Avelumab in Participants With Merkel Cell Carcinoma (JAVELIN Merkel 200)

Carcinoma, Merkel Cell Clinical Trial

Official title:

A Phase II, Open-Label, Multicenter Trial to Investigate the Clinical Activity and Safety of Avelumab (MSB0010718C) in Subjects With Merkel Cell Carcinoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02155647
• Other study ID #: 100070-003
• Secondary ID: 2014-000445-79
• Status: Completed
• Phase: Phase 2
• Start date: July 3, 2014
• Est. completion date: May 3, 2023

Study information

• Verified date: February 2024
• Source: EMD Serono
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a multicenter, international, single-arm, open-label, Phase 2 trial to evaluate the efficacy and safety of avelumab in participants with metastatic Merkel cell carcinoma (MCC).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 204
• Est. completion date: May 3, 2023
• Est. primary completion date: May 2, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Signed written informed consent
• Age 18 years and above
• Histologically proven MCC
• Participants must have received at least 1 line of chemotherapy for metastatic MCC and must have progressed after the most recent line of chemotherapy
• For Part B - Participants must not have received any prior systemic treatment for metastatic MCC. Prior chemotherapy treatment in the adjuvant setting (no clinically detectable disease; no metastatic disease) is allowable if the end of treatment occurred at least 6 months prior to study start)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
• Disease must be measurable with at least 1 uni-dimensional measurable lesion by RECIST Version 1.1 (including skin lesions)
• Adequate hematological, hepatic and renal function (renal function considered adequate as per protocol definition)
• Highly effective contraception for both male and female participants, if the risk of conception exists
• Fresh Biopsy or Archival Tumor Tissue
• Estimated life expectancy of more than 12 weeks

Exclusion Criteria:

• Participation in another interventional clinical trial within the past 30 days (participation in observational studies is permitted)
• Concurrent treatment with a non permitted drug
• Prior therapy with any antibody/drug targeting T-cell coregulatory proteins (immune checkpoints) such as antiprogrammed death 1 (PD-1), anti-PD-L1, or anticytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody; for Part B, the Investigator must consult with the Medical Monitor and consider other co-regulatory targets such as 4-1BB
• Concurrent anticancer treatment (for example, cytoreductive therapy, radiotherapy [with the exception of palliative bone-directed radiotherapy, or radiotherapy administered on non-target superficial lesions], immune therapy, or cytokine therapy except for erythropoietin). Radiotherapy administered to superficial lesions is not allowed if such lesions are considered target lesions in the efficacy evaluation or may influence the efficacy evaluation of the investigational agent
• Major surgery for any reason, except diagnostic biopsy, within 4 weeks and/or if the participant has not fully recovered from the surgery within 4 weeks
• Concurrent systemic therapy with steroids or other immunosuppressive agents, or use of any investigational drug within 28 days before the start of trial treatment. Short-term administration of systemic steroids (that is, for allergic reactions or the management of immune-related adverse events [irAE]) while on study is allowed. Also, participants requiring hormone replacement with corticosteroids for adrenal insufficiency are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses <= 10 mg or equivalent prednisone per day. Note: Participants receiving bisphosphonate or denosumab are eligible.
• Participants with active central nervous system (CNS) metastases are excluded. Participants with a history of treated CNS metastases (by surgery or radiation therapy) are not eligible unless they have fully recovered from treatment, demonstrated no progression for at least 2 months, and do not require continued steroid therapy
• Previous malignant disease (other than MCC) within the last 5 years with the exception of basal or squamous cell carcinoma of the skin and for Part A cervical carcinoma in situ or for Part B carcinoma in situ (skin, bladder, cervical, colorectal, breast or low grade prostatic intraepithelial neoplasia or Grade 1 prostate cancer)
• Prior organ transplantation, including allogeneic stem-cell transplantation
• Part A: Known history of testing positive for HIV or known acquired immunodeficiency syndrome (AIDS) or any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection. For Part B, known history of testing positive for HIV or known AIDS in consultation with the Medical Monitor or HBV or HCV infection at screening (positive HBV surface antigen or HCV RNA if anti- HCV antibody screening test positive).
• Active or history of any autoimmune disease (except for participants with vitiligo) or immunodeficiencies that required treatment with systemic immunosuppressive drugs
• Known severe hypersensitivity reactions to monoclonal antibodies (Grade greater than or equal to (>=) 3 NCI CTCAE v 4.0), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma)
• Persisting toxicity related to prior therapy Grade > 1 NCI-CTCAE v 4.0; however, sensory neuropathy Grade <= 2 is acceptable 14. Pregnancy or lactation
• Known alcohol or drug abuse
• Clinically significant (that is, active) cardiovascular disease: cerebral vascular accident / stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class >= II), or serious cardiac arrhythmia requiring medication
• 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
• Non oncology vaccine therapies for prevention of infectious disease (for example, seasonal flu vaccine, human papilloma virus vaccine) within 4 weeks of trial drug administration. Vaccination while on trial is also prohibited except for administration of inactivated vaccines (for example, inactivated seasonal influenza vaccine)

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Merkel Cell

Intervention

Drug:
• Avelumab
Avelumab was administered at a dose of 10 milligram per kilogram (mg/kg) as 1-hour intravenous infusion once every 2 weeks until therapeutic failure, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the trial or investigational medicinal product occurs.

Locations

Country	Name	City	State
Australia	Peter MacCallum Cancer Centre	East Melbourne	Victoria
Australia	St John of God Subiaco Hospital	Perth	Western Australia
Australia	Port Macquarie Base Hospital	Port Macquarie	New South Wales
Australia	Tasman Oncology Research Ltd	Southport	Queensland
Australia	Royal North Shore Hospital	St Leonards	New South Wales
Australia	Princess Alexandra Hospital	Woolloongabba	Queensland
France	CHU Besançon - Hôpital Jean Minjoz	Besançon Cedex	Doubs
France	Groupe Hospitalier Saint André - Hôpital Saint André	Bordeaux
France	Hôpital Ambroise Paré - Boulogne-Billancourt	Boulogne Billancourt
France	CHU Tours - Hôpital Trousseau	Chambray Les Tours
France	CHU de Dijon - Hopital du Bocage	Dijon
France	CHU de Grenoble - Hôpital A Michallon	Grenoble
France	Hopital Claude Huriez - CHU Lille	Lille cedex	Nord
France	CHU de Limoges - Hôpital Dupuytren	Limoges
France	Hôpital de la Timone	Marseille cedex 05	Bouches-du-Rhône
France	CHU Nantes - Hôtel Dieu	Nantes Cedex 1	Loire Atlantique
France	CHU Nice - Hopital de l Archet 2	Nice cedex 3	Alpes Maritimes
France	Hôpital Saint-Louis	Paris Cedex 10	Paris
France	Centre Hospitalier Lyon Sud	Pierre Benite cedex	Rhone
France	Institut Gustave Roussy	Villejuif cedex	Val De Marne
Germany	Charite Universitaetsmedizin Berlin - Campus Charite Mitte	Berlin
Germany	St. Josef-Hospital Universitaetsklinikum	Bochum	Nordrhein Westfalen
Germany	Universitaetsklinikum Carl Gustav Carus TU Dresden	Dresden	Sachsen
Germany	Helios Klinikum Erfurt	Erfurt	Thueringen
Germany	Universitaetsklinikum Essen	Essen	Nordrhein Westfalen
Germany	Klinikum der Johann Wolfgang Goethe-Universitaet	Frankfurt	Hessen
Germany	Universitaetsklinikum Heidelberg	Heidelberg	Baden Wuerttemberg
Germany	Universitaetsklinikum Schleswig-Holstein - Klinik fuer Allgemeine Innere Medizin	Kiel	Schleswig Holstein
Germany	Universitaetsklinikum Koeln	Koeln	Nordrhein Westfalen
Germany	Universitaetsklinikum Schleswig Holstein - Campus Luebeck	Luebeck	Schleswig Holstein
Germany	Fachklinik Hornheide	Muenster	Nordrhein Westfalen
Italy	Fondazione del Piemonte per l'Oncologia IRCC Candiolo	Candiolo	Torino
Italy	Fondazione IRCCS Istituto Nazionale dei Tumori	Milano
Italy	IEO Istituto Europeo di Oncologia	Milano
Italy	Istituto Nazionale Tumori Fondazione G.Pascale	Napoli
Italy	IOV - Istituto Oncologico Veneto IRCCS	Padova
Italy	Azienda Ospedaliera di Perugia Ospedale S. Maria della Misericordia	Perugia
Italy	Arcispedale S. Maria Nuova Azienda Ospedaliera di Reggio Emilia	Reggio Emilia
Italy	Istituto Nazionale Tumori Regina Elena IRCCS	Roma
Italy	A.O.U. Senese Policlinico Santa Maria alle Scotte	Siena
Japan	National Cancer Center Hospital	Chuo-ku
Japan	Shizuoka Cancer Center	Shizuoka	Shizuoka-Ken
Spain	Hospital Clinic i Provincial de Barcelona	Barcelona
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Hospital General Universitario Gregorio Marañon	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital General Universitario de Valencia	Valencia
United States	University of Colorado	Aurora	Colorado
United States	National Cancer Institute	Bethesda	Maryland
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	The Angeles Clinic and Research Institute - West LA	Los Angeles	California
United States	UCLA Medical Center	Los Angeles	California
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Mount Sinai	New York	New York
United States	Peggy & Charles Stephenson Oklahoma Cancer Center	Oklahoma City	Oklahoma
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of Washington - Seattle Cancer Care Alliance	Seattle	Washington
United States	H. Lee Moffitt Cancer Center and Research Institute, Inc	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
EMD Serono Research & Development Institute, Inc.

Countries where clinical trial is conducted

United States,  Australia,  France,  Germany,  Italy,  Japan,  Spain, 

References & Publications (9)

Bharmal M, Fofana F, Barbosa CD, Williams P, Mahnke L, Marrel A, Schlichting M. Psychometric properties of the FACT-M questionnaire in patients with Merkel cell carcinoma. Health Qual Life Outcomes. 2017 Dec 22;15(1):247. doi: 10.1186/s12955-017-0815-5. E — View Citation

Bharmal M, Nolte S, Lebbe C, Mortier L, Brohl AS, Fazio N, Grob JJ, Pusceddu S, Hanna GJ, Hassel JC, Kiecker F, Ellers-Lenz B, Bajars M, Guzel G, Nghiem P, Hunger M, Schlichting M, Henry-Szatkowski M, D'Angelo SP. Health-related quality of life trajectory — View Citation

D'Angelo SP, Bhatia S, Brohl AS, Hamid O, Mehnert JM, Terheyden P, Shih KC, Brownell I, Lebbe C, Lewis KD, Linette GP, Milella M, Georges S, Shah P, Ellers-Lenz B, Bajars M, Guzel G, Nghiem PT. Avelumab in patients with previously treated metastatic Merke — View Citation

D'Angelo SP, Russell J, Lebbe C, Chmielowski B, Gambichler T, Grob JJ, Kiecker F, Rabinowits G, Terheyden P, Zwiener I, Bajars M, Hennessy M, Kaufman HL. Efficacy and Safety of First-line Avelumab Treatment in Patients With Stage IV Metastatic Merkel Cell — View Citation

Kaufman HL, Dias Barbosa C, Guillemin I, Lambert J, Mahnke L, Bharmal M. Living with Merkel Cell Carcinoma (MCC): Development of a Conceptual Model of MCC Based on Patient Experiences. Patient. 2018 Aug;11(4):439-449. doi: 10.1007/s40271-018-0301-0. — View Citation

Kaufman HL, Russell J, Hamid O, Bhatia S, Terheyden P, D'Angelo SP, Shih KC, Lebbe C, Linette GP, Milella M, Brownell I, Lewis KD, Lorch JH, Chin K, Mahnke L, von Heydebreck A, Cuillerot JM, Nghiem P. Avelumab in patients with chemotherapy-refractory meta — View Citation

Kaufman HL, Russell JS, Hamid O, Bhatia S, Terheyden P, D'Angelo SP, Shih KC, Lebbe C, Milella M, Brownell I, Lewis KD, Lorch JH, von Heydebreck A, Hennessy M, Nghiem P. Updated efficacy of avelumab in patients with previously treated metastatic Merkel ce — View Citation

Kelly K, Manitz J, Patel MR, D'Angelo SP, Apolo AB, Rajan A, Kasturi V, Speit I, Bajars M, Warth J, Gulley JL. Efficacy and immune-related adverse event associations in avelumab-treated patients. J Immunother Cancer. 2020 Nov;8(2):e001427. doi: 10.1136/ji — View Citation

Lambert J, Marrel A, D'Angelo SP, Burgess MA, Chmielowski B, Fazio N, Gambichler T, Grob JJ, Lebbe C, Robert C, Russell J, Guzel G, Bharmal M. Patient Experiences with Avelumab in Treatment-Naive Metastatic Merkel Cell Carcinoma: Longitudinal Qualitative — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Per Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1	Confirmed BOR was determined according to RECIST 1.1and as adjudicated by an Independent Endpoint Review Committee(IERC) and defined as best response of any of complete response (CR), partial response(PR), stable disease(SD) and progressive disease(PD) recorded from date of randomization until disease progression/recurrence(taking smallest measurement recorded since start of treatment as reference). CR:Disappearance of all evidence of target/non-target lesions. PR:At least 30%reduction from baseline in sum of longest diameter(SLD) of all lesions. SD:Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD:at least a20% increase in SLD, taking as reference smallest SLD recorded from baseline/appearance of 1or more new lesions and unequivocal progression of non-target lesions. CR or PR must be confirmed by a subsequent tumor assessment preferably at next scheduled 6-weekly assessment, but no sooner than 5 weeks after initial documentation of CR or PR.	Up to 113 weeks
Primary	Part B: Durable Response Rate (DRR)	Durable response is defined as an objective response (confirmed complete response [CR] or confirmed Partial response [PR]) according to Response Evaluation Criteria in Solid Tumors version (RECIST) 1.1, determined by the Independent Endpoint Review Committee (IERC), with a duration of at least 6 months. The DRR was determined as the percentage of participants with an objective response in terms of CR or PR according to RECIST 1.1, as determined by the IERC, with a duration of at least 6 months. 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.	Up to 161 weeks
Secondary	Part A: Duration of Response According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1	The duration of response as determined from IERC tumor assessment was calculated for each participant with a confirmed response (CR or PR) as the time from first observation of response until first observation of documented disease progression or death when death occurs within 12 weeks of the last tumor assessment, whichever occurs first. 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. Results were calculated based on Kaplan-Meier estimates.	Up to 325 weeks
Secondary	Part A: Progression-Free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1	The PFS time (based on IERC tumor assessments), according to the RECIST 1.1, was defined as the time from first administration of study treatment until first observation of PD or death when death occurred within 12 weeks of the last tumor assessment or first administration of study treatment (whichever was later). PFS time (in months) was defined as: (date of PD or death - date of the first dose of study treatment + 1)/30.4375 (months). 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.	Up to 325 weeks
Secondary	Part A: Number of Participants With Treatment-Related (TR) Treatment-Emergent Adverse Events (TEAEs), Treatment-Related Serious TEAEs and Treatment-Related TEAEs Leading to Death	Related Adverse events (AE) were defined according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE) as adverse events with relationship to study treatment reported by the investigator. 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. Treatment-emergent are events between first dose of study drug that were absent before treatment or that worsened relative to pre-treatment state up to 30 days after last administration. TEAEs included both Serious TEAEs and non-serious TEAEs. Related TEAEs are defined as events with a relationship of missing, unknown, or yes.	Up to 325 weeks
Secondary	Part A: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs)	The laboratory measurements included hematology, liver function and blood chemistry. Number of participants with clinically significant abnormalities with Grade greater than or equals to (>=) 3 in laboratory values reported as TEAEs were reported. Clinically Significance was decided by investigator.	Up to 325 weeks
Secondary	Part A: Number of Participants With Clinically Significant Abnormalities in Vital Signs Reported as Treatment Emergent Adverse Events (TEAEs)	Vital signs including body temperature, body weight, respiratory rate, heart rate (after 5-minute rest), and arterial blood pressure (after 5-minute rest) were evaluated. Number of participants with clinically significant abnormalities in Vital Signs reported as TEAEs. Clinically Significance was decided by investigator.	Up to 325 weeks
Secondary	Part A: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG)	A 12-lead ECG was recorded after the participant has been in a supine position breathing quietly for 5 minutes. The ECG results was used to evaluate the heart rate, atrial ventricular conduction, PR interval, QRS, QTcF and QTcB. Number of participants with clinical significant abnormalities in ECG parameter reported here. Clinically Significance was decided by investigator.	Up to 325 weeks
Secondary	Part A: Interim Analysis: Overall Survival (OS) Time	The OS time was defined as the time from first administration of trial treatment until death. The OS time was analyzed using the Kaplan-Meier method.	Up to 87 weeks (Data reported are per pre-specified interim analysis with a data cut-off date of 3 Mar 2016)
Secondary	Part A: Final Analysis: Overall Survival (OS) Time	The OS time was defined as the time from first administration of trial treatment until death. The OS time was analyzed using the Kaplan-Meier method.	Time from first administration of trial treatment until death (Up to 325 weeks)
Secondary	Part A: Participant's Response Status According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 at 6 and 12 Months	The response status at 6 and 12 months after start of trial treatment according to RECIST 1.1 (as determined by the IERC) was determined. A participant was considered to be in response at the given timepoint (6 or 12 months after the start of the participant's treatment) if the participant had a documented response (PR or CR) prior to that timepoint, and neither died nor experienced disease progression according to the RECIST 1.1 nor was lost to follow-up up to the given timepoint. 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. Percentage of participants in response and not in response according to RECIST1.1 at 6 and 12 months were reported.	At Month 6 and 12
Secondary	Part A: Number of Participants With Positive Treatment Emergent Anti-Avelumab Antibodies	Serum samples were analyzed by a validated electrochemiluminesce immunoassay to detect the presence of anti-avelumab antibodies. Samples that screened positive were subsequently tested in a confirmatory assay. Those confirmed positive were titered for a quasi-quantitative result. Number of participants with positive treatment emergent anti-Avelumab antibodies were reported. Participants not positive prior to treatment with avelumab and with at least one positive result in the human-Antihuman Antibodies assay were characterized as treatment-emergent.	Up to 80 weeks
Secondary	Part A: Serum Concentration at End of Infusion (CEOI) of Avelumab	Serum concentration at end of infusion (CEOI) of Avelumab is reported.	Day 1, 43, 85, 169, 253, 337 and 421
Secondary	Part A: Minimum Serum Post-dose (Ctrough) Concentration of Aveluamb	Minimum serum post-dose (Ctrough) concentration of avelumab was reported.	Day 15, 29, 43, 57, 71, 85, 99, 169, 211, 253, 337 and 421
Secondary	Part B: Interim Analysis: Overall Survival (OS) Time	The OS time was defined as the time from first administration of study treatment until the date of death. OS was calculated using following formula = (date of death - date of the first dose of study treatment + 1)/30.4375 (months).	Up to 161 weeks (Data reported are per pre-specified interim analysis with a data cut-off date of 2 May 2019)
Secondary	Part B: Final Analysis: Overall Survival (OS) Time	The OS time was defined as the time from first administration of study treatment until the date of death. OS was calculated using following formula = (date of death - date of the first dose of study treatment + 1)/30.4375 (months).	Time from first administration of trial treatment until death (Up to 396 weeks)
Secondary	Part B: Number of Participants With Confirmed Best Overall Response (BOR) as Per Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1	Confirmed BOR was determined according to RECIST 1.1and as adjudicated by an Independent Endpoint Review Committee(IERC) and defined as best response of any of complete response (CR), partial response(PR), stable disease(SD) and progressive disease(PD) recorded from date of randomization until disease progression/recurrence(taking smallest measurement recorded since start of treatment as reference). CR:Disappearance of all evidence of target/non-target lesions. PR:At least 30%reduction from baseline in sum of longest diameter(SLD) of all lesions. SD:Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD:at least a20% increase in SLD, taking as reference smallest SLD recorded from baseline/appearance of 1or more new lesions and unequivocal progression of non-target lesions. CR or PR must be confirmed by a subsequent tumor assessment preferably at next scheduled 6-weekly assessment, but no sooner than 5 weeks after initial documentation of CR or PR.	Up to 396 weeks
Secondary	Part B: Duration of Response According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1	The duration of response as determined from IERC tumor assessment was calculated for each participant with a confirmed response (CR or PR) as the time from first observation of response until first observation of documented disease progression or death when death occurs within 12 weeks of the last tumor assessment, whichever occurs first. 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.	Up to 396 weeks
Secondary	Part B: Progression-Free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1	The PFS time (based on IERC tumor assessments), according to the RECIST 1.1, was defined as the time from first administration of study treatment until first observation of PD or death when death occurred within 12 weeks of the last tumor assessment or first administration of study treatment (whichever was later). PFS time (in months) was defined as: (date of PD or death - date of the first dose of study treatment + 1)/30.4375 (months). 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.	Up to 396 weeks
Secondary	Part B: Number of Participants With Treatment-Related (TR) Treatment-Emergent Adverse Events (TEAEs), Treatment-Related Serious TEAEs and Treatment-Related TEAEs Leading to Death	Related Adverse events (AE) were defined according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE) as adverse events with relationship to study treatment reported by the investigator. 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. Treatment-emergent are events between first dose of study drug that were absent before treatment or that worsened relative to pre-treatment state up to 30 days after last administration. TEAEs included both Serious TEAEs and non-serious TEAEs. Related TEAEs are defined as events with a relationship of missing, unknown, or yes.	Up to 396 weeks
Secondary	Part B: Participant's Response Status According to RECIST 1.1 at 6 and 12 Months	The response status at 6 and 12 months after start of trial treatment according to RECIST 1.1 (as determined by the IERC) was determined. A participant was considered to be in response at the given timepoint (6 or 12 months after the start of the participant's treatment) if the participant had a documented response (PR or CR) prior to that timepoint, and neither died nor experienced disease progression according to the RECIST 1.1 nor was lost to follow-up up to the given timepoint. 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. Percentage of participants in response and not in response according to RECIST1.1 at 6 and 12 months were reported.	At Month 6 and 12
Secondary	Part B: Number of Participants With Positive Treatment Emergent Anti-Avelumab Antibodies	Serum samples were analyzed by a validated electrochemiluminescence immunoassay to detect the presence of antidrug antibodies (ADA). Samples that screened positive were subsequently tested in a confirmatory assay. Those that confirmed positive were titered for a quasi-quantitative result. Number of participants with positive treatment emergent anti-Avelumab antibodies were reported. Participants not positive prior to treatment with avelumab and with at least one positive result in the human-Antihuman Antibodies assay were characterized as treatment-emergent.	Up to 161 weeks
Secondary	Part B: Serum Concentration at End of Infusion (CEOI) of Avelumab	Serum concentration at end of infusion (CEOI) of Avelumab is reported.	At Day 1, 43 and 169
Secondary	Part B: Minimum Serum Post-dose (Ctrough) Concentration of Aveluamb	Minimum serum post-dose (Ctrough) concentration of avelumab was reported.	Day 15, Day 29, Day 43, Day 85, Day 127, Day 169, Day 253, Day 337, Day 421, Day 505, Day 589, Day 673

External Links

•   Trial Awareness and Transparency website