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

• ClinicalTrials.gov Identifier: NCT04291885
• Recruitment Status: Recruiting
• First Posted: March 2, 2020
• Last Update Posted: April 15, 2024
• Sponsor: Melanoma and Skin Cancer Trials Limited
• Information provided by (Responsible Party): Melanoma and Skin Cancer Trials Limited

Tracking Information

• First Submitted Date: February 6, 2020
• First Posted Date: March 2, 2020
• Last Update Posted Date: April 15, 2024
• Actual Study Start Date: October 26, 2020
• Estimated Primary Completion Date: April 1, 2027 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 18, 2021)

Recurrence-free survival (RFS) [ Time Frame: 24 Months ]

Recurrence-free survival (RFS) as the primary endpoint, is anticipated to be analysed over an average planned follow-up of 3.5 years. An analysis of RFS at the 24 month time point of follow-up will also be conducted as it is anticipated that the minimum follow-up for participants 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.

Original Primary Outcome Measures (submitted: February 28, 2020)

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 followup 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.

Current Secondary Outcome Measures (submitted: January 18, 2021)

• Overall survival (OS) [ Time Frame: 24 Months ]
  Overall survival rates at 12 and 24 months. Overall survival is defined as the time from treatment initiation to the date of death due to any cause.
• Disease-specific survival (DSS) [ Time Frame: 24 Months ]
  Disease-specific survival at 24 months from treatment initiation. Disease-specific survival is the percentage of participants who have not died from Merkel Cell Carcinoma
• 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.
• 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.
• 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.
• 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).

Original Secondary Outcome Measures (submitted: February 28, 2020)

• 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.
• 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.
• 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.
• 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.
• 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.
• 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).

Current Other Pre-specified Outcome Measures (submitted: January 18, 2021)

• 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 from adjuvant treatment.
• 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.
• 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.
• 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.

Original Other Pre-specified Outcome Measures (submitted: February 28, 2020)

• Rate of Merkel cell polyomavirus positivity in stage I-III Merkel cell carcinoma [ Time Frame: 24 Months ]
  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.
• 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.
• 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.
• Utility of circulating biomarkers in predicting recurrence in early stage MCC [ Time Frame: 24 Months ]
  To address whether circulating biomarkers are associated with recurrence in early stage MCC.

Descriptive Information

• Brief Title: Immunotherapy Adjuvant Trial in Patients With Stage I-III Merkel Cell Carcinoma
• Official Title: A Randomised, Placebo-controlled, Phase II Trial of Adjuvant Avelumab in Patients With Stage I-III Merkel Cell Carcinoma
• Brief Summary: The I-MAT trial is a randomised, placebo-controlled, phase II trial of adjuvant Avelumab in patients with stage I-III Merkel cell carcinoma aiming to explore the efficacy of avelumab as adjuvant immunotherapy.
• 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). Participants on the trial will receive either avelumab or placebo for 6 months. 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.
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

Double-blind

Primary Purpose: Treatment

Condition

• Merkel Cell Carcinoma
• Merkel Cell Carcinoma, Stage I
• Merkel Cell Carcinoma, Stage II
• Merkel Cell Carcinoma, Stage III
• Neuroendocrine Tumors
• Carcinoma Neuroendocrine Skin

Intervention

• Drug: Avelumab
  Avelumab IV infusion
  Other Names:

  • anti-PD-L1
  • Bavencio
• Drug: Placebo
  Placebo IV infusion

Study Arms

• Experimental: Avelumab
  6 months of Avelumab at a dose of 800mg as a 60-minute intravenous (IV) infusion once every 2 weeks (13 doses)
  Intervention: Drug: Avelumab
• Placebo Comparator: Placebo
  6 months of Placebo as a 60-minute intravenous (IV) infusion once every 2 weeks (13 doses)
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 28, 2020): 132
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: April 1, 2028
• Estimated Primary Completion Date: April 1, 2027 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

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

   • clinical stage I;
   • pathological stage I with positive LVSI only;
   • 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Melanoma and Skin Cancer Trials Ltd Project officer; +61 3 9903 9022; imat@masc.org.au

• Listed Location Countries: Australia, New Zealand

Administrative Information

• NCT Number: NCT04291885
• Other Study ID Numbers: 03.18
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Melanoma and Skin Cancer Trials Limited
• Original Responsible Party: Same as current
• Current Study Sponsor: Melanoma and Skin Cancer Trials Limited
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Chair: Wen Xu, MBBS, FRACP; Princess Alexandra Hospital

• PRS Account: Melanoma and Skin Cancer Trials Limited
• Verification Date: April 2024