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Avelumab in Metastatic or Locally Advanced Solid Tumors (JAVELIN Solid Tumor JPN)

Sponsor
Merck KGaA, Darmstadt, Germany (Industry)
Overall Status
Completed
CT.gov ID
NCT01943461
Collaborator
(none)
57
Enrollment
1
Location
4
Arms
72.7
Actual Duration (Months)
0.8
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This was a Phase 1, open-label, dose-escalation trial of avelumab (antibody targeting programmed death ligand 1 [anti PD-L1]) in Japanese participants with metastatic or locally advanced solid tumors, followed by a consecutive expansion part in Asian participants with gastric cancer.

Condition or Disease Intervention/Treatment Phase
  • Drug: Avelumab 3 mg/kg
  • Drug: Avelumab 10 mg/kg
  • Drug: Avelumab 20 mg/kg
 Phase 1

Study Design

Study Type:
Interventional
Actual Enrollment :
57 participants
Allocation:
Non-Randomized
Intervention Model:
Sequential Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I Trial to Investigate the Tolerability, Safety, Pharmacokinetics, Biological and Clinical Activity of Avelumab (MSB0010718C) in Japanese Subjects With Metastatic or Locally Advanced Solid Tumors, With Expansion Part in Asian Subjects With Gastric Cancer
Actual Study Start Date :
Sep 2, 2013
Actual Primary Completion Date :
Jan 7, 2015
Actual Study Completion Date :
Sep 25, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: Dose-escalation Cohort: Avelumab 3 mg/kg

Drug: Avelumab 3 mg/kg
Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose- escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
Other Names:
  • anti PD-L1
  • MSB0010718C

    		•
    Experimental: Dose-escalation Cohort: Avelumab 10 mg/kg

    Drug: Avelumab 10 mg/kg
    Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose- escalation cohort and expansion cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    Experimental: Dose-escalation Cohort: Avelumab 20 mg/kg

    Drug: Avelumab 20 mg/kg
    Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose- escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    Experimental: Expansion Cohort: Avelumab 10 mg/kg

    Drug: Avelumab 10 mg/kg
    Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose- escalation cohort and expansion cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.

    Outcome Measures

    Primary Outcome Measures

    1. Dose-escalation Cohorts: Number of Participants With Dose Limiting Toxicities (DLTs) [Baseline up to 3 weeks]

      DLT: any Grade greater than or equal to (>=) 3 or Adverse Events (AE) according to National Cancer Institute Common Toxicity Criteria for AE Version 4.03 (NCI-CTCAE v4.03); observed during first 3 weeks of dose-escalation part and as being related to Avelumab by Investigator/Sponsor. Following events were not considered as DLT: Grade 3 infusion-related reaction resolving to (<=) Grade 1 within 6 hours and controlled with medical management; Transient (<=6 hours) Grade 3 flulike symptoms/fever controlled with medical management and resolved to <= Grade 1;Transient (<=24 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that resolved to <=Grade1 with/without medical management, Grade 3 diarrhea, Grade 3 skin toxicity, Grade3 out-of-range laboratory values without any clinical correlate that resolves to <= Grade 1 or Baseline in < 7 days after medical management; Tumor flare phenomenon defined as local pain, irritation, rash localized at sites of known or suspected tumor.

    Secondary Outcome Measures

    1. Dose-escalation Cohorts: Area Under the Serum Concentration-Time Curve From the Time of Dosing to the Time of the Last Observation (AUC0-t) of Avelumab [Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion]

      Area under the serum concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated by linear trapezoidal summation.

    2. Dose-escalation Cohorts: Area Under the Serum Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Avelumab [Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion]

      Area under the curve from the time of dosing extrapolated to infinity was calculated by the linear trapezoidal summation and extrapolated to infinity using Clast/Lambda z after the first intravenous infusion. "Clast" was the last quantifiable concentration and "Lambda z" was terminal elimination rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase.

    3. Dose-escalation Cohorts: Maximum Observed Serum Concentration (Cmax) of Avelumab [Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion]

      Cmax was obtained directly from the concentration versus time curve.

    4. Dose-escalation Cohorts: Time to Reach Maximum Observed Serum Concentration (Tmax) of Avelumab [Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion]

      Tmax was time to reach maximum observed serum concentration obtained directly from the concentration versus time curve.

    5. Dose-escalation Cohorts: Terminal Half-Life (t1/2) of Avelumab [Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion]

      t1/2 was the time measured for the concentration to decrease by one half, determined as 0.693/Lambda z, here Lambda z was the terminal elimination rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase.

    6. Dose-escalation Cohorts: Terminal Elimination Rate Constant (Lambda z) of Avelumab [Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion]

      Terminal elimination rate constant was determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase. Participant wise data was reported for this outcome measure.

    7. Dose-escalation Cohorts: Programmed Death Ligand 1 (PD-L1) Receptor Occupancy [Pre-infusion on Day 1; 4 and 48 hours after infusion on Day 3; Pre-infusion on Days 15, 29, 43, and 85]

      Percentage of PD-L1 receptors occupied by avelumab on human lymphocytes (CD3+ cells) was assessed by flow cytometry on peripheral blood mononuclear cell (PBMC) samples. Greater than or equal to [>=] 85 percent [%] of cell viability was required for reliable receptor occupancy assessment.

    8. Dose-escalation Cohorts: Absolute Value of Cytokine Levels [Day 1 (Pre-infusion), Day 3 (48 hours after infusion), Day 8 (168 hours after infusion), Day 15 (Pre-infusion), Day 43 (Pre-infusion), Day 45 (48 hours after infusion), Day 50 (168 hours after infusion)]

      Cytokine analysis was performed to evaluate levels of Rantes, Monocyte chemoattractant protein-1 (MCP-1) and various interleukins (including IL-1 beta, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-13, IL-8), Tumor necrosis factors-alpha (TNF-alpha) and Interferon-gamma (IFN-gamma) in serum samples.

    9. Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels [Baseline (Day 1 [Pre-infusion]), Day 3 (48 hours after infusion), Day 8 (168 hours after infusion), Day 15 (Pre-infusion), Day 43 (Pre-infusion), Day 45 (48 hours after infusion), Day 50 (168 hours after infusion)]

      Cytokine analysis was performed to evaluate levels of Rantes, Monocyte chemoattractant protein-1 (MCP-1) and various interleukins (including IL-1beta, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-13, IL-8), Tumor necrosis factors-alpha (TNF-alpha) and Interferon-gamma (IFN-gamma) in serum samples. Log fold change from baseline (logFC) was defined as logFC (cytokine at time t) = log (cytokine signal at time t) - log (cytokine signal at baseline).

    10. Dose-escalation Cohorts: Number of Participants With Treatment-Emergent Positive Human Anti-Human Antibody (HAHA) [Day 15 up to Day 2205]

      Participants not having positive HAHA prior to treatment with Avelumab and with at least one positive post-baseline result in the HAHA assay were termed as treatment-emergent. Treatment-emergent participants were further classified as Transient Positive or Persistent positive. Participants were considered as transient positive if time between first and last positive result was less than 16 weeks apart and a negative result at the most recent visit. Participants were considered as persistent positive if time between first and last positive result greater than or equal to [>=] 16 weeks apart or a positive evaluation at the most recent visit. Number of participants with treatment-emergent positive HAHA were reported.

    11. Dose-escalation Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation [Time from first dose of study treatment up to 2205 days]

      An Adverse Event (AE) was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs were those events with onset dates occurring during the on-treatment period for the first time, or if the worsening of an event was during the on-treatment period. TEAEs included both serious TEAEs and non-serious TEAEs.

    12. Expansion Cohort: Area Under the Serum Concentration-Time Curve From the Time of Dosing to the End of Dose Interval (AUC0-336hour [hr]) of Avelumab [Within 6 hours before and the end of the 1-hour infusion (Day 1) and 336 hours after end of infusion]

      AUC0-336hour was defined as area under the serum concentration-time curve from the time of dosing to the end of dose interval (336 hr). It was calculated by linear trapezoidal summation.

    13. Expansion Cohort: Serum Trough Concentration Levels (Ctrough) of Avelumab [Within 6 hours before the 1-hour infusion on Day 15, Day 29, Day 43, Day 85, Day 127 and Day 169.]

      Ctrough was defined as the trough or minimum serum concentration.

    14. Expansion Cohort: Number of Participants With Programmed Death Ligand 1 (PD-L1) Tumor Expression [Time from first dose of study treatment up to 1906 days]

      The PD-L1 expression was evaluated using an established antiPD-L1 immunohistochemistry (IHC) assay.

    15. Expansion Cohort: Absolute Values of Cytokine Levels [Day 1 (Pre-infusion), Day 8 (168 hour after infusion) and Day 43 (Pre-infusion)]

      Cytokine analysis was performed to evaluate levels of Monocyte chemoattractant protein-1 (MCP-1) and various interleukins (including IL-5, IL-6, IL-8), Tumor necrosis factors-alpha (TNF-alpha) and Interferon-gamma (IFN-gamma) in serum samples.

    16. Expansion Cohort: Log Fold Change From Baseline in Cytokine Levels [Baseline (Day 1 [Pre-infusion]), Day 8 (168 hour after infusion) and Day 43 (Pre-infusion)]

      Cytokine analysis was performed to evaluate levels of Monocyte chemoattractant protein-1 (MCP-1) and various interleukins (including IL-5, IL-6, IL-8), Tumor necrosis factors-alpha (TNF-alpha) and Interferon-gamma (IFN-gamma) in serum samples. Log fold change from baseline (logFC) was defined as logFC (cytokine at time t) = log (cytokine signal at time t) - log (cytokine signal at baseline).

    17. Expansion Cohort: Number of Participants With Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [Time from first dose of study treatment up to 1906 days]

      Confirmed BOR was defined as the best response of any of the complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from the date of randomization until disease progression or recurrence (taking the smallest measurement recorded since the start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. SD: Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. Number of participants with best overall response in each category (CR, PR, SD, PD) was reported.

    18. Expansion Cohort: Number of Participants With Immune-related Best Overall Response (irBOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [Time from first dose of study treatment up to 1906 days]

      BOR: best response of any of immune related complete response (irCR), immune related partial response (irPR), immune related stable disease (irSD) and immune related progressive disease (irPD) recorded from the date of randomization until disease progression or recurrence (taking the smallest measurement recorded since the start of treatment as reference). irCR: Complete disappearance of all tumor lesions (both index and non-index lesions with no new measurable/unmeasurable lesions). irPR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions). irSD: SLD of target and new measurable lesions neither irCR, irPR, or irPD. irPD: SLD of target and new measurable lesions increases greater than or equal to [>=] 20%, confirmed by a repeat, consecutive observations at least 4 weeks from the date first documented. Number of participants with immune-related best overall response in each category (irCR, irPR, irSD, irPD) was reported.

    19. Expansion Cohort: Progression-Free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [Time from first dose of study treatment up to 1906 days]

      PFS was defined as the time from date of randomization until date of the first documentation of progressive disease (PD) or death due to any cause in the absence of documented PD, whichever occurs first. PD was defined as at least a 20 percent (%) increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. PFS was measured using Kaplan-Meier (KM) estimates.

    20. Expansion Cohort: Immune-related Progression-Free Survival (irPFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [Time from first dose of study treatment up to 1906 days]

      irPFS was defined as the time from the first dose of study treatment to the date of first documentation of immune-related progressive disease [irPD] (which was subsequently confirmed) or death due to any cause, whichever occurred first. irPD was defined as the sum of the longest diameters of target and new measurable lesions increases greater than or equal to [>=] 20 percent (%), confirmed by a repeat, consecutive observations at least 4 weeks from the date first documented.

    21. Expansion Cohort: Overall Survival (OS) Time [Time from first dose of study treatment up to 1906 days]

      The OS time was defined as the time from randomization to the date of death. The participants who were still alive at the time of data analysis or who were lost to follow-up OS time was censored at the last recorded date that the participant was known to be alive before the data cutoff date. OS was measured using Kaplan-Meier (KM) estimates.

    22. Expansion Cohort: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation [Time from first dose of study treatment up to 1906 days]

      An Adverse Event (AE) was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs were those events with onset dates occurring during the on-treatment period for the first time, or if the worsening of an event was during the on-treatment period. TEAEs included both serious TEAEs and non-serious TEAEs.

    23. Expansion Cohort: Number of Participants With Treatment-Emergent Positive Human Anti-Human Antibody (HAHA) [Day 15 up to Day 1906]

      Number of participants with positive HAHA were reported. Participants not having positive HAHA prior to treatment with avelumab and with at least one positive post-baseline result in the HAHA assay were characterized as treatment-emergent. Treatment-emergent participants were further classified as Transient Positive or Persistent positive participants were considered as transient positive if time between first and last positive result was less than 16 weeks apart and a negative result at the most recent visit. Participants were considered as persistent positive if time between first and last positive result >=16 weeks apart or a positive evaluation at the most recent visit.

    Eligibility Criteria

    Criteria

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

    • Signed written informed consent

    • Male or female participants aged greater than or equal to (>=) 20 years

    • For dose escalation part: Histologically or cytologically proven metastatic or locally advanced solid tumors, for which no standard therapy exists or standard therapy has failed

    • For expansion part:

    • Availability of fresh and archive tumor in formalin fixed paraffin embedded tissue

    • With histologically or cytologically confirmed recurrent or refractory unresectable Stage IV gastric or gastro-esophageal junctional adenocarcinoma (according to American Joint Committee on Cancer/Union Internationale Contre le Cancer [UICC] 7th edition) and whose disease progressed after one or two prior chemotherapy regimen(s) involving both fluoropyrimidines and platinum

    • Presence of at least 1 measurable lesion according to RECIST version 1.1

    • Participants should not have severe peritoneal metastases. The following criteria were applied:

    • No clinical ileus or subileus

    • No moderate-to-severe ascites (participants with ascites restricted to the perihepatic space or pelvic cavity)

    • Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at the trial entry and an estimated life expectancy of at least 3 months

    • Adequate hematological, hepatic and renal function as defined in the protocol

    • All participants must agree to use effective means of contraception with their partner from entry into the trial through 6 months after the last dose of avelumab

    Exclusion Criteria:

    • Concurrent treatment with a non-permitted drug

    • Prior therapy with any antibody/drug targeting T cell co-regulatory proteins (immune checkpoints)

    • Concurrent anticancer treatment or concurrent systemic therapy with steroids or other immunosuppressive agents, or use of any investigational drug within 30 days before the start of trial treatment. Short-term administration of steroids (that is, for allergic reactions or the management of immune-related adverse events [irAE]) is allowed

    • Previous malignant disease within the last 5 years with the exception of adequately treated non-melanoma skin cancer, in situ cancer, or other cancer

    • Non-oncology vaccine therapies for prevention of infection disease (e.g. seasonal flu vaccine, human papilloma virus vaccine) within 4 weeks of study drug administration. Vaccination while on study is also prohibited except for administration of the inactivated influenza vaccine.

    • Pregnancy or lactation period

    • Known alcohol or drug abuse

    • Clinically significant (that is, active) cardiovascular disease

    • All other significant diseases (for example, inflammatory bowel disease), which, in the opinion of the investigator, might impair the participant's tolerance of trial treatment

    • Any psychiatric condition that would prohibit the understanding or rendering of informed consent

    • Legal incapacity or limited legal capacity

    • Other protocol defined exclusion criteria could apply

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Research site Darmstadt Germany

    Sponsors and Collaborators

    • Merck KGaA, Darmstadt, Germany

    Investigators

    • Study Director: Medical Responsible, Merck KGaA, Darmstadt, Germany

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    Responsible Party:
    Merck KGaA, Darmstadt, Germany
    ClinicalTrials.gov Identifier:
    NCT01943461
    Other Study ID Numbers:
    • EMR 100070-002
    First Posted:
    Sep 17, 2013
    Last Update Posted:
    Sep 30, 2020
    Last Verified:
    Sep 1, 2020
    Keywords provided by Merck KGaA, Darmstadt, Germany
    Solid Tumors
    MSB0010718C
    anti PD-L1
    avelumab
    Phase 1
    Additional relevant MeSH terms:
    Neoplasms
    Avelumab
    Antibodies, Monoclonal

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Dose-escalation Cohort: Avelumab 3 mg/kg Dose-escalation Cohort: Avelumab 10 mg/kg Dose-escalation Cohort: Avelumab 20 mg/kg Expansion Cohort: Avelumab 10 mg/kg
    Arm/Group Description Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the expansion cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    Period Title: Overall Study
    STARTED 5 6 6 40
    COMPLETED 5 6 6 40
    NOT COMPLETED 0 0 0 0

    Baseline Characteristics

    Arm/Group Title Dose-escalation Cohort: Avelumab 3 mg/kg Dose-escalation Cohort: Avelumab 10 mg/kg Dose-escalation Cohort: Avelumab 20 mg/kg Expansion Cohort: Avelumab 10 mg/kg Total
    Arm/Group Description Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the expansion cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Total of all reporting groups
    Overall Participants 5 6 6 40 57
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    3
    60%
    5
    83.3%
    2
    33.3%
    22
    55%
    32
    56.1%
    >=65 years
    2
    40%
    1
    16.7%
    4
    66.7%
    18
    45%
    25
    43.9%
    Sex: Female, Male (Count of Participants)
    Female
    2
    40%
    2
    33.3%
    3
    50%
    11
    27.5%
    18
    31.6%
    Male
    3
    60%
    4
    66.7%
    3
    50%
    29
    72.5%
    39
    68.4%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Not Hispanic or Latino
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    5
    100%
    6
    100%
    6
    100%
    40
    100%
    57
    100%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    5
    100%
    6
    100%
    6
    100%
    40
    100%
    57
    100%
    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%
    0
    0%
    0
    0%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%

    Outcome Measures

    1. Primary Outcome
    Title Dose-escalation Cohorts: Number of Participants With Dose Limiting Toxicities (DLTs)
    Description DLT: any Grade greater than or equal to (>=) 3 or Adverse Events (AE) according to National Cancer Institute Common Toxicity Criteria for AE Version 4.03 (NCI-CTCAE v4.03); observed during first 3 weeks of dose-escalation part and as being related to Avelumab by Investigator/Sponsor. Following events were not considered as DLT: Grade 3 infusion-related reaction resolving to (<=) Grade 1 within 6 hours and controlled with medical management; Transient (<=6 hours) Grade 3 flulike symptoms/fever controlled with medical management and resolved to <= Grade 1;Transient (<=24 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that resolved to <=Grade1 with/without medical management, Grade 3 diarrhea, Grade 3 skin toxicity, Grade3 out-of-range laboratory values without any clinical correlate that resolves to <= Grade 1 or Baseline in < 7 days after medical management; Tumor flare phenomenon defined as local pain, irritation, rash localized at sites of known or suspected tumor.
    Time Frame Baseline up to 3 weeks

    Outcome Measure Data

    Analysis Population Description
    DLT analysis set included all participants with data used for implementing the dose-escalation schedule.
    Arm/Group Title Dose-escalation Cohort: Avelumab 3 mg/kg Dose-escalation Cohort: Avelumab 10 mg/kg Dose-escalation Cohort: Avelumab 20 mg/kg
    Arm/Group Description Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    Measure Participants 3 6 6
    Count of Participants [Participants]
    0
    0%
    0
    0%
    0
    0%
    2. Secondary Outcome
    Title Dose-escalation Cohorts: Area Under the Serum Concentration-Time Curve From the Time of Dosing to the Time of the Last Observation (AUC0-t) of Avelumab
    Description Area under the serum concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated by linear trapezoidal summation.
    Time Frame Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) analysis set included all participants who have received at least 1 dose of study treatment and provided at least 1 measurable post-dose concentration.
    Arm/Group Title Dose-escalation Cohort: Avelumab 3 mg/kg Dose-escalation Cohort: Avelumab 10 mg/kg Dose-escalation Cohort: Avelumab 20 mg/kg
    Arm/Group Description Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    Measure Participants 5 6 6
    Geometric Mean (Geometric Coefficient of Variation) [hour*microgram per milliliter(hr*mcg/mL)]
    5120
    (32.5)
    20100
    (40.0)
    46800
    (23.1)
    3. Secondary Outcome
    Title Dose-escalation Cohorts: Area Under the Serum Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Avelumab
    Description Area under the curve from the time of dosing extrapolated to infinity was calculated by the linear trapezoidal summation and extrapolated to infinity using Clast/Lambda z after the first intravenous infusion. "Clast" was the last quantifiable concentration and "Lambda z" was terminal elimination rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase.
    Time Frame Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion

    Outcome Measure Data

    Analysis Population Description
    PK analysis set included all participants who have received at least 1 dose of study treatment and provided at least 1 measurable post-dose concentration.
    Arm/Group Title Dose-escalation Cohort: Avelumab 3 mg/kg Dose-escalation Cohort: Avelumab 10 mg/kg Dose-escalation Cohort: Avelumab 20 mg/kg
    Arm/Group Description Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    Measure Participants 5 6 6
    Geometric Mean (Geometric Coefficient of Variation) [hr*mcg/mL]
    6040
    (27.5)
    24000
    (47.4)
    53700
    (24.3)
    4. Secondary Outcome
    Title Dose-escalation Cohorts: Maximum Observed Serum Concentration (Cmax) of Avelumab
    Description Cmax was obtained directly from the concentration versus time curve.
    Time Frame Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion

    Outcome Measure Data

    Analysis Population Description
    PK analysis set included all participants who have received at least 1 dose of study treatment and provided at least 1 measurable post-dose concentration.
    Arm/Group Title Dose-escalation Cohort: Avelumab 3 mg/kg Dose-escalation Cohort: Avelumab 10 mg/kg Dose-escalation Cohort: Avelumab 20 mg/kg
    Arm/Group Description Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    Measure Participants 5 6 6
    Geometric Mean (Geometric Coefficient of Variation) [mcg/mL]
    64
    (22.2)
    179
    (19.6)
    459
    (13.6)
    5. Secondary Outcome
    Title Dose-escalation Cohorts: Time to Reach Maximum Observed Serum Concentration (Tmax) of Avelumab
    Description Tmax was time to reach maximum observed serum concentration obtained directly from the concentration versus time curve.
    Time Frame Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion

    Outcome Measure Data

    Analysis Population Description
    PK analysis set included all participants who have received at least 1 dose of study treatment and provided at least 1 measurable post-dose concentration.
    Arm/Group Title Dose-escalation Cohort: Avelumab 3 mg/kg Dose-escalation Cohort: Avelumab 10 mg/kg Dose-escalation Cohort: Avelumab 20 mg/kg
    Arm/Group Description Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    Measure Participants 5 6 6
    Median (Full Range) [hour]
    1.683
    1.533
    1.683
    6. Secondary Outcome
    Title Dose-escalation Cohorts: Terminal Half-Life (t1/2) of Avelumab
    Description t1/2 was the time measured for the concentration to decrease by one half, determined as 0.693/Lambda z, here Lambda z was the terminal elimination rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase.
    Time Frame Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion

    Outcome Measure Data

    Analysis Population Description
    PK analysis set included all participants who have received at least 1 dose of study treatment and provided at least 1 measurable post-dose concentration.
    Arm/Group Title Dose-escalation Cohort: Avelumab 3 mg/kg Dose-escalation Cohort: Avelumab 10 mg/kg Dose-escalation Cohort: Avelumab 20 mg/kg
    Arm/Group Description Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    Measure Participants 5 6 6
    Geometric Mean (Geometric Coefficient of Variation) [hour]
    94
    (31.7)
    122
    (33.1)
    112
    (11.6)
    7. Secondary Outcome
    Title Dose-escalation Cohorts: Terminal Elimination Rate Constant (Lambda z) of Avelumab
    Description Terminal elimination rate constant was determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase. Participant wise data was reported for this outcome measure.
    Time Frame Within 6 hours before the infusion, at end of 1-hour infusion (Day 1), 0.5, 1, 2, 4, 6,12, 24, 36, 48, 168 hours after end of infusion

    Outcome Measure Data

    Analysis Population Description
    PK analysis set included all participants who have received at least 1 dose of study treatment and provided at least 1 measurable post-dose concentration. The summarized data was not available for these arms therefore individual data was presented. Here, "Number Analyzed" signifies specific participant evaluated in respective arm.
    Arm/Group Title Dose-escalation Cohort: Avelumab 3 mg/kg Dose-escalation Cohort: Avelumab 10 mg/kg Dose-escalation Cohort: Avelumab 20 mg/kg
    Arm/Group Description Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    Measure Participants 5 6 6
    Participant 1
    0.00667
    0.0103
    0.00568
    Participant 2
    0.0114
    0.00456
    0.00750
    Participant 3
    0.00868
    0.00456
    0.00604
    Participant 4
    0.00663
    0.00508
    0.00568
    Participant 5
    0.00501
    0.00476
    0.00666
    Participant 6
    0.00662
    0.00562
    8. Secondary Outcome
    Title Dose-escalation Cohorts: Programmed Death Ligand 1 (PD-L1) Receptor Occupancy
    Description Percentage of PD-L1 receptors occupied by avelumab on human lymphocytes (CD3+ cells) was assessed by flow cytometry on peripheral blood mononuclear cell (PBMC) samples. Greater than or equal to [>=] 85 percent [%] of cell viability was required for reliable receptor occupancy assessment.
    Time Frame Pre-infusion on Day 1; 4 and 48 hours after infusion on Day 3; Pre-infusion on Days 15, 29, 43, and 85

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set included all participants who have received at least 1 dose of study treatment.
    Arm/Group Title Dose-escalation Cohort: Avelumab 3 mg/kg Dose-escalation Cohort: Avelumab 10 mg/kg Dose-escalation Cohort: Avelumab 20 mg/kg
    Arm/Group Description Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    Measure Participants 5 6 6
    Mean (Standard Deviation) [percentage of receptors]
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    9. Secondary Outcome
    Title Dose-escalation Cohorts: Absolute Value of Cytokine Levels
    Description Cytokine analysis was performed to evaluate levels of Rantes, Monocyte chemoattractant protein-1 (MCP-1) and various interleukins (including IL-1 beta, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-13, IL-8), Tumor necrosis factors-alpha (TNF-alpha) and Interferon-gamma (IFN-gamma) in serum samples.
    Time Frame Day 1 (Pre-infusion), Day 3 (48 hours after infusion), Day 8 (168 hours after infusion), Day 15 (Pre-infusion), Day 43 (Pre-infusion), Day 45 (48 hours after infusion), Day 50 (168 hours after infusion)

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set included all participants who have received at least 1 dose of study treatment. Here "number analyzed" signified those participants who were evaluable for this outcome measure at the specified time points for the given category.
    Arm/Group Title Dose-escalation Cohort: Avelumab 3 mg/kg Dose-escalation Cohort: Avelumab 10 mg/kg Dose-escalation Cohort: Avelumab 20 mg/kg
    Arm/Group Description Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    Measure Participants 5 6 6
    IFN-gamma: Day 1: Pre-Infusion
    9.094
    (5.030)
    5.928
    (4.331)
    7.723
    (2.533)
    IFN-gamma: Day 3: 48 hours After Infusion
    17.716
    (10.063)
    10.868
    (3.609)
    18.810
    (12.499)
    IFN-gamma: Day 8: 168 hours After Infusion
    15.016
    (17.665)
    8.782
    (3.118)
    12.198
    (5.882)
    IFN-gamma: Day 15: Pre-Infusion
    21.347
    (23.831)
    8.937
    (2.557)
    17.998
    (18.306)
    IFN-gamma: Day 43: Pre-Infusion
    9.758
    (3.838)
    15.947
    (10.844)
    14.863
    (13.232)
    IFN-gamma: Day 45: 48 hours After Infusion
    21.153
    (19.586)
    25.295
    (28.939)
    41.253
    (63.326)
    IFN-gamma: Day 50: 168 hours After Infusion
    11.635
    (6.705)
    16.503
    (16.671)
    9.860
    (4.818)
    IL-12P70: Day 1: Pre-Infusion
    0.200
    (0.000)
    0.412
    (0.401)
    0.200
    (0.000)
    IL-12P70: Day 3: 48 hours After Infusion
    0.200
    (0.000)
    0.395
    (0.373)
    0.270
    (0.171)
    IL-12P70: Day 8: 168 hours After Infusion
    0.200
    (0.000)
    0.368
    (0.412)
    0.237
    (0.090)
    IL-12P70: Day 15: Pre- Infusion
    0.200
    (0.000)
    0.395
    (0.478)
    0.200
    (0.000)
    IL-12P70: Day 43: Pre- Infusion
    0.200
    (0.000)
    0.465
    (0.375)
    0.200
    (0.000)
    IL-12P70: Day 45: 48 hours After Infusion
    0.200
    (0.000)
    0.447
    (0.419)
    0.265
    (0.130)
    IL-12P70: Day 50: 168 hours After Infusion
    0.200
    (0.000)
    0.488
    (0.479)
    0.348
    (0.184)
    IL-10: Day 1: Pre-Infusion
    0.442
    (0.470)
    0.504
    (0.290)
    0.526
    (0.401)
    IL-10: Day 3: 48 hours After Infusion
    0.768
    (0.495)
    0.850
    (0.506)
    0.960
    (0.634)
    IL-10: Day 8: 168 hours After Infusion
    0.675
    (0.680)
    0.993
    (0.779)
    1.107
    (0.805)
    IL-10: Day 15: Pre- Infusion
    0.686
    (0.415)
    1.013
    (0.838)
    1.045
    (0.949)
    IL-10: Day 43: Pre -Infusion
    0.790
    (0.770)
    2.098
    (3.332)
    1.248
    (1.495)
    IL-10: Day 45: 48 hours After Infusion
    1.574
    (2.463)
    3.826
    (7.268)
    2.185
    (3.464)
    IL-10: Day 50:168 hours After Infusion
    0.906
    (1.227)
    2.199
    (3.698)
    0.628
    (0.411)
    IL-13: Day 1: Pre-Infusion
    0.540
    (0.426)
    0.972
    (0.230)
    1.430
    (0.637)
    IL-13: Day 3: 48 hours After Infusion
    0.314
    (0.165)
    0.995
    (0.525)
    1.260
    (0.890)
    IL-13: Day 8: 168 hours After Infusion
    0.684
    (0.407)
    1.000
    (0.372)
    1.052
    (0.586)
    IL-13: Day 15: Pre- Infusion
    0.456
    (0.301)
    1.073
    (0.297)
    1.032
    (0.564)
    IL-13: Day 43: Pre- Infusion
    0.508
    (0.377)
    1.080
    (0.513)
    1.453
    (0.668)
    IL-13: Day 45: 48 hours After Infusion
    0.650
    (0.398)
    0.840
    (0.312)
    0.848
    (0.469)
    IL-13: Day 50:168 hours After Infusion 4
    0.680
    (0.344)
    0.910
    (0.574)
    0.985
    (0.534)
    IL-1beta: Day 1: Pre-Infusion
    0.255
    (0.000)
    0.255
    (0.000)
    0.255
    (0.000)
    IL-1beta: Day 3: 48 hours After Infusion
    0.255
    (0.000)
    0.255
    (0.000)
    0.346
    (0.222)
    IL-1beta: Day 8: 168 hours After Infusion
    0.255
    (0.000)
    0.348
    (0.227)
    0.255
    (0.000)
    IL-1beta: Day 15: Pre- Infusion
    0.255
    (0.000)
    0.255
    (0.000)
    0.255
    (0.000)
    IL-1beta: Day 43: Pre- Infusion
    0.255
    (0.000)
    0.363
    (0.263)
    0.255
    (0.000)
    IL-1beta: Day 45: 48 hours After Infusion
    0.255
    (0.000)
    0.543
    (0.704)
    0.255
    (0.000)
    IL-1beta: Day 50: 168 hours After Infusion
    0.255
    (0.000)
    0.516
    (0.639)
    0.255
    (0.000)
    IL-2: Day 1: Pre-Infusion
    0.400
    (0.220)
    0.452
    (0.274)
    0.458
    (0.472)
    IL-2: Day 3: 48 hours After Infusion
    0.396
    (0.126)
    0.670
    (0.334)
    0.608
    (0.490)
    IL-2: Day 8: 168 hours After Infusion
    0.354
    (0.162)
    0.475
    (0.330)
    0.675
    (0.886)
    IL-2: Day 15: Pre-Infusion
    0.320
    (0.130)
    0.300
    (0.209)
    0.417
    (0.397)
    IL-2: Day 43: Pre- Infusion
    0.388
    (0.148)
    0.500
    (0.273)
    0.470
    (0.362)
    IL-2: Day 45: 48 hours After Infusion
    0.438
    (0.388)
    0.470
    (0.345)
    0.488
    (0.404)
    IL-2: Day 50: 168 hours After Infusion
    0.448
    (0.241)
    0.465
    (0.278)
    0.485
    (0.411)
    IL-4: Day 1: Pre-Infusion
    0.100
    (0.000)
    0.100
    (0.000)
    0.100
    (0.000)
    IL-4: Day 3: 48 hours After Infusion
    0.100
    (0.000)
    0.100
    (0.000)
    0.100
    (0.000)
    IL-4: Day 8: 168 hours After Infusion
    0.100
    (0.000)
    0.100
    (0.000)
    0.130
    (0.073)
    IL-4: Day 15: Pre-Infusion
    0.100
    (0.000)
    0.100
    (0.000)
    0.100
    (0.000)
    IL-4: Day 43: Pre- Infusion
    0.100
    (0.000)
    0.100
    (0.000)
    0.100
    (0.000)
    IL-4: Day 45: 48 hours After Infusion
    0.100
    (0.000)
    0.100
    (0.000)
    0.100
    (0.000)
    IL-4: Day 50: 168 hours After Infusion
    0.100
    (0.000)
    0.100
    (0.000)
    0.100
    (0.000)
    IL-6: Day 1: Pre-Infusion
    1.372
    (0.917)
    3.633
    (6.078)
    1.245
    (0.238)
    IL-6: Day 3: 48 hours After Infusion
    1.398
    (0.713)
    3.843
    (5.018)
    6.433
    (11.449)
    IL-6: Day 8: 168 hours After Infusion
    1.740
    (1.270)
    2.922
    (3.538)
    1.788
    (0.529)
    IL-6: Day 15: Pre- Infusion
    2.032
    (2.620)
    3.325
    (2.939)
    1.890
    (1.097)
    IL-6: Day 43: Pre- Infusion
    2.215
    (3.279)
    1.978
    (2.070)
    2.995
    (2.500)
    IL-6: Day 45: 48 hours After Infusion
    2.888
    (4.548)
    3.583
    (6.013)
    3.065
    (2.355)
    IL-6: Day 50: 168 hours After Infusion
    1.468
    (1.544)
    4.082
    (6.986)
    5.533
    (4.287)
    MCP-1: Day 1: Pre-Infusion
    243.664
    (55.976)
    209.280
    (31.895)
    268.415
    (52.240)
    MCP-1: Day 3: 48 hours After Infusion
    289.148
    (69.117)
    250.230
    (71.660)
    276.765
    (30.402)
    MCP-1: Day 8: 168 hours After Infusion
    257.706
    (69.318)
    229.240
    (56.104)
    292.260
    (47.383)
    MCP-1: Day 15: Pre- Infusion
    257.888
    (93.740)
    226.445
    (28.636)
    267.008
    (38.395)
    MCP-1: Day 43: Pre- Infusion
    282.053
    (65.125)
    218.855
    (45.141)
    228.460
    (53.309)
    MCP-1: Day 45: 48 hours After Infusion
    258.265
    (57.606)
    268.657
    (84.748)
    235.265
    (40.957)
    MCP-1: Day 50: 168 hours After Infusion
    274.320
    (49.826)
    241.980
    (70.308)
    242.380
    (15.451)
    Rantes: Day 1: Pre-Infusion
    32292.35
    (24365.33)
    33583.68
    (26542.38)
    35038.29
    (6936.25)
    Rantes: Day 3: 48 hours After Infusion
    31514.77
    (13931.92)
    54874.62
    (45162.06)
    29282.41
    (3512.35)
    Rantes: Day 8: 168 hours After Infusion
    36607.67
    (19388.38)
    52933.35
    (37662.84)
    28655.39
    (8282.64)
    Rantes: Day 15: Pre-Infusion
    59985.74
    (21964.23)
    45301.97
    (19703.88)
    34758.15
    (9429.32)
    Rantes: Day 43: Pre-Infusion
    30657.45
    (6773.47)
    43532.09
    (25175.05)
    36738.48
    (10865.40)
    Rantes: Day 45: 48 hours After Infusion
    28777.63
    (10267.15)
    41629.09
    (25017.89)
    34107.87
    (15731.50)
    Rantes: Day 50: 168 hours After Infusion
    38235.52
    (6740.02)
    52287.81
    (35615.67)
    41265.30
    (9052.83)
    TNF-alpha: Day 1: Pre-Infusion
    2.304
    (0.564)
    2.582
    (0.986)
    2.188
    (0.650)
    TNF-alpha: Day 3: 48 hours After Infusion
    3.482
    (0.971)
    4.403
    (1.578)
    3.607
    (1.579)
    TNF-alpha: Day 8: 168 hours After Infusion
    2.440
    (0.763)
    3.233
    (1.174)
    2.682
    (0.994)
    TNF-alpha: Day 15: Pre-Infusion
    2.832
    (1.523)
    3.155
    (1.154)
    2.720
    (0.969)
    TNF-alpha: Day 43: Pre-Infusion
    2.720
    (0.908)
    3.490
    (1.987)
    2.698
    (1.063)
    TNF-alpha: Day 45: 48 hours After Infusion
    3.983
    (3.359)
    3.935
    (2.316)
    3.218
    (1.807)
    TNF-alpha: Day 50: 168 hours After Infusion
    3.180
    (2.200)
    3.967
    (2.515)
    2.525
    (0.965)
    IL-8: Day 1: Pre-Infusion
    23.210
    (26.035)
    20.517
    (7.254)
    31.667
    (34.892)
    IL-8: Day 3: 48 hours After Infusion
    30.122
    (28.378)
    31.717
    (14.891)
    44.033
    (42.682)
    IL-8: Day 8: 168 hours After Infusion
    31.082
    (35.176)
    29.750
    (20.021)
    36.500
    (40.883)
    IL-8: Day 15: Pre- Infusion
    24.372
    (25.645)
    23.817
    (12.850)
    46.967
    (68.781)
    IL-8: Day 43: Pre-Infusion
    56.310
    (88.524)
    25.733
    (14.433)
    17.600
    (5.614)
    IL-8: Day 45: 48 hours After Infusion
    51.015
    (74.760)
    30.083
    (17.206)
    21.300
    (7.806)
    IL-8: Day 50: 168 hours After Infusion
    65.448
    (104.447)
    28.783
    (11.963)
    19.028
    (9.162)
    10. Secondary Outcome
    Title Dose-escalation Cohorts: Log Fold Change From Baseline in Cytokine Levels
    Description Cytokine analysis was performed to evaluate levels of Rantes, Monocyte chemoattractant protein-1 (MCP-1) and various interleukins (including IL-1beta, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-13, IL-8), Tumor necrosis factors-alpha (TNF-alpha) and Interferon-gamma (IFN-gamma) in serum samples. Log fold change from baseline (logFC) was defined as logFC (cytokine at time t) = log (cytokine signal at time t) - log (cytokine signal at baseline).
    Time Frame Baseline (Day 1 [Pre-infusion]), Day 3 (48 hours after infusion), Day 8 (168 hours after infusion), Day 15 (Pre-infusion), Day 43 (Pre-infusion), Day 45 (48 hours after infusion), Day 50 (168 hours after infusion)

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set included all participants who have received at least 1 dose of study treatment. Here "number analyzed" signified those participants who were evaluable for this outcome measure at the specified time points for the given category.
    Arm/Group Title Dose-escalation Cohort: Avelumab 3 mg/kg Dose-escalation Cohort: Avelumab 10 mg/kg Dose-escalation Cohort: Avelumab 20 mg/kg
    Arm/Group Description Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    Measure Participants 5 6 6
    IFN-gamma: Day 3: 48 hours After Infusion
    0.903
    (1.258)
    1.038
    (0.689)
    1.096
    (0.975)
    IFN-gamma: Day 8: 168 hours After Infusion
    0.280
    (1.365)
    0.722
    (0.945)
    0.600
    (0.243)
    IFN-gamma: Day 15: Pre-Infusion
    0.396
    (1.958)
    0.779
    (0.654)
    0.867
    (0.690)
    IFN-gamma: Day 43: Pre-Infusion
    0.071
    (0.800)
    1.335
    (1.735)
    0.631
    (0.593)
    IFN-gamma: Day 45: 48 hours After Infusion
    0.768
    (1.925)
    1.617
    (2.037)
    1.215
    (1.576)
    IFN-gamma: Day 50: 168 hours After Infusion
    0.234
    (1.385)
    1.045
    (2.010)
    0.273
    (0.249)
    IL-12P70: Day 3: 48 hours After Infusion
    0.000
    (0.000)
    -0.030
    (0.750)
    0.272
    (0.666)
    IL-12P70: Day 8: 168 hours After Infusion
    0.000
    (0.000)
    -0.203
    (0.504)
    0.178
    (0.437)
    IL-12P70: Day 15: Pre- Infusion
    0.000
    (0.000)
    -0.174
    (0.524)
    0.000
    (0.000)
    IL-12P70: Day 43: Pre- Infusion
    0.000
    (0.000)
    0.239
    (0.990)
    0.000
    (0.000)
    IL-12P70: Day 45: 48 hours After Infusion
    0.000
    (0.000)
    0.087
    (0.950)
    0.300
    (0.601)
    IL-12P70: Day 50: 168 hours After Infusion
    0.000
    (0.000)
    0.151
    (1.033)
    0.643
    (0.770)
    IL-10: Day 3: 48 hours After Infusion
    1.103
    (0.888)
    0.743
    (0.371)
    0.942
    (0.199)
    IL-10: Day 8: 168 hours After Infusion
    0.624
    (1.081)
    0.704
    (0.962)
    1.088
    (0.348)
    IL-10: Day 15: Pre- Infusion
    0.972
    (0.691)
    0.720
    (0.978)
    0.942
    (0.444)
    IL-10: Day 43: Pre-Infusion
    0.919
    (0.736)
    1.072
    (1.452)
    1.317
    (1.238)
    IL-10: Day 45: 48 hours After Infusion
    0.976
    (1.416)
    1.375
    (1.767)
    1.467
    (1.758)
    IL-10: Day 50:168 hours After Infusion
    0.633
    (1.122)
    1.041
    (1.680)
    0.761
    (0.713)
    IL-13: Day 3: 48 hours After Infusion
    -0.541
    (0.980)
    -0.170
    (0.844)
    -0.416
    (1.245)
    IL-13: Day 8: 168 hours After Infusion
    0.407
    (0.896)
    -0.004
    (0.245)
    -0.581
    (0.490)
    IL-13: Day 15: Pre- Infusion
    -0.133
    (1.191)
    0.125
    (0.467)
    -0.603
    (0.519)
    IL-13: Day 43: Pre- Infusion
    0.353
    (1.670)
    -0.044
    (0.866)
    0.200
    (0.391)
    IL-13: Day 45: 48 hours After Infusion
    0.769
    (1.778)
    -0.327
    (0.729)
    -0.660
    (0.560)
    IL-13: Day 50:168 hours After Infusion 4
    0.867
    (1.796)
    -0.427
    (1.082)
    -0.319
    (0.615)
    IL-1beta: Day 3: 48 hours After Infusion
    0.000
    (0.000)
    0.000
    (0.000)
    0.275
    (0.673)
    IL-1beta: Day 8: 168 hours After Infusion
    0.000
    (0.000)
    0.278
    (0.681)
    0.000
    (0.000)
    IL-1beta: Day 15: Pre- Infusion
    0.000
    (0.000)
    0.000
    (0.000)
    0.000
    (0.000)
    IL-1beta: Day 43: Pre-Infusion
    0.000
    (0.000)
    0.303
    (0.743)
    0.000
    (0.000)
    IL-1beta: Day 45: 48 hours After Infusion
    0.000
    (0.000)
    0.493
    (1.207)
    0.000
    (0.000)
    IL-1beta: Day 50: 168 hours After Infusion
    0.000
    (0.000)
    0.473
    (1.158)
    0.000
    (0.000)
    IL-2: Day 3: 48 hours After Infusion
    0.108
    (1.340)
    0.664
    (0.749)
    0.531
    (0.628)
    IL-2: Day 8: 168 hours After Infusion
    -0.118
    (1.230)
    0.035
    (0.906)
    0.326
    (0.545)
    IL-2: Day 15: Pre-Infusion
    -0.228
    (1.134)
    -0.577
    (1.055)
    -0.059
    (0.096)
    IL-2: Day 43: Pre- Infusion
    0.296
    (1.375)
    0.211
    (0.754)
    -0.193
    (0.243)
    IL-2: Day 45: 48 hours After Infusion
    0.194
    (1.675)
    0.009
    (0.892)
    -0.175
    (0.202)
    IL-2: Day 50: 168 hours After Infusion
    0.432
    (1.547)
    0.099
    (0.608)
    -0.188
    (0.220)
    IL-4: Day 3: 48 hours After Infusion
    0.000
    (0.000)
    0.000
    (0.000)
    0.000
    (0.000)
    IL-4: Day 8: 168 hours After Infusion
    0.000
    (0.000)
    0.000
    (0.000)
    0.248
    (0.606)
    IL-4: Day 15: Pre-Infusion
    0.000
    (0.000)
    0.000
    (0.000)
    0.000
    (0.000)
    IL-4: Day 43: Pre- Infusion
    0.000
    (0.000)
    0.000
    (0.000)
    0.000
    (0.000)
    IL-4: Day 45: 48 hours After Infusion
    0.000
    (0.000)
    0.000
    (0.000)
    0.000
    (0.000)
    IL-4: Day 50: 168 hours After Infusion
    0.000
    (0.000)
    0.000
    (0.000)
    0.000
    (0.000)
    IL-6: Day 3: 48 hours After Infusion
    0.153
    (0.897)
    0.660
    (0.816)
    1.196
    (1.614)
    IL-6: Day 8: 168 hours After Infusion
    0.314
    (0.421)
    0.194
    (0.618)
    0.498
    (0.321)
    IL-6: Day 15: Pre- Infusion
    0.069
    (1.455)
    0.451
    (1.457)
    0.474
    (0.572)
    IL-6: Day 43: Pre- Infusion
    0.068
    (0.949)
    -0.009
    (0.980)
    1.112
    (0.898)
    IL-6: Day 45: 48 hours After Infusion
    0.273
    (1.187)
    0.116
    (0.676)
    1.158
    (0.998)
    IL-6: Day 50: 168 hours After Infusion
    0.064
    (0.573)
    0.279
    (0.690)
    1.883
    (1.287)
    MCP-1: Day 3: 48 hours After Infusion
    0.242
    (0.206)
    0.213
    (0.296)
    0.062
    (0.234)
    MCP-1: Day 8: 168 hours After Infusion
    0.067
    (0.278)
    0.110
    (0.297)
    0.132
    (0.202)
    MCP-1: Day 15: Pre- Infusion
    -0.010
    (0.684)
    0.120
    (0.141)
    0.005
    (0.211)
    MCP-1: Day 43: Pre- Infusion
    0.173
    (0.358)
    0.055
    (0.343)
    -0.232
    (0.150)
    MCP-1: Day 45: 48 hours After Infusion
    0.045
    (0.209)
    0.318
    (0.383)
    -0.176
    (0.183)
    MCP-1: Day 50: 168 hours After Infusion
    0.144
    (0.226)
    0.180
    (0.394)
    -0.118
    (0.420)
    Rantes: Day 3: 48 hours After Infusion
    0.198
    (0.849)
    0.589
    (0.927)
    -0.242
    (0.383)
    Rantes: Day 8: 168 hours After Infusion
    0.289
    (1.709)
    0.615
    (0.866)
    -0.325
    (0.625)
    Rantes: Day 15: Pre-Infusion
    0.997
    (1.992)
    0.582
    (0.649)
    -0.025
    (0.360)
    Rantes: Day 43: Pre-Infusion
    0.389
    (1.452)
    0.450
    (0.765)
    -0.079
    (0.306)
    Rantes: Day 45: 48 hours After Infusion
    0.249
    (1.947)
    0.353
    (0.809)
    -0.257
    (0.487)
    Rantes: Day 50: 168 hours After Infusion
    0.718
    (1.386)
    0.656
    (0.634)
    0.107
    (0.326)
    TNF-alpha: Day 3: 48 hours After Infusion
    0.589
    (0.443)
    0.770
    (0.314)
    0.646
    (0.388)
    TNF-alpha: Day 8: 168 hours After Infusion
    0.065
    (0.378)
    0.343
    (0.195)
    0.262
    (0.144)
    TNF-alpha: Day 15: Pre-Infusion
    0.182
    (0.805)
    0.301
    (0.090)
    0.292
    (0.158)
    TNF-alpha: Day 43: Pre-Infusion
    0.329
    (0.253)
    0.365
    (0.304)
    0.216
    (0.184)
    TNF-alpha: Day 45: 48 hours After Infusion
    0.612
    (0.848)
    0.527
    (0.376)
    0.382
    (0.422)
    TNF-alpha: Day 50: 168 hours After Infusion
    0.400
    (0.672)
    0.507
    (0.378)
    0.119
    (0.134)
    IL-8: Day 3: 48 hours After Infusion
    0.604
    (0.553)
    0.539
    (0.400)
    0.554
    (0.484)
    IL-8: Day 8: 168 hours After Infusion
    0.444
    (0.313)
    0.393
    (0.406)
    0.189
    (0.145)
    IL-8: Day 15: Pre- Infusion
    0.201
    (0.560)
    0.118
    (0.467)
    0.256
    (0.536)
    IL-8: Day 43: Pre-Infusion
    0.773
    (1.073)
    0.241
    (0.388)
    0.033
    (0.367)
    IL-8: Day 45: 48 hours After Infusion
    0.858
    (0.885)
    0.451
    (0.330)
    0.283
    (0.499)
    IL-8: Day 50: 168 hours After Infusion
    0.924
    (1.088)
    0.441
    (0.284)
    0.081
    (0.798)
    11. Secondary Outcome
    Title Dose-escalation Cohorts: Number of Participants With Treatment-Emergent Positive Human Anti-Human Antibody (HAHA)
    Description Participants not having positive HAHA prior to treatment with Avelumab and with at least one positive post-baseline result in the HAHA assay were termed as treatment-emergent. Treatment-emergent participants were further classified as Transient Positive or Persistent positive. Participants were considered as transient positive if time between first and last positive result was less than 16 weeks apart and a negative result at the most recent visit. Participants were considered as persistent positive if time between first and last positive result greater than or equal to [>=] 16 weeks apart or a positive evaluation at the most recent visit. Number of participants with treatment-emergent positive HAHA were reported.
    Time Frame Day 15 up to Day 2205

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set included all participants who have received at least 1 dose of study treatment.
    Arm/Group Title Dose-escalation Cohort: Avelumab 3 mg/kg Dose-escalation Cohort: Avelumab 10 mg/kg Dose-escalation Cohort: Avelumab 20 mg/kg
    Arm/Group Description Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    Measure Participants 5 6 6
    Transient positive treatment emergent
    0
    0%
    0
    0%
    0
    0%
    Persistent positive treatment emergent
    1
    20%
    0
    0%
    0
    0%
    12. Secondary Outcome
    Title Dose-escalation Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation
    Description An Adverse Event (AE) was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs were those events with onset dates occurring during the on-treatment period for the first time, or if the worsening of an event was during the on-treatment period. TEAEs included both serious TEAEs and non-serious TEAEs.
    Time Frame Time from first dose of study treatment up to 2205 days

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set included all participants who have received at least 1 dose of study treatment.
    Arm/Group Title Dose-escalation Cohort: Avelumab 3 mg/kg Dose-escalation Cohort: Avelumab 10 mg/kg Dose-escalation Cohort: Avelumab 20 mg/kg
    Arm/Group Description Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    Measure Participants 5 6 6
    TEAEs
    5
    100%
    6
    100%
    5
    83.3%
    Serious TEAEs
    1
    20%
    0
    0%
    2
    33.3%
    TEAEs Leading To Discontinuation
    0
    0%
    0
    0%
    1
    16.7%
    TEAEs Leading To Death
    1
    20%
    0
    0%
    0
    0%
    13. Secondary Outcome
    Title Expansion Cohort: Area Under the Serum Concentration-Time Curve From the Time of Dosing to the End of Dose Interval (AUC0-336hour [hr]) of Avelumab
    Description AUC0-336hour was defined as area under the serum concentration-time curve from the time of dosing to the end of dose interval (336 hr). It was calculated by linear trapezoidal summation.
    Time Frame Within 6 hours before and the end of the 1-hour infusion (Day 1) and 336 hours after end of infusion

    Outcome Measure Data

    Analysis Population Description
    PK analysis set included all participants who have received at least 1 dose of study treatment and provided at least 1 measurable post-dose concentration. Here "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure.
    Arm/Group Title Expansion Cohort: Avelumab 10 mg/kg
    Arm/Group Description Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the expansion cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    Measure Participants 37
    Mean (Standard Deviation) [mcg/mL]
    14.525
    (6.3064)
    14. Secondary Outcome
    Title Expansion Cohort: Serum Trough Concentration Levels (Ctrough) of Avelumab
    Description Ctrough was defined as the trough or minimum serum concentration.
    Time Frame Within 6 hours before the 1-hour infusion on Day 15, Day 29, Day 43, Day 85, Day 127 and Day 169.

    Outcome Measure Data

    Analysis Population Description
    PK analysis set: all participants who have received at least 1 dose of study treatment and provided at least 1 measurable post-dose concentration. "Overall Number of Participants Analyzed" = participants evaluable for this outcome measure and "Number analyzed" = participants who were evaluable at the specified time points for the given category.
    Arm/Group Title Expansion Cohort: Avelumab 10 mg/kg
    Arm/Group Description Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the expansion cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    Measure Participants 37
    Day 15
    14.525
    (6.3064)
    Day 29
    17.366
    (9.2981)
    Day 43
    19.686
    (9.0747)
    Day 85
    25.125
    (14.4089)
    Day 127
    22.544
    (16.7706)
    Day 169
    20.857
    (23.2820)
    15. Secondary Outcome
    Title Expansion Cohort: Number of Participants With Programmed Death Ligand 1 (PD-L1) Tumor Expression
    Description The PD-L1 expression was evaluated using an established antiPD-L1 immunohistochemistry (IHC) assay.
    Time Frame Time from first dose of study treatment up to 1906 days

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set included all participants who have received at least 1 dose of study treatment.
    Arm/Group Title Expansion Cohort: Avelumab 10 mg/kg
    Arm/Group Description Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the expansion cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    Measure Participants 40
    Count of Participants [Participants]
    11
    220%
    16. Secondary Outcome
    Title Expansion Cohort: Absolute Values of Cytokine Levels
    Description Cytokine analysis was performed to evaluate levels of Monocyte chemoattractant protein-1 (MCP-1) and various interleukins (including IL-5, IL-6, IL-8), Tumor necrosis factors-alpha (TNF-alpha) and Interferon-gamma (IFN-gamma) in serum samples.
    Time Frame Day 1 (Pre-infusion), Day 8 (168 hour after infusion) and Day 43 (Pre-infusion)

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set included all participants who have received at least 1 dose of study treatment. Here "Number Analyzed" = participants who were evaluable for this outcome measure at the specified time points for the given category.
    Arm/Group Title Expansion Cohort: Avelumab 10 mg/kg
    Arm/Group Description Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the expansion cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    Measure Participants 40
    IFN-gamma: Day 1: Pre-Infusion
    28.125
    (97.504)
    IFN-gamma: Day 8: 168 hours post Infusion
    23.063
    (25.899)
    IFN-gamma: Day 43: Pre-Infusion
    19.215
    (22.041)
    IL-5: Day 1: Pre-Infusion
    1.139
    (1.596)
    IL-5: Day 8: 168 hours Post Infusion
    1.492
    (2.135)
    IL-5: Day 43: Pre-Infusion
    1.632
    (1.958)
    IL-6: Day 1: Pre-Infusion
    3.502
    (7.968)
    IL-6: Day 8: 168 hours Post Infusion
    4.102
    (8.479)
    IL-6: Day 43: Pre-Infusion
    1.501
    (1.555)
    MCP-1: Day 1: Pre-Infusion
    671.025
    (203.263)
    MCP-1: Day 8: 168 hours Post Infusion
    730.466
    (284.028)
    MCP-1: Day 43: Pre-Infusion
    775.411
    (280.839)
    TNF-alpha: Day 1: Pre-Infusion
    3.674
    (2.081)
    TNF-alpha: Day 8: 168 hours Post Infusion
    4.475
    (4.195)
    TNF-alpha: Day 43: Pre-Infusion
    3.694
    (1.195)
    IL-8: Day 1: Pre-Infusion
    46.254
    (43.728)
    IL-8: Day 8: 168 hours Post Infusion
    54.107
    (56.734)
    IL-8: Day 43: Pre-Infusion
    38.674
    (30.178)
    17. Secondary Outcome
    Title Expansion Cohort: Log Fold Change From Baseline in Cytokine Levels
    Description Cytokine analysis was performed to evaluate levels of Monocyte chemoattractant protein-1 (MCP-1) and various interleukins (including IL-5, IL-6, IL-8), Tumor necrosis factors-alpha (TNF-alpha) and Interferon-gamma (IFN-gamma) in serum samples. Log fold change from baseline (logFC) was defined as logFC (cytokine at time t) = log (cytokine signal at time t) - log (cytokine signal at baseline).
    Time Frame Baseline (Day 1 [Pre-infusion]), Day 8 (168 hour after infusion) and Day 43 (Pre-infusion)

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set included all participants who have received at least 1 dose of study treatment. Here "Number analyzed" = participants who were evaluable for this outcome measure at the specified time points for the given category.
    Arm/Group Title Expansion Cohort: Avelumab 10 mg/kg
    Arm/Group Description Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the expansion cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    Measure Participants 40
    IFN-gamma: Day 8: 168 hours Post Infusion
    0.697
    (1.140)
    IFN-gamma: Day 43: Pre-Infusion
    0.484
    (1.371)
    IL-5: Day 8: 168 hours Post Infusion
    0.080
    (1.209)
    IL-5: Day 43: Pre-Infusion
    0.192
    (1.466)
    IL-6: Day 8: 168 hours Post Infusion
    0.476
    (2.172)
    IL-6: Day 43: Pre-Infusion
    0.880
    (2.184)
    MCP-1: Day 8: 168 hours Post Infusion
    0.082
    (0.353)
    MCP-1: Day 43: Pre-Infusion
    0.115
    (0.420)
    TNF-alpha: Day 8: 168 hours Post Infusion
    0.209
    (0.377)
    TNF-alpha: Day 43: Pre-Infusion
    0.156
    (0.366)
    IL-8: Day 8: 168 hours Post Infusion
    0.199
    (0.444)
    IL-8: Day 43: Pre-Infusion
    0.256
    (0.664)
    18. Secondary Outcome
    Title Expansion Cohort: Number of Participants With Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
    Description Confirmed BOR was defined as the best response of any of the complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from the date of randomization until disease progression or recurrence (taking the smallest measurement recorded since the start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. SD: Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. Number of participants with best overall response in each category (CR, PR, SD, PD) was reported.
    Time Frame Time from first dose of study treatment up to 1906 days

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set included all participants who have received at least 1 dose of study treatment.
    Arm/Group Title Expansion Cohort: Avelumab 10 mg/kg
    Arm/Group Description Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the expansion cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    Measure Participants 40
    Complete response (CR)
    1
    20%
    Partial Response (PR)
    3
    60%
    Stable disease (SD)
    17
    340%
    Progressive disease (PD)
    17
    340%
    Non-evaluable (NE)
    2
    40%
    19. Secondary Outcome
    Title Expansion Cohort: Number of Participants With Immune-related Best Overall Response (irBOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
    Description BOR: best response of any of immune related complete response (irCR), immune related partial response (irPR), immune related stable disease (irSD) and immune related progressive disease (irPD) recorded from the date of randomization until disease progression or recurrence (taking the smallest measurement recorded since the start of treatment as reference). irCR: Complete disappearance of all tumor lesions (both index and non-index lesions with no new measurable/unmeasurable lesions). irPR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions). irSD: SLD of target and new measurable lesions neither irCR, irPR, or irPD. irPD: SLD of target and new measurable lesions increases greater than or equal to [>=] 20%, confirmed by a repeat, consecutive observations at least 4 weeks from the date first documented. Number of participants with immune-related best overall response in each category (irCR, irPR, irSD, irPD) was reported.
    Time Frame Time from first dose of study treatment up to 1906 days

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set included all participants who have received at least 1 dose of study treatment.
    Arm/Group Title Expansion Cohort: Avelumab 10 mg/kg
    Arm/Group Description Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the expansion cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    Measure Participants 40
    Immune-related Complete response (irCR)
    1
    20%
    Immune-related Partial Response (irPR)
    3
    60%
    Immune-related Stable disease (irSD)
    21
    420%
    Immune-related Progressive disease (irPD)
    9
    180%
    Non-evaluable (NE)
    6
    120%
    20. Secondary Outcome
    Title Expansion Cohort: Progression-Free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
    Description PFS was defined as the time from date of randomization until date of the first documentation of progressive disease (PD) or death due to any cause in the absence of documented PD, whichever occurs first. PD was defined as at least a 20 percent (%) increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. PFS was measured using Kaplan-Meier (KM) estimates.
    Time Frame Time from first dose of study treatment up to 1906 days

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set included all participants who have received at least 1 dose of study treatment.
    Arm/Group Title Expansion Cohort: Avelumab 10 mg/kg
    Arm/Group Description Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the expansion cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    Measure Participants 40
    Median (95% Confidence Interval) [weeks]
    10.64
    21. Secondary Outcome
    Title Expansion Cohort: Immune-related Progression-Free Survival (irPFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
    Description irPFS was defined as the time from the first dose of study treatment to the date of first documentation of immune-related progressive disease [irPD] (which was subsequently confirmed) or death due to any cause, whichever occurred first. irPD was defined as the sum of the longest diameters of target and new measurable lesions increases greater than or equal to [>=] 20 percent (%), confirmed by a repeat, consecutive observations at least 4 weeks from the date first documented.
    Time Frame Time from first dose of study treatment up to 1906 days

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set included all participants who have received at least 1 dose of study treatment.
    Arm/Group Title Expansion Cohort: Avelumab 10 mg/kg
    Arm/Group Description Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the expansion cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    Measure Participants 40
    Median (95% Confidence Interval) [weeks]
    12.00
    22. Secondary Outcome
    Title Expansion Cohort: Overall Survival (OS) Time
    Description The OS time was defined as the time from randomization to the date of death. The participants who were still alive at the time of data analysis or who were lost to follow-up OS time was censored at the last recorded date that the participant was known to be alive before the data cutoff date. OS was measured using Kaplan-Meier (KM) estimates.
    Time Frame Time from first dose of study treatment up to 1906 days

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set included all participants who have received at least 1 dose of study treatment.
    Arm/Group Title Expansion Cohort: Avelumab 10 mg/kg
    Arm/Group Description Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the expansion cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    Measure Participants 40
    Median (95% Confidence Interval) [months]
    8.87
    23. Secondary Outcome
    Title Expansion Cohort: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation
    Description An Adverse Event (AE) was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs were those events with onset dates occurring during the on-treatment period for the first time, or if the worsening of an event was during the on-treatment period. TEAEs included both serious TEAEs and non-serious TEAEs.
    Time Frame Time from first dose of study treatment up to 1906 days

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set included all participants who have received at least one dose of study treatment.
    Arm/Group Title Expansion Cohort: Avelumab 10 mg/kg
    Arm/Group Description Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the expansion cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    Measure Participants 40
    TEAEs
    40
    800%
    Serious TEAEs
    11
    220%
    TEAEs Leading to Discontinuation
    7
    140%
    TEAEs Leading To Death
    3
    60%
    24. Secondary Outcome
    Title Expansion Cohort: Number of Participants With Treatment-Emergent Positive Human Anti-Human Antibody (HAHA)
    Description Number of participants with positive HAHA were reported. Participants not having positive HAHA prior to treatment with avelumab and with at least one positive post-baseline result in the HAHA assay were characterized as treatment-emergent. Treatment-emergent participants were further classified as Transient Positive or Persistent positive participants were considered as transient positive if time between first and last positive result was less than 16 weeks apart and a negative result at the most recent visit. Participants were considered as persistent positive if time between first and last positive result >=16 weeks apart or a positive evaluation at the most recent visit.
    Time Frame Day 15 up to Day 1906

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set included all participants who have received at least 1 dose of study treatment. Here, "Overall Number of Participants Analyzed" signified participants who were evaluable for this outcome measure.
    Arm/Group Title Expansion Cohort: Avelumab 10 mg/kg
    Arm/Group Description Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the expansion cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    Measure Participants 38
    Transient positive treatment emergent
    2
    40%
    Persistent positive treatment emergent
    5
    100%

    Adverse Events

    Time Frame Dose-escalation Cohort: up to 2205 days and Expansion Cohort: up to 1906 days
    Adverse Event Reporting Description
    Arm/Group Title Dose-escalation Cohort: Avelumab 3 mg/kg Dose-escalation Cohort: Avelumab 10 mg/kg Dose-escalation Cohort: Avelumab 20 mg/kg Expansion Cohort: Avelumab 10 mg/kg
    Arm/Group Description Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg once every 2 weeks in the dose-escalation cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred. Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg once every 2 weeks in the expansion cohort until disease progression, unacceptable toxicity or withdrawal from the study or study drug occurred.
    All Cause Mortality
    Dose-escalation Cohort: Avelumab 3 mg/kg Dose-escalation Cohort: Avelumab 10 mg/kg Dose-escalation Cohort: Avelumab 20 mg/kg Expansion Cohort: Avelumab 10 mg/kg
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 4/5 (80%) 3/6 (50%) 4/6 (66.7%) 36/40 (90%)
    Serious Adverse Events
    Dose-escalation Cohort: Avelumab 3 mg/kg Dose-escalation Cohort: Avelumab 10 mg/kg Dose-escalation Cohort: Avelumab 20 mg/kg Expansion Cohort: Avelumab 10 mg/kg
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/5 (20%) 0/6 (0%) 2/6 (33.3%) 11/40 (27.5%)
    Cardiac disorders
    Myocardial infarction 0/5 (0%) 0/6 (0%) 0/6 (0%) 1/40 (2.5%)
    Gastrointestinal disorders
    Ileus 0/5 (0%) 0/6 (0%) 0/6 (0%) 2/40 (5%)
    Gastric haemorrhage 0/5 (0%) 0/6 (0%) 0/6 (0%) 2/40 (5%)
    Intestinal obstruction 0/5 (0%) 0/6 (0%) 0/6 (0%) 1/40 (2.5%)
    Upper gastrointestinal haemorrhage 0/5 (0%) 0/6 (0%) 0/6 (0%) 1/40 (2.5%)
    Gastrointestinal haemorrhage 0/5 (0%) 0/6 (0%) 0/6 (0%) 1/40 (2.5%)
    General disorders
    Disease progression 1/5 (20%) 0/6 (0%) 0/6 (0%) 2/40 (5%)
    Multiple organ dysfunction syndrome 0/5 (0%) 0/6 (0%) 0/6 (0%) 1/40 (2.5%)
    Infections and infestations
    Biliary tract infection 0/5 (0%) 0/6 (0%) 0/6 (0%) 1/40 (2.5%)
    Investigations
    Platelet count decreased 0/5 (0%) 0/6 (0%) 1/6 (16.7%) 0/40 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain 0/5 (0%) 0/6 (0%) 0/6 (0%) 1/40 (2.5%)
    Nervous system disorders
    Altered state of consciousness 1/5 (20%) 0/6 (0%) 0/6 (0%) 0/40 (0%)
    Headache 1/5 (20%) 0/6 (0%) 0/6 (0%) 0/40 (0%)
    Tonic convulsion 0/5 (0%) 0/6 (0%) 1/6 (16.7%) 0/40 (0%)
    Other (Not Including Serious) Adverse Events
    Dose-escalation Cohort: Avelumab 3 mg/kg Dose-escalation Cohort: Avelumab 10 mg/kg Dose-escalation Cohort: Avelumab 20 mg/kg Expansion Cohort: Avelumab 10 mg/kg
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 5/5 (100%) 6/6 (100%) 5/6 (83.3%) 38/40 (95%)
    Blood and lymphatic system disorders
    Anaemia 1/5 (20%) 0/6 (0%) 1/6 (16.7%) 12/40 (30%)
    Anaemia of malignant disease 0/5 (0%) 1/6 (16.7%) 0/6 (0%) 0/40 (0%)
    Iron deficiency anaemia 1/5 (20%) 0/6 (0%) 0/6 (0%) 0/40 (0%)
    Ear and labyrinth disorders
    Vertigo 1/5 (20%) 0/6 (0%) 1/6 (16.7%) 0/40 (0%)
    Endocrine disorders
    Hyporthyroidism 0/5 (0%) 1/6 (16.7%) 0/6 (0%) 0/40 (0%)
    Hyperthyroidism 0/5 (0%) 0/6 (0%) 0/6 (0%) 3/40 (7.5%)
    Eye disorders
    Retinal vein occlusion 0/5 (0%) 0/6 (0%) 1/6 (16.7%) 0/40 (0%)
    Visual impairment 1/5 (20%) 0/6 (0%) 0/6 (0%) 0/40 (0%)
    Eye discharge 0/5 (0%) 0/6 (0%) 1/6 (16.7%) 0/40 (0%)
    Gastrointestinal disorders
    Vomiting 2/5 (40%) 1/6 (16.7%) 2/6 (33.3%) 9/40 (22.5%)
    Nausea 3/5 (60%) 1/6 (16.7%) 0/6 (0%) 11/40 (27.5%)
    Stomatitis 1/5 (20%) 3/6 (50%) 0/6 (0%) 0/40 (0%)
    Abdominal pain 1/5 (20%) 0/6 (0%) 0/6 (0%) 5/40 (12.5%)
    Constipation 0/5 (0%) 1/6 (16.7%) 0/6 (0%) 3/40 (7.5%)
    Diarrhoea 1/5 (20%) 0/6 (0%) 0/6 (0%) 4/40 (10%)
    Cheilitis 0/5 (0%) 0/6 (0%) 0/6 (0%) 3/40 (7.5%)
    Dysphagia 0/5 (0%) 1/6 (16.7%) 0/6 (0%) 0/40 (0%)
    Flatulence 1/5 (20%) 0/6 (0%) 0/6 (0%) 0/40 (0%)
    Gastric ulcer 0/5 (0%) 1/6 (16.7%) 0/6 (0%) 0/40 (0%)
    Haematemesis 0/5 (0%) 1/6 (16.7%) 0/6 (0%) 0/40 (0%)
    Oesophagitis 0/5 (0%) 1/6 (16.7%) 0/6 (0%) 0/40 (0%)
    Periodontal disease 1/5 (20%) 0/6 (0%) 0/6 (0%) 0/40 (0%)
    Toothache 1/5 (20%) 0/6 (0%) 0/6 (0%) 0/40 (0%)
    Abdominal pain upper 0/5 (0%) 1/6 (16.7%) 0/6 (0%) 0/40 (0%)
    General disorders
    Pyrexia 1/5 (20%) 2/6 (33.3%) 1/6 (16.7%) 7/40 (17.5%)
    Non-cardiac chest pain 1/5 (20%) 1/6 (16.7%) 0/6 (0%) 0/40 (0%)
    Fatigue 0/5 (0%) 1/6 (16.7%) 0/6 (0%) 5/40 (12.5%)
    Influenza like illness 1/5 (20%) 0/6 (0%) 0/6 (0%) 0/40 (0%)
    Oedema peripheral 1/5 (20%) 0/6 (0%) 0/6 (0%) 0/40 (0%)
    Malaise 0/5 (0%) 0/6 (0%) 0/6 (0%) 4/40 (10%)
    Immune system disorders
    Seasonal allergy 1/5 (20%) 0/6 (0%) 0/6 (0%) 0/40 (0%)
    Infections and infestations
    Nasopharyngitis 1/5 (20%) 1/6 (16.7%) 1/6 (16.7%) 3/40 (7.5%)
    Upper respiratory tract infection 1/5 (20%) 0/6 (0%) 0/6 (0%) 4/40 (10%)
    Oral herpes 0/5 (0%) 0/6 (0%) 1/6 (16.7%) 0/40 (0%)
    Pneumonia 0/5 (0%) 1/6 (16.7%) 0/6 (0%) 0/40 (0%)
    Conjunctivitis 0/5 (0%) 0/6 (0%) 1/6 (16.7%) 0/40 (0%)
    Influenza 1/5 (20%) 0/6 (0%) 0/6 (0%) 0/40 (0%)
    Paronychia 1/5 (20%) 0/6 (0%) 0/6 (0%) 0/40 (0%)
    Injury, poisoning and procedural complications
    Infusion related reaction 1/5 (20%) 2/6 (33.3%) 2/6 (33.3%) 5/40 (12.5%)
    Investigations
    White blood cell count decreased 1/5 (20%) 2/6 (33.3%) 0/6 (0%) 0/40 (0%)
    Electrocardiogram QT prolonged 0/5 (0%) 1/6 (16.7%) 0/6 (0%) 3/40 (7.5%)
    Weight decreased 1/5 (20%) 1/6 (16.7%) 0/6 (0%) 5/40 (12.5%)
    Alanine aminotransferase increased 0/5 (0%) 0/6 (0%) 1/6 (16.7%) 0/40 (0%)
    Aspartate aminotransferase increased 0/5 (0%) 0/6 (0%) 1/6 (16.7%) 0/40 (0%)
    Blood alkaline phosphatase increased 0/5 (0%) 0/6 (0%) 1/6 (16.7%) 0/40 (0%)
    Blood bilirubin increased 0/5 (0%) 0/6 (0%) 1/6 (16.7%) 0/40 (0%)
    Blood creatinine increased 1/5 (20%) 0/6 (0%) 0/6 (0%) 0/40 (0%)
    Eosinophil count increased 0/5 (0%) 0/6 (0%) 1/6 (16.7%) 0/40 (0%)
    Neutrophil count decreased 0/5 (0%) 1/6 (16.7%) 0/6 (0%) 0/40 (0%)
    Metabolism and nutrition disorders
    Decreased appetite 0/5 (0%) 0/6 (0%) 1/6 (16.7%) 9/40 (22.5%)
    Hyperuricaemia 0/5 (0%) 1/6 (16.7%) 0/6 (0%) 0/40 (0%)
    Hypoglycaemia 0/5 (0%) 1/6 (16.7%) 0/6 (0%) 0/40 (0%)
    Hyponatraemia 0/5 (0%) 0/6 (0%) 1/6 (16.7%) 0/40 (0%)
    Hypoalbuminaemia 0/5 (0%) 0/6 (0%) 0/6 (0%) 4/40 (10%)
    Hypertriglyceridaemia 0/5 (0%) 0/6 (0%) 1/6 (16.7%) 0/40 (0%)
    Musculoskeletal and connective tissue disorders
    Back pain 0/5 (0%) 1/6 (16.7%) 0/6 (0%) 0/40 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain 0/5 (0%) 2/6 (33.3%) 1/6 (16.7%) 0/40 (0%)
    Tumour pain 0/5 (0%) 0/6 (0%) 0/6 (0%) 4/40 (10%)
    Nervous system disorders
    Headache 1/5 (20%) 1/6 (16.7%) 1/6 (16.7%) 0/40 (0%)
    Peripheral sensory neuropathy 0/5 (0%) 1/6 (16.7%) 0/6 (0%) 0/40 (0%)
    Dysgeusia 0/5 (0%) 0/6 (0%) 0/6 (0%) 3/40 (7.5%)
    Dizziness 1/5 (20%) 1/6 (16.7%) 0/6 (0%) 0/40 (0%)
    Psychiatric disorders
    Insomnia 0/5 (0%) 1/6 (16.7%) 1/6 (16.7%) 3/40 (7.5%)
    Renal and urinary disorders
    Proteinuria 0/5 (0%) 0/6 (0%) 0/6 (0%) 4/40 (10%)
    Ureterolithiasis 0/5 (0%) 1/6 (16.7%) 0/6 (0%) 0/40 (0%)
    Respiratory, thoracic and mediastinal disorders
    Cough 1/5 (20%) 1/6 (16.7%) 0/6 (0%) 0/40 (0%)
    Pleural effusion 0/5 (0%) 1/6 (16.7%) 0/6 (0%) 0/40 (0%)
    Skin and subcutaneous tissue disorders
    Rash maculo-papular 2/5 (40%) 1/6 (16.7%) 1/6 (16.7%) 3/40 (7.5%)
    Pruritus 2/5 (40%) 1/6 (16.7%) 0/6 (0%) 7/40 (17.5%)
    Dry skin 0/5 (0%) 1/6 (16.7%) 0/6 (0%) 5/40 (12.5%)
    Rash 0/5 (0%) 1/6 (16.7%) 0/6 (0%) 4/40 (10%)
    Dermatitis acneiform 1/5 (20%) 1/6 (16.7%) 0/6 (0%) 0/40 (0%)
    Seborrhoea 0/5 (0%) 1/6 (16.7%) 0/6 (0%) 0/40 (0%)
    Skin atrophy 1/5 (20%) 0/6 (0%) 0/6 (0%) 0/40 (0%)
    Vascular disorders
    Hypertension 0/5 (0%) 1/6 (16.7%) 1/6 (16.7%) 0/40 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Communication Center
    Organization Merck KGaA, Darmstadt, Germany
    Phone +49-6151-72-5200
    Email service@emdgroup.com
    Responsible Party:
    Merck KGaA, Darmstadt, Germany
    ClinicalTrials.gov Identifier:
    NCT01943461
    Other Study ID Numbers:
    • EMR 100070-002
    First Posted:
    Sep 17, 2013
    Last Update Posted:
    Sep 30, 2020
    Last Verified:
    Sep 1, 2020