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Immunotherapy Adjuvant Trial in Patients With Stage I-III Merkel Cell Carcinoma (I-MAT)

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ClinicalTrials.gov Identifier: NCT04291885
Recruitment Status : Recruiting
First Posted : March 2, 2020
Last Update Posted : November 20, 2020
Sponsor:
Information provided by (Responsible Party):
Melanoma and Skin Cancer Trials Limited

Brief Summary:
The I-MAT trial is a phase II randomised and placebo-controlled trial for patients with stage I-III Merkel cell carcinoma (MCC) to explore efficacy and tolerability of avelumab as adjuvant immunotherapy.

Condition or disease Intervention/treatment Phase
Merkel Cell Carcinoma Merkel Cell Carcinoma, Stage I Merkel Cell Carcinoma, Stage II Merkel Cell Carcinoma, Stage III Neuroendocrine Tumors Carcinoma Neuroendocrine Skin Drug: Avelumab Drug: Placebo Phase 2

Detailed Description:

The I-MAT trial is a phase II, prospective, randomised, placebo-controlled, multi-institutional trial for patients with stage I-III Merkel cell carcinoma (MCC). Treatment will be avelumab vs placebo for 6 months duration. The primary aim of the I-MAT trial is to develop an effective, well-tolerated adjuvant immunotherapy regimen for patients with stage I-III MCC, post a range of definitive loco-regional treatment options.

Biological differences for Merkel Cell Polyomavirus (MCPyV)-positive versus MCPyV-negative patients in the adjuvant setting will be explored.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 132 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double-blind
Primary Purpose: Treatment
Official Title: A Randomised, Placebo-controlled, Phase II Trial of Adjuvant Avelumab in Patients With Stage I-III Merkel Cell Carcinoma
Actual Study Start Date : October 8, 2020
Estimated Primary Completion Date : December 2025
Estimated Study Completion Date : December 2028


Arm Intervention/treatment
Experimental: Avelumab
6 months of Avelumab at a dose of 800mg as a 60-minute IV infusion once every 2 weeks (13 doses)
Drug: Avelumab
Avelumab IV infusion
Other Names:
  • anti-PD-L1
  • Bavencio

Placebo Comparator: Placebo
6 months of Placebo as a 60-minute IV infusion once every 2 weeks (13 doses)
Drug: Placebo
Placebo IV infusion




Primary Outcome Measures :
  1. Recurrence-free survival (RFS) [ Time Frame: 24 Months ]
    RFS, the primary endpoint, is anticipated to be analysed over an average planned follow-up of 3.5 years per participant. An analysis of RFS at the 24 month time point of follow-up per participant will also be conducted as it is anticipated that the minimum follow-up per patient will be 24 months and the sample size rationale utilises RFS rates at 24 months in historical controls. RFS is defined as the time from treatment initiation until the first date of any signs or symptoms of recurrence of tumour.


Secondary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: 24 Months ]
    OS rates at specific landmark timepoints of 12 and 24 months. OS is defined as the time from treatment initiation to the date of death due to any cause.

  2. Disease-specific survival (DSS) [ Time Frame: 24 Months ]
    DSS is the percentage of participants who have not died from Merkel Cell Carcinoma at 24 months from treatment initiation.

  3. Rate of loco-regional failure free survival (LRFFS) [ Time Frame: 24 Months ]
    Rate of loco-regional failure free survival (LRFFS) is defined as the time from treatment initiation to the first recurrence of the loco-regional tumour.

  4. Distant metastasis-free survival (DMFS) [ Time Frame: 24 Months ]
    DMFS is defined as the time from treatment initiation to the first evidence of distant metastatic disease.

  5. Treatment toxicity and tolerability as assessed by NCI CTCAE v5.0 [ Time Frame: 24 Months ]
    Rate of treatment-related adverse events (AEs). Safety will be measured by serious adverse events (SAEs) and AEs assessed as per NCI CTCAE v5.0, including immune-related adverse events.

  6. Patient-reported quality of life (QoL) as assessed by FACT-M questionnaire [ Time Frame: 24 Months ]
    FACT-M form (version 4) will be utilised. This will include patient-reported questions relating to physical wellbeing, social/family wellbeing, emotional wellbeing, functional wellbeing and additional patient concerns which are measured from 0-4 (Not at all - Very Much).


Other Outcome Measures:
  1. Rate of Merkel cell polyomavirus positivity in stage I-III Merkel cell carcinoma [ Time Frame: 24 Months ]
    To identify Merkel cell polyomavirus MCPyV virus status. To correlate viral aetiology-rate of Merkel cell polyomavirus (MCPyV) positivity in pathology specimens in stage I-III Merkel cell carcinoma- with outcome following adjuvant treatment.

  2. Correlating whole exome sequencing (WES) and ribonucleic acid (RNA) expression with immunotherapy response and outcomes in early stage MCC [ Time Frame: 24 Months ]
    To evaluate the relationship between somatic mutations in cancer genes or the total mutation burden of the cancer with immunotherapy response and outcome following adjuvant therapy.

  3. Correlating immune infiltrates by multiplex immunohistochemistry (IHC) with survival endpoints [ Time Frame: 24 Months ]
    To address whether immune infiltrates and PD-L1 expression are associated with survival endpoints.

  4. Utility of circulating biomarkers in predicting recurrence in early stage MCC [ Time Frame: 24 Months ]
    To identify predictive biomarkers for response and resistance to immunotherapy in patients with stage I-III MCC using archival tissue and peripheral blood.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histologically confirmed Merkel cell carcinoma (MCC) which is either:

    • clinical stage I (pathological stage I MCC patients are not eligible for the study);
    • clinical or pathological stage II (including IIA and IIB);
    • clinical or pathological stage III (including IIIA and IIIB).
  2. Absence of distant metastatic disease on baseline 18-Fludeoxyglucose (18FDG) - Positron Emission Tomography (PET) / Computed Tomography (CT) scan.
  3. 18 years of age or older.
  4. Eastern Cooperative Oncology Group (ECOG) of 0 - 2.
  5. Willing and able to provide written informed consent and comply with all study requirements.
  6. Adequate haematological, liver and renal function as determined by the screening laboratory values outlined in the protocol obtained within 14 days prior to randomisation
  7. Agreeable to collection of archival tumour material. Where possible, the most recently acquired tumour specimen should be provided.
  8. Women of child bearing potential (WOCBP) must have a negative serum or urine pregnancy test within 72 hours prior to the start of treatment

Exclusion Criteria:

  1. Ongoing or recent (within 5 years) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments, which may suggest significant risk for immune-related adverse events.
  2. Prior treatment with an agent that blocks the PD-1/PD-L1 pathway.
  3. Previous cancer immunotherapy, specifically interferon, anti-CD137, or anti-CTLA-4 antibody or any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways are not permitted.
  4. Prior treatment with other immune-modulating agents that was within fewer than 28 days prior to the first dose of Avelumab.
  5. Active infection requiring antibiotics within 7 days of study entry.
  6. Active tuberculosis.
  7. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
  8. Uncontrolled infection with hepatitis B or hepatitis C virus (HBV or HCV) infection; Patients with previously successfully treated HCV, with positive anti-HCV antibody but undetectable (HCV) ribonucleic acid (RNA) levels are allowed on trial.
  9. Current use of immunosuppressive medication, except for the following: a. intranasal, inhaled, topical steroids, or local steroid injection ; b. systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c. steroids as premedication for hypersensitivity reactions
  10. Any systemic anti-cancer treatment (chemotherapy, targeted systemic therapy) investigational or standard of care, within 28 days of the first dose of Avelumab or planned to occur during the study period. Patients receiving bisphosphonates or denosumab will not be excluded.
  11. Pregnant or breastfeeding.
  12. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organising pneumonia (i.e., bronchiolitis obliterans, cryptogenic organising pneumonia), or evidence of active pneumonitis on screening chest CT scan).
  13. Uncontrolled cardiac disease including not limited to symptomatic congestive heart failure, unstable angina pectoris, life-threatening cardiac arrhythmia
  14. Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v5 Grade 3).
  15. Use of live attenuated vaccines within 28 days of first dose of Avelumab.
  16. Any acute or chronic psychiatric problems that, in the opinion of the Investigator, make the patient ineligible for participation due to compliance concerns.
  17. Patients with prior allogeneic stem cell or solid organ transplantation.
  18. Patients who are involuntarily incarcerated.
  19. No evidence of other malignancy in the past 3 years, with exception of tumours with negligible risk of metastasis or death.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04291885


Contacts
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Contact: Narelle Williams +61414579120 imat@masc.org.au

Locations
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Australia, New South Wales
Chris O'Brien Lifehouse Not yet recruiting
Sydney, New South Wales, Australia, 2050
Contact: Dr Jenny Lee    0293831014    Jenny.Lee@lh.org.au   
Principal Investigator: Dr Jenny Lee         
Melanoma Institute Australia Not yet recruiting
Sydney, New South Wales, Australia, 2065
Contact: Prof Georgina Long    0299117336    Georgina.Long@sydney.edu.au   
Principal Investigator: Prof Georgina Long         
Royal North Shore Hospital Recruiting
Sydney, New South Wales, Australia, 2065
Contact: A/Prof Alexander Guminski    0299265020    Alexander.Guminski@health.nsw.gov.au   
Principal Investigator: A/Prof Alexander Guminski         
Westmead Hospital Recruiting
Sydney, New South Wales, Australia, 2145
Contact: Prof Michael Veness    0288905200    Michael.Veness@health.nsw.gov.au   
Principal Investigator: Prof Michael Veness         
Calvary Mater Hospital Recruiting
Sydney, New South Wales, Australia, 2298
Contact: Dr Ina Nordman    0240143190    Ina.Nordman@calvarymater.org.au   
Principal Investigator: Dr Ina Nordman         
Australia, Queensland
Royal Brisbane and Woman's Hospital Not yet recruiting
Brisbane, Queensland, Australia, 4029
Contact: Dr Melissa Eastgate    0736469917    Melissa.Eastgate@health.qld.gov.au   
Principal Investigator: Dr Melissa Eastgate         
Townsville Hospital Recruiting
Townsville, Queensland, Australia
Contact: Dr Madhavi Chilkuri    0744331801    Madhavi.Chilkuri@health.qld.gov.au   
Principal Investigator: Dr Madhavi Chilkuri         
Princess Alexandra Hospital Recruiting
Woolloongabba, Queensland, Australia, 4102
Contact: A/Prof Victoria Atkinson    0731762111    victoria.atkinson@health.qld.gov.au   
Principal Investigator: Dr Wen Xu         
Principal Investigator: A/Professor Victoria Atkinson         
Australia, South Australia
Royal Adelaide Hospital Recruiting
Adelaide, South Australia, Australia, 5000
Contact: Prof Michael Brown    0883027827    MichaelP.Brown@sa.gov.au   
Principal Investigator: Prof Michael Brown         
Australia, Victoria
Alfred Hospital Recruiting
Melbourne, Victoria, Australia, 3000
Contact: Prof Mark Shackleton    0390763129    mark.shackleton@monash.edu   
Principal Investigator: Prof Mark Shackleton         
Peter MacCallum Cancer Centre Recruiting
Melbourne, Victoria, Australia, 3000
Contact: A/Prof Shahneen Sandhu    0385595000    Shahneen.Sandhu@petermac.org   
Principal Investigator: A/Prof Shahneen Sandhu         
Australia, Western Australia
Affinity Oncology Not yet recruiting
Perth, Western Australia, Australia, 6150
Contact: A/Prof Adnan Khattak    08 6152 2222    Muhammad.Khattak@health.wa.gov.au   
Principal Investigator: A/Prof Muhammad Adnan Khattak         
Sponsors and Collaborators
Melanoma and Skin Cancer Trials Limited
Investigators
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Study Chair: Wen Xu, MBBS, FRACP Princess Alexandra Hospital
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Responsible Party: Melanoma and Skin Cancer Trials Limited
ClinicalTrials.gov Identifier: NCT04291885    
Other Study ID Numbers: 03.18
First Posted: March 2, 2020    Key Record Dates
Last Update Posted: November 20, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Carcinoma, Merkel Cell
Carcinoma
Neuroendocrine Tumors
Carcinoma, Neuroendocrine
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Polyomavirus Infections
DNA Virus Infections
Virus Diseases
Tumor Virus Infections
Adenocarcinoma