Clinical trial NCT04291885: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Merkel Cell Carcinoma
Merkel Cell Carcinoma, Stage I
Merkel Cell Carcinoma, Stage II
Merkel Cell Carcinoma, Stage III
Neuroendocrine Tumors
Carcinoma Neuroendocrine Skin
Lead sponsor: Melanoma and Skin Cancer Trials Limited
Sponsor class: OTHER
First posted: 2020-03-02
Enrollment: 122
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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 cycle 1 day 1 of study drug dose.
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. Evidence of other malignancy in the past 3 years, with exception of tumours with negligible risk of metastasis or death.

Primary outcomes:
measure: Recurrence-free survival (RFS)
timeFrame: 24 Months
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: 24 Months
measure: Disease-specific survival (DSS)
timeFrame: 24 Months
measure: Rate of loco-regional failure free survival (LRFFS)
timeFrame: 24 Months
measure: Distant metastasis-free survival (DMFS)
timeFrame: 24 Months
measure: Treatment toxicity and tolerability as assessed by NCI CTCAE v5.0
timeFrame: 24 Months
measure: Patient-reported quality of life (QoL) as assessed by FACT-M questionnaire
timeFrame: 24 Months
Other outcomes:
measure: Rate of Merkel cell polyomavirus positivity in stage I-III Merkel cell carcinoma
timeFrame: 24 Months
measure: Correlating whole exome sequencing (WES) and ribonucleic acid (RNA) expression with immunotherapy response and outcomes in early stage MCC
timeFrame: 24 Months
measure: Correlating immune infiltrates by multiplex immunohistochemistry (IHC) with survival endpoints
timeFrame: 24 Months
measure: Utility of circulating biomarkers in predicting recurrence in early stage MCC
timeFrame: 24 Months
Locations:
city: Port Macquarie
country: Australia
facility: Port Macquarie Base Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Chris O'Brien Lifehouse
state: New South Wales
city: Sydney
country: Australia
facility: Melanoma Institute Australia
state: New South Wales
city: Sydney
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Calvary Mater Hospital
state: New South Wales
city: Wollongong
country: Australia
facility: Cancer Care Wollongong
state: New South Wales
city: Brisbane
country: Australia
facility: Royal Brisbane and Woman's Hospital
state: Queensland
city: Bundaberg
country: Australia
facility: Cancer Care Service, Bundaberg Base Hospital
state: Queensland
city: Cairns
country: Australia
facility: Cairns Hospital
state: Queensland
city: Hervey Bay
country: Australia
facility: Cancer Care Service, Hervey Bay Hospital
state: Queensland
city: Mackay
country: Australia
facility: Mackay Hospital and Health Service
state: Queensland
city: Southport
country: Australia
facility: Tasman Health Care
state: Queensland
city: Townsville
country: Australia
facility: Townsville Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Hobart
country: Australia
facility: Icon Cancer Centre Hobart
state: Tasmania
city: Melbourne
country: Australia
facility: Alfred Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Auckland
country: New Zealand
facility: Auckland City Hospital
Study officials:
affiliation: Princess Alexandra Hospital
name: A/Prof Wen Xu, MBBS, FRACP
role: STUDY_CHAIR
References: