (1.1%) 1
    Duodenal ulcer 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Gastric ulcer 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Gastric ulcer haemorrhage 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Gastrointestinal haemorrhage 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Lower gastrointestinal haemorrhage 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 2/91 (2.2%) 2
    General disorders
    Fatigue 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Pain 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Pyrexia 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Infections and infestations
    Appendicitis 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Diverticulitis 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Infection 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Lung infection 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 2 3/91 (3.3%) 3
    Pneumonia 0/3 (0%) 0 0/6 (0%) 0 6/90 (6.7%) 6 1/91 (1.1%) 1
    Retroperitoneal abscess 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Septic shock 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Urinary tract infection 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 2
    Injury, poisoning and procedural complications
    Compression fracture 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Tracheal haemorrhage 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Investigations
    Neutrophil count decreased 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Metabolism and nutrition disorders
    Decreased appetite 0/3 (0%) 0 0/6 (0%) 0 3/90 (3.3%) 3 0/91 (0%) 0
    Electrolyte imbalance 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gastric cancer 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Lymphangiosis carcinomatosa 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Tumour pain 1/3 (33.3%) 1 0/6 (0%) 0 0/90 (0%) 0 0/91 (0%) 0
    Nervous system disorders
    Cerebral ischaemia 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Optic neuritis 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Presyncope 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Spinal cord paralysis 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Syncope 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Psychiatric disorders
    Delirium 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Panic disorder 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Renal and urinary disorders
    Renal impairment 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Haemoptysis 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Interstitial lung disease 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Pneumothorax 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Pulmonary artery thrombosis 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Pulmonary embolism 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Pulmonary haemorrhage 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Vascular disorders
    Deep vein thrombosis 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 2 1/91 (1.1%) 1
    Shock 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Superior vena cava syndrome 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Other (Not Including Serious) Adverse Events
    Phase 1b: Cohort 1 Phase 1b: Cohort 2 Phase 2: GC+N (Gemcitabine, Cisplatin + Necitumumab) Phase 2: GC (Gemcitabine, Cisplatin)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/3 (100%) 6/6 (100%) 90/90 (100%) 91/91 (100%)
    Blood and lymphatic system disorders
    Anaemia 1/3 (33.3%) 1 5/6 (83.3%) 8 43/90 (47.8%) 55 53/91 (58.2%) 65
    Febrile neutropenia 0/3 (0%) 0 0/6 (0%) 0 6/90 (6.7%) 6 3/91 (3.3%) 3
    Haemorrhagic diathesis 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Leukopenia 1/3 (33.3%) 3 4/6 (66.7%) 10 5/90 (5.6%) 10 2/91 (2.2%) 2
    Neutropenia 1/3 (33.3%) 3 3/6 (50%) 8 13/90 (14.4%) 19 13/91 (14.3%) 25
    Thrombocytopenia 2/3 (66.7%) 4 4/6 (66.7%) 4 2/90 (2.2%) 2 7/91 (7.7%) 9
    Cardiac disorders
    Angina pectoris 0/3 (0%) 0 1/6 (16.7%) 1 1/90 (1.1%) 1 0/91 (0%) 0
    Atrial fibrillation 0/3 (0%) 0 1/6 (16.7%) 1 1/90 (1.1%) 1 1/91 (1.1%) 1
    Atrial tachycardia 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Atrioventricular block second degree 0/3 (0%) 0 1/6 (16.7%) 1 0/90 (0%) 0 0/91 (0%) 0
    Bundle branch block left 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Conduction disorder 1/3 (33.3%) 1 1/6 (16.7%) 1 0/90 (0%) 0 0/91 (0%) 0
    Palpitations 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Supraventricular extrasystoles 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Ear and labyrinth disorders
    Hypoacusis 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 2 2/91 (2.2%) 2
    Tinnitus 0/3 (0%) 0 0/6 (0%) 0 3/90 (3.3%) 3 7/91 (7.7%) 8
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 2/91 (2.2%) 2
    Eye disorders
    Cataract 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 2 0/91 (0%) 0
    Chalazion 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 2 0/91 (0%) 0
    Conjunctival haemorrhage 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Dry eye 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Eye discharge 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Eye disorder 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Lacrimation increased 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Optic nerve disorder 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Trichiasis 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Gastrointestinal disorders
    Abdominal discomfort 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 2 1/91 (1.1%) 1
    Abdominal distension 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Abdominal pain 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 2 1/91 (1.1%) 1
    Abdominal pain upper 0/3 (0%) 0 0/6 (0%) 0 5/90 (5.6%) 7 2/91 (2.2%) 2
    Anal erosion 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Anal fistula 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Cheilitis 0/3 (0%) 0 0/6 (0%) 0 6/90 (6.7%) 6 2/91 (2.2%) 2
    Constipation 2/3 (66.7%) 2 4/6 (66.7%) 5 58/90 (64.4%) 76 53/91 (58.2%) 74
    Dental caries 0/3 (0%) 0 1/6 (16.7%) 1 0/90 (0%) 0 1/91 (1.1%) 1
    Diarrhoea 1/3 (33.3%) 1 2/6 (33.3%) 2 26/90 (28.9%) 43 21/91 (23.1%) 23
    Dry mouth 0/3 (0%) 0 1/6 (16.7%) 1 0/90 (0%) 0 0/91 (0%) 0
    Duodenal ulcer 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Dyspepsia 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Enterocolitis 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 1/91 (1.1%) 1
    Gastritis 0/3 (0%) 0 0/6 (0%) 0 3/90 (3.3%) 3 1/91 (1.1%) 1
    Gastrointestinal disorder 1/3 (33.3%) 1 0/6 (0%) 0 1/90 (1.1%) 1 1/91 (1.1%) 1
    Gastrooesophageal reflux disease 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 2/91 (2.2%) 2
    Haemorrhoidal haemorrhage 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Haemorrhoids 0/3 (0%) 0 0/6 (0%) 0 3/90 (3.3%) 3 1/91 (1.1%) 1
    Nausea 2/3 (66.7%) 7 5/6 (83.3%) 10 55/90 (61.1%) 111 54/91 (59.3%) 95
    Oesophageal stenosis 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Oesophagitis 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Oral pain 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 1/91 (1.1%) 1
    Periodontal disease 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 1/91 (1.1%) 1
    Proctalgia 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Stomatitis 2/3 (66.7%) 3 3/6 (50%) 5 37/90 (41.1%) 48 11/91 (12.1%) 11
    Toothache 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 2 1/91 (1.1%) 1
    Vomiting 0/3 (0%) 0 3/6 (50%) 5 17/90 (18.9%) 28 16/91 (17.6%) 22
    General disorders
    Asthenia 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 3 0/91 (0%) 0
    Chest discomfort 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Chest pain 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 2 0/91 (0%) 0
    Chills 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 1/91 (1.1%) 1
    Extravasation 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 2 0/91 (0%) 0
    Face oedema 0/3 (0%) 0 0/6 (0%) 0 4/90 (4.4%) 7 6/91 (6.6%) 7
    Fatigue 1/3 (33.3%) 1 3/6 (50%) 4 17/90 (18.9%) 39 13/91 (14.3%) 18
    Hypothermia 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Influenza like illness 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 1/91 (1.1%) 1
    Infusion site extravasation 0/3 (0%) 0 0/6 (0%) 0 4/90 (4.4%) 4 4/91 (4.4%) 5
    Infusion site reaction 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 1/91 (1.1%) 1
    Injection site pain 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 3 2/91 (2.2%) 2
    Injection site reaction 0/3 (0%) 0 0/6 (0%) 0 4/90 (4.4%) 7 1/91 (1.1%) 1
    Localised oedema 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Malaise 1/3 (33.3%) 1 2/6 (33.3%) 2 34/90 (37.8%) 49 32/91 (35.2%) 44
    Mucosal inflammation 0/3 (0%) 0 0/6 (0%) 0 3/90 (3.3%) 5 0/91 (0%) 0
    Non-cardiac chest pain 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Oedema 0/3 (0%) 0 1/6 (16.7%) 1 1/90 (1.1%) 1 0/91 (0%) 0
    Oedema peripheral 0/3 (0%) 0 0/6 (0%) 0 10/90 (11.1%) 16 10/91 (11%) 12
    Pain 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 5/91 (5.5%) 5
    Pyrexia 0/3 (0%) 0 0/6 (0%) 0 18/90 (20%) 18 15/91 (16.5%) 21
    Hepatobiliary disorders
    Hepatic function abnormal 0/3 (0%) 0 0/6 (0%) 0 3/90 (3.3%) 3 2/91 (2.2%) 2
    Infections and infestations
    Angular cheilitis 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 2 0/91 (0%) 0
    Bronchitis 1/3 (33.3%) 1 0/6 (0%) 0 2/90 (2.2%) 3 1/91 (1.1%) 1
    Candida infection 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Conjunctivitis 1/3 (33.3%) 1 1/6 (16.7%) 2 7/90 (7.8%) 9 1/91 (1.1%) 1
    Dacryocanaliculitis 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Dermatophytosis of nail 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Enteritis infectious 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Eye infection 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Folliculitis 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 2 0/91 (0%) 0
    Gastroenteritis 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Gastroenteritis viral 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Hordeolum 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Infection 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 2/91 (2.2%) 2
    Influenza 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Lip infection 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Lung infection 0/3 (0%) 0 0/6 (0%) 0 8/90 (8.9%) 8 5/91 (5.5%) 5
    Nasopharyngitis 0/3 (0%) 0 1/6 (16.7%) 1 2/90 (2.2%) 4 4/91 (4.4%) 4
    Onychomycosis 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Oral candidiasis 1/3 (33.3%) 1 0/6 (0%) 0 2/90 (2.2%) 2 0/91 (0%) 0
    Oral herpes 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Paronychia 1/3 (33.3%) 1 2/6 (33.3%) 3 44/90 (48.9%) 48 0/91 (0%) 0
    Periodontitis 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Pharyngitis 0/3 (0%) 0 1/6 (16.7%) 1 1/90 (1.1%) 1 2/91 (2.2%) 2
    Pleural infection 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Pneumonia 0/3 (0%) 0 1/6 (16.7%) 1 2/90 (2.2%) 2 5/91 (5.5%) 5
    Rash pustular 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 2 0/91 (0%) 0
    Sinusitis 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Skin infection 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 2 4/91 (4.4%) 4
    Staphylococcal infection 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Tinea infection 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Tinea manuum 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Tinea pedis 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Tonsillitis 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Upper respiratory tract infection 0/3 (0%) 0 0/6 (0%) 0 11/90 (12.2%) 12 10/91 (11%) 11
    Urinary tract infection 0/3 (0%) 0 0/6 (0%) 0 5/90 (5.6%) 5 2/91 (2.2%) 2
    Wound infection 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Injury, poisoning and procedural complications
    Compression fracture 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 2 0/91 (0%) 0
    Contusion 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Fall 0/3 (0%) 0 0/6 (0%) 0 3/90 (3.3%) 3 2/91 (2.2%) 2
    Fracture 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 2/91 (2.2%) 2
    Infusion related reaction 0/3 (0%) 0 0/6 (0%) 0 3/90 (3.3%) 3 3/91 (3.3%) 6
    Injury 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Injury corneal 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Laceration 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Ligament sprain 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Radiation oesophagitis 1/3 (33.3%) 1 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Skin abrasion 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Thermal burn 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Tracheal haemorrhage 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Venous injury 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Wound complication 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Investigations
    Alanine aminotransferase increased 2/3 (66.7%) 2 1/6 (16.7%) 4 18/90 (20%) 28 16/91 (17.6%) 22
    Amylase increased 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 2 1/91 (1.1%) 3
    Aspartate aminotransferase increased 0/3 (0%) 0 1/6 (16.7%) 3 17/90 (18.9%) 27 9/91 (9.9%) 15
    Blood alkaline phosphatase increased 0/3 (0%) 0 1/6 (16.7%) 3 9/90 (10%) 10 2/91 (2.2%) 4
    Blood bilirubin increased 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Blood cholesterol increased 0/3 (0%) 0 0/6 (0%) 0 3/90 (3.3%) 5 2/91 (2.2%) 2
    Blood creatine phosphokinase decreased 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Blood creatine phosphokinase increased 0/3 (0%) 0 1/6 (16.7%) 1 5/90 (5.6%) 5 0/91 (0%) 0
    Blood creatinine increased 0/3 (0%) 0 1/6 (16.7%) 1 8/90 (8.9%) 12 10/91 (11%) 15
    Blood urea increased 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 3 2/91 (2.2%) 2
    C-reactive protein increased 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Creatinine renal clearance decreased 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Electrocardiogram qt prolonged 1/3 (33.3%) 1 0/6 (0%) 0 1/90 (1.1%) 1 1/91 (1.1%) 1
    Electrocardiogram st segment depression 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Electrocardiogram t wave inversion 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Gamma-glutamyltransferase increased 0/3 (0%) 0 0/6 (0%) 0 7/90 (7.8%) 8 3/91 (3.3%) 3
    Glucose urine present 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Lymphocyte count decreased 0/3 (0%) 0 0/6 (0%) 0 4/90 (4.4%) 11 7/91 (7.7%) 15
    Neutrophil count decreased 1/3 (33.3%) 2 3/6 (50%) 7 53/90 (58.9%) 119 45/91 (49.5%) 91
    Platelet count decreased 1/3 (33.3%) 1 2/6 (33.3%) 5 49/90 (54.4%) 96 46/91 (50.5%) 81
    Platelet count increased 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 2 1/91 (1.1%) 1
    Protein total decreased 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Urine output decreased 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Weight decreased 1/3 (33.3%) 1 0/6 (0%) 0 13/90 (14.4%) 16 11/91 (12.1%) 13
    Weight increased 0/3 (0%) 0 0/6 (0%) 0 7/90 (7.8%) 12 5/91 (5.5%) 8
    White blood cell count decreased 1/3 (33.3%) 2 2/6 (33.3%) 2 49/90 (54.4%) 99 39/91 (42.9%) 70
    White blood cells urine positive 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Metabolism and nutrition disorders
    Decreased appetite 2/3 (66.7%) 6 4/6 (66.7%) 9 62/90 (68.9%) 112 48/91 (52.7%) 87
    Dehydration 1/3 (33.3%) 1 0/6 (0%) 0 4/90 (4.4%) 5 4/91 (4.4%) 4
    Diabetes mellitus 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 3 3/91 (3.3%) 6
    Glucose tolerance impaired 0/3 (0%) 0 1/6 (16.7%) 1 3/90 (3.3%) 4 1/91 (1.1%) 1
    Hypercalcaemia 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 2 4/91 (4.4%) 4
    Hyperglycaemia 0/3 (0%) 0 0/6 (0%) 0 6/90 (6.7%) 9 4/91 (4.4%) 4
    Hyperkalaemia 0/3 (0%) 0 0/6 (0%) 0 8/90 (8.9%) 23 11/91 (12.1%) 19
    Hypermagnesaemia 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 3 1/91 (1.1%) 1
    Hypernatraemia 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Hypertriglyceridaemia 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 1/91 (1.1%) 1
    Hyperuricaemia 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Hypoalbuminaemia 1/3 (33.3%) 1 1/6 (16.7%) 1 12/90 (13.3%) 14 8/91 (8.8%) 8
    Hypocalcaemia 1/3 (33.3%) 1 1/6 (16.7%) 5 9/90 (10%) 15 3/91 (3.3%) 4
    Hypochloraemia 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Hypoglycaemia 0/3 (0%) 0 0/6 (0%) 0 3/90 (3.3%) 4 0/91 (0%) 0
    Hypokalaemia 0/3 (0%) 0 0/6 (0%) 0 3/90 (3.3%) 5 3/91 (3.3%) 4
    Hypomagnesaemia 0/3 (0%) 0 2/6 (33.3%) 7 35/90 (38.9%) 54 8/91 (8.8%) 8
    Hyponatraemia 0/3 (0%) 0 2/6 (33.3%) 4 12/90 (13.3%) 15 24/91 (26.4%) 36
    Hypophosphataemia 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 2
    Hypoproteinaemia 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/3 (0%) 0 1/6 (16.7%) 1 4/90 (4.4%) 4 2/91 (2.2%) 2
    Arthritis 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 2 1/91 (1.1%) 1
    Back pain 0/3 (0%) 0 2/6 (33.3%) 2 5/90 (5.6%) 5 4/91 (4.4%) 4
    Bursitis 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Flank pain 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Muscular weakness 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Musculoskeletal chest pain 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Musculoskeletal pain 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 1/91 (1.1%) 1
    Musculoskeletal stiffness 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Myalgia 0/3 (0%) 0 0/6 (0%) 0 4/90 (4.4%) 5 4/91 (4.4%) 4
    Myositis 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Neck pain 0/3 (0%) 0 1/6 (16.7%) 1 0/90 (0%) 0 0/91 (0%) 0
    Osteoarthritis 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 2 0/91 (0%) 0
    Osteoporosis 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 2 0/91 (0%) 0
    Pain in extremity 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Spinal osteoarthritis 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 2 4/91 (4.4%) 4
    Lymphangiosis carcinomatosa 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Tumour associated fever 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 1/91 (1.1%) 1
    Tumour pain 0/3 (0%) 0 0/6 (0%) 0 6/90 (6.7%) 6 9/91 (9.9%) 9
    Nervous system disorders
    Coordination abnormal 0/3 (0%) 0 1/6 (16.7%) 1 0/90 (0%) 0 0/91 (0%) 0
    Dementia with lewy bodies 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Depressed level of consciousness 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 1/91 (1.1%) 1
    Dizziness 1/3 (33.3%) 1 1/6 (16.7%) 1 5/90 (5.6%) 5 3/91 (3.3%) 4
    Dysgeusia 2/3 (66.7%) 2 2/6 (33.3%) 2 19/90 (21.1%) 22 9/91 (9.9%) 11
    Headache 0/3 (0%) 0 1/6 (16.7%) 1 7/90 (7.8%) 7 6/91 (6.6%) 7
    Paralysis 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Paralysis recurrent laryngeal nerve 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Peripheral sensory neuropathy 1/3 (33.3%) 1 0/6 (0%) 0 4/90 (4.4%) 4 1/91 (1.1%) 1
    Presyncope 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Syncope 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 2 0/91 (0%) 0
    Tremor 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Vagus nerve disorder 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Psychiatric disorders
    Adjustment disorder 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Anxiety 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Delirium 0/3 (0%) 0 0/6 (0%) 0 3/90 (3.3%) 3 1/91 (1.1%) 1
    Depression 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 2/91 (2.2%) 2
    Insomnia 2/3 (66.7%) 2 1/6 (16.7%) 1 15/90 (16.7%) 17 19/91 (20.9%) 24
    Panic disorder 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 2 0/91 (0%) 0
    Renal and urinary disorders
    Acute kidney injury 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Chronic kidney disease 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Dysuria 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Haematuria 0/3 (0%) 0 0/6 (0%) 0 5/90 (5.6%) 5 1/91 (1.1%) 1
    Haemoglobinuria 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Proteinuria 0/3 (0%) 0 0/6 (0%) 0 7/90 (7.8%) 8 5/91 (5.5%) 6
    Renal impairment 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 4/91 (4.4%) 4
    Urinary incontinence 0/3 (0%) 0 1/6 (16.7%) 1 0/90 (0%) 0 0/91 (0%) 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia 0/3 (0%) 0 0/5 (0%) 0 0/79 (0%) 0 1/81 (1.2%) 1
    Scrotal swelling 0/3 (0%) 0 0/5 (0%) 0 1/79 (1.3%) 1 0/81 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Bronchial obstruction 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Bronchostenosis 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Cough 0/3 (0%) 0 0/6 (0%) 0 3/90 (3.3%) 3 5/91 (5.5%) 5
    Dry throat 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Dysaesthesia pharynx 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Dysphonia 0/3 (0%) 0 0/6 (0%) 0 3/90 (3.3%) 3 2/91 (2.2%) 2
    Dyspnoea 1/3 (33.3%) 1 0/6 (0%) 0 3/90 (3.3%) 3 4/91 (4.4%) 4
    Epistaxis 0/3 (0%) 0 3/6 (50%) 3 12/90 (13.3%) 12 2/91 (2.2%) 2
    Haemoptysis 0/3 (0%) 0 0/6 (0%) 0 4/90 (4.4%) 4 3/91 (3.3%) 3
    Hiccups 2/3 (66.7%) 4 2/6 (33.3%) 5 42/90 (46.7%) 68 49/91 (53.8%) 86
    Hypoxia 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 2/91 (2.2%) 2
    Interstitial lung disease 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Laryngeal inflammation 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 2 0/91 (0%) 0
    Lung infiltration 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Nasal inflammation 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 2 0/91 (0%) 0
    Organising pneumonia 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Oropharyngeal pain 0/3 (0%) 0 0/6 (0%) 0 3/90 (3.3%) 3 2/91 (2.2%) 2
    Pharyngeal inflammation 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Pleural effusion 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 1/91 (1.1%) 1
    Pleuritic pain 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Pneumonia aspiration 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Pneumonitis 0/3 (0%) 0 1/6 (16.7%) 1 0/90 (0%) 0 0/91 (0%) 0
    Pneumothorax 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Productive cough 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Pulmonary haemorrhage 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 4/91 (4.4%) 4
    Pulmonary thrombosis 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Rhinitis allergic 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 2 1/91 (1.1%) 1
    Sleep apnoea syndrome 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Skin and subcutaneous tissue disorders
    Acne 0/3 (0%) 0 0/6 (0%) 0 3/90 (3.3%) 3 0/91 (0%) 0
    Alopecia 0/3 (0%) 0 3/6 (50%) 3 18/90 (20%) 18 18/91 (19.8%) 18
    Decubitus ulcer 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 3 0/91 (0%) 0
    Dermatitis 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Dermatitis acneiform 2/3 (66.7%) 2 3/6 (50%) 3 72/90 (80%) 79 6/91 (6.6%) 6
    Dermatitis bullous 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Dermatitis contact 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 2/91 (2.2%) 2
    Drug eruption 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Dry skin 1/3 (33.3%) 1 3/6 (50%) 3 48/90 (53.3%) 49 8/91 (8.8%) 8
    Eczema 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1
    Erythema 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 4/91 (4.4%) 4
    Erythema multiforme 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Miliaria 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 1/91 (1.1%) 1
    Onychomadesis 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Palmar erythema 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Palmar-plantar erythrodysaesthesia syndrome 0/3 (0%) 0 0/6 (0%) 0 6/90 (6.7%) 6 0/91 (0%) 0
    Pruritus 0/3 (0%) 0 0/6 (0%) 0 8/90 (8.9%) 9 3/91 (3.3%) 3
    Purpura 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Rash 1/3 (33.3%) 1 1/6 (16.7%) 1 10/90 (11.1%) 11 7/91 (7.7%) 10
    Rash maculo-papular 1/3 (33.3%) 1 1/6 (16.7%) 1 6/90 (6.7%) 8 11/91 (12.1%) 12
    Skin exfoliation 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Skin fissures 0/3 (0%) 0 0/6 (0%) 0 5/90 (5.6%) 5 0/91 (0%) 0
    Skin hyperpigmentation 1/3 (33.3%) 1 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Skin toxicity 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Skin ulcer 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 1/91 (1.1%) 1
    Urticaria 0/3 (0%) 0 0/6 (0%) 0 4/90 (4.4%) 4 6/91 (6.6%) 6
    Surgical and medical procedures
    Dermabrasion 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Vascular disorders
    Arteriosclerosis 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 1/91 (1.1%) 1
    Embolism 0/3 (0%) 0 0/6 (0%) 0 4/90 (4.4%) 4 1/91 (1.1%) 1
    Hot flush 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Hypertension 0/3 (0%) 0 1/6 (16.7%) 1 5/90 (5.6%) 5 9/91 (9.9%) 10
    Hypotension 0/3 (0%) 0 0/6 (0%) 0 2/90 (2.2%) 2 1/91 (1.1%) 1
    Jugular vein thrombosis 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Orthostatic hypotension 0/3 (0%) 0 0/6 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 2
    Phlebitis 0/3 (0%) 0 0/6 (0%) 0 3/90 (3.3%) 3 3/91 (3.3%) 4
    Thrombophlebitis 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Thrombosis 0/3 (0%) 0 0/6 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0
    Vascular pain 0/3 (0%) 0 2/6 (33.3%) 5 3/90 (3.3%) 7 3/91 (3.3%) 6
    Vasculitis 0/3 (0%) 0 0/6 (0%) 0 4/90 (4.4%) 6 7/91 (7.7%) 14

    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 and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    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:
    NCT01763788
    Other Study ID Numbers:
    • 14461
    • I4X-JE-JFCM
    First Posted:
    Jan 9, 2013
    Last Update Posted:
    Oct 25, 2019
    Last Verified:
    Dec 1, 2018