Clinical trial NCT02155647: Avelumab in Participants With Merkel Cell Carcinoma (JAVELIN Merkel 200)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Carcinoma, Merkel Cell
Keywords: Carcinoma, Merkel Cell
MSB0010718C
avelumab
Bavencio
anti PD-L1
JAVELIN Merkel 200
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
First posted: 2014-06-04
Enrollment: 204
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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).


Eligibility criteria: 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)

Primary outcomes:
measure: Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Per Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1
timeFrame: Up to 113 weeks
measure: Part B: Durable Response Rate (DRR)
timeFrame: Up to 161 weeks
Secondary outcomes:
measure: Part A: Duration of Response According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1
timeFrame: Up to 325 weeks
measure: Part A: Progression-Free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1
timeFrame: Up to 325 weeks
measure: 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
timeFrame: Up to 325 weeks
measure: Part A: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs)
timeFrame: Up to 325 weeks
measure: Part A: Number of Participants With Clinically Significant Abnormalities in Vital Signs Reported as Treatment Emergent Adverse Events (TEAEs)
timeFrame: Up to 325 weeks
measure: Part A: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG)
timeFrame: Up to 325 weeks
measure: Part A: Interim Analysis: Overall Survival (OS) Time
timeFrame: Up to 87 weeks (Data reported are per pre-specified interim analysis with a data cut-off date of 3 Mar 2016)
measure: Part A: Final Analysis: Overall Survival (OS) Time
timeFrame: Time from first administration of trial treatment until death (Up to 325 weeks)
measure: Part A: Participant's Response Status According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 at 6 and 12 Months
timeFrame: At Month 6 and 12
measure: Part A: Number of Participants With Positive Treatment Emergent Anti-Avelumab Antibodies
timeFrame: Up to 80 weeks
measure: Part A: Serum Concentration at End of Infusion (CEOI) of Avelumab
timeFrame: Day 1, 43, 85, 169, 253, 337 and 421
measure: Part A: Minimum Serum Post-dose (Ctrough) Concentration of Aveluamb
timeFrame: Day 15, 29, 43, 57, 71, 85, 99, 169, 211, 253, 337 and 421
measure: Part B: Interim Analysis: Overall Survival (OS) Time
timeFrame: Up to 161 weeks (Data reported are per pre-specified interim analysis with a data cut-off date of 2 May 2019)
measure: Part B: Final Analysis: Overall Survival (OS) Time
timeFrame: Time from first administration of trial treatment until death (Up to 396 weeks)
measure: Part B: Number of Participants With Confirmed Best Overall Response (BOR) as Per Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1
timeFrame: Up to 396 weeks
measure: Part B: Duration of Response According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1
timeFrame: Up to 396 weeks
measure: Part B: Progression-Free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1
timeFrame: Up to 396 weeks
measure: 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
timeFrame: Up to 396 weeks
measure: Part B: Participant's Response Status According to RECIST 1.1 at 6 and 12 Months
timeFrame: At Month 6 and 12
measure: Part B: Number of Participants With Positive Treatment Emergent Anti-Avelumab Antibodies
timeFrame: Up to 161 weeks
measure: Part B: Serum Concentration at End of Infusion (CEOI) of Avelumab
timeFrame: At Day 1, 43 and 169
measure: Part B: Minimum Serum Post-dose (Ctrough) Concentration of Aveluamb
timeFrame: Day 15, Day 29, Day 43, Day 85, Day 127, Day 169, Day 253, Day 337, Day 421, Day 505, Day 589, Day 673
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: Los Angeles
country: United States
facility: The Angeles Clinic and Research Institute - West LA
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research Institute, Inc
state: Florida
city: Bethesda
country: United States
facility: National Cancer Institute
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey
state: New Jersey
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Mount Sinai
state: New York
city: Oklahoma City
country: United States
facility: Peggy & Charles Stephenson Oklahoma Cancer Center
state: Oklahoma
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Seattle
country: United States
facility: University of Washington - Seattle Cancer Care Alliance
state: Washington
city: Port Macquarie
country: Australia
facility: Port Macquarie Base Hospital
state: New South Wales
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Southport
country: Australia
facility: Tasman Oncology Research Ltd
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: East Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Perth
country: Australia
facility: St John of God Subiaco Hospital
state: Western Australia
city: Nice cedex 3
country: France
facility: CHU Nice - Hopital de l Archet 2
state: Alpes Maritimes
city: Marseille cedex 05
country: France
facility: Hôpital de la Timone
state: Bouches-du-Rhône
city: Besançon Cedex
country: France
facility: CHU Besançon - Hôpital Jean Minjoz
state: Doubs
city: Nantes Cedex 1
country: France
facility: CHU Nantes - Hôtel Dieu
state: Loire Atlantique
city: Lille cedex
country: France
facility: Hopital Claude Huriez - CHU Lille
state: Nord
city: Paris Cedex 10
country: France
facility: Hôpital Saint-Louis
state: Paris
city: Pierre Benite cedex
country: France
facility: Centre Hospitalier Lyon Sud
state: Rhone
city: Villejuif cedex
country: France
facility: Institut Gustave Roussy
state: Val De Marne
city: Bordeaux
country: France
facility: Groupe Hospitalier Saint André - Hôpital Saint André
city: Boulogne Billancourt
country: France
facility: Hôpital Ambroise Paré - Boulogne-Billancourt
city: Chambray Les Tours
country: France
facility: CHU Tours - Hôpital Trousseau
city: Dijon
country: France
facility: CHU de Dijon - Hopital du Bocage
city: Grenoble
country: France
facility: CHU de Grenoble - Hôpital A Michallon
city: Limoges
country: France
facility: CHU de Limoges - Hôpital Dupuytren
city: Heidelberg
country: Germany
facility: Universitaetsklinikum Heidelberg
state: Baden Wuerttemberg
city: Frankfurt
country: Germany
facility: Klinikum der Johann Wolfgang Goethe-Universitaet
state: Hessen
city: Bochum
country: Germany
facility: St. Josef-Hospital Universitaetsklinikum
state: Nordrhein Westfalen
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
state: Nordrhein Westfalen
city: Koeln
country: Germany
facility: Universitaetsklinikum Koeln
state: Nordrhein Westfalen
city: Muenster
country: Germany
facility: Fachklinik Hornheide
state: Nordrhein Westfalen
city: Dresden
country: Germany
facility: Universitaetsklinikum Carl Gustav Carus TU Dresden
state: Sachsen
city: Kiel
country: Germany
facility: Universitaetsklinikum Schleswig-Holstein - Klinik fuer Allgemeine Innere Medizin
state: Schleswig Holstein
city: Luebeck
country: Germany
facility: Universitaetsklinikum Schleswig Holstein - Campus Luebeck
state: Schleswig Holstein
city: Erfurt
country: Germany
facility: Helios Klinikum Erfurt
state: Thueringen
city: Berlin
country: Germany
facility: Charite Universitaetsmedizin Berlin - Campus Charite Mitte
city: Candiolo
country: Italy
facility: Fondazione del Piemonte per l'Oncologia IRCC Candiolo
state: Torino
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
city: Milano
country: Italy
facility: IEO Istituto Europeo di Oncologia
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori Fondazione G.Pascale
city: Padova
country: Italy
facility: IOV - Istituto Oncologico Veneto IRCCS
city: Perugia
country: Italy
facility: Azienda Ospedaliera di Perugia Ospedale S. Maria della Misericordia
city: Reggio Emilia
country: Italy
facility: Arcispedale S. Maria Nuova Azienda Ospedaliera di Reggio Emilia
city: Roma
country: Italy
facility: Istituto Nazionale Tumori Regina Elena IRCCS
city: Siena
country: Italy
facility: A.O.U. Senese Policlinico Santa Maria alle Scotte
city: Shizuoka
country: Japan
facility: Shizuoka Cancer Center
state: Shizuoka-Ken
city: Chuo-ku
country: Japan
facility: National Cancer Center Hospital
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial de Barcelona
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Valencia
country: Spain
facility: Hospital General Universitario de Valencia
Study officials:
affiliation: Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References:
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 metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol. 2016 Oct;17(10):1374-1385. doi: 10.1016/S1470-2045(16)30364-3. Epub 2016 Sep 1.
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 cell carcinoma after >/=1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial. J Immunother Cancer. 2018 Jan 19;6(1):7. doi: 10.1186/s40425-017-0310-x.
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 Carcinoma: A Preplanned Interim Analysis of a Clinical Trial. JAMA Oncol. 2018 Sep 1;4(9):e180077. doi: 10.1001/jamaoncol.2018.0077. Epub 2018 Sep 13.
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 Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial. J Immunother Cancer. 2020 May;8(1):e000674. doi: 10.1136/jitc-2020-000674.
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 Interview Findings from JAVELIN Merkel 200, a Registrational Clinical Trial. Patient. 2020 Aug;13(4):457-467. doi: 10.1007/s40271-020-00428-5.
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.
citation: 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.
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/jitc-2020-001427.
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 of treatment-naive patients with Merkel cell carcinoma receiving avelumab. Future Oncol. 2020 Sep;16(27):2089-2099. doi: 10.2217/fon-2020-0426. Epub 2020 Sep 17.
citation: Grisic AM, Xiong W, Tanneau L, Jonsson S, Friberg LE, Karlsson MO, Dai H, Zheng J, Girard P, Khandelwal A. Model-Based Characterization of the Bidirectional Interaction Between Pharmacokinetics and Tumor Growth Dynamics in Patients with Metastatic Merkel Cell Carcinoma Treated with Avelumab. Clin Cancer Res. 2022 Apr 1;28(7):1363-1371. doi: 10.1158/1078-0432.CCR-21-2662.
citation: D'Angelo SP, Lebbe C, Mortier L, Brohl AS, Fazio N, Grob JJ, Prinzi N, Hanna GJ, Hassel JC, Kiecker F, Georges S, Ellers-Lenz B, Shah P, Guzel G, Nghiem P. First-line avelumab in a cohort of 116 patients with metastatic Merkel cell carcinoma (JAVELIN Merkel 200): primary and biomarker analyses of a phase II study. J Immunother Cancer. 2021 Jul;9(7):e002646. doi: 10.1136/jitc-2021-002646.
citation: Bharmal M, Nolte S, Henry-Szatkowski M, Hennessy M, Schlichting M. Update on the psychometric properties and minimal important difference (MID) thresholds of the FACT-M questionnaire for use in treatment-naive and previously treated patients with metastatic Merkel cell carcinoma. Health Qual Life Outcomes. 2020 May 19;18(1):145. doi: 10.1186/s12955-020-01402-3.
citation: Bullement A, Willis A, Amin A, Schlichting M, Hatswell AJ, Bharmal M. Evaluation of survival extrapolation in immuno-oncology using multiple pre-planned data cuts: learnings to aid in model selection. BMC Med Res Methodol. 2020 May 6;20(1):103. doi: 10.1186/s12874-020-00997-x.
citation: Novakovic AM, Wilkins JJ, Dai H, Wade JR, Neuteboom B, Brar S, Bello CL, Girard P, Khandelwal A. Changing Body Weight-Based Dosing to a Flat Dose for Avelumab in Metastatic Merkel Cell and Advanced Urothelial Carcinoma. Clin Pharmacol Ther. 2020 Mar;107(3):588-596. doi: 10.1002/cpt.1645. Epub 2019 Nov 18.
citation: Bharmal M, Guillemin I, Marrel A, Arnould B, Lambert J, Hennessy M, Fofana F. How to address the challenges of evaluating treatment benefits-risks in rare diseases? A convergent mixed methods approach applied within a Merkel cell carcinoma phase 2 clinical trial. Orphanet J Rare Dis. 2018 Jun 18;13(1):95. doi: 10.1186/s13023-018-0835-1.