Clinical Trials /

Immune Checkpoint Inhibitor In High Risk Oral Premalignant Lesions

NCT04504552

Description:

This trial is designed as a prospective, multi-centre, open-label, single-arm, phase II study. Oral Premalignant Lesions (OPL) may be considered the equilibrium phase of the immunoediting concept, i.e. a dynamic process between the tumour cells and the immune system including surveillance by the immune system or tumour progression. Thus, an imbalance in immunosuppressive microenvironment is a possible key in malignant transformation. In this regard, the activation of the PD-1/PD-L1 pathway has a central role, witnessed by the expression of PD-L1 by multiple cell types within the microenvironment of OPL (tumour-associated macrophages, fibroblasts, lymphocytes) and by the fact that PD-L1 expression in epithelial and subepithelial cells is associated with malignant transformation. The use of checkpoint inhibitors in this setting seems to be justified by this rationale. Employing intermediate end-point markers during preventive strategies against OPL may allow the conduction of smaller trials, able to give insights for designing larger studies and to better select the population receiving benefit from the treatment. In this regard, the evaluation of phenotypic changes (reduction in size or in grade of dysplasia) may not be enough to assess the potential benefit of an intervention. Modulation of molecular markers may be more precise indicator of oral cancer risk in patients with OPL. Thus, the change in LOH at critical loci may be considered intermediate end-point biomarkers of prevention as well as predictors of cancer risk at baseline. Previous experience with anti-EGFR agents showed the feasibility of such measures in a prevention trial.

Related Conditions:
  • Oral Cavity Carcinoma
  • Oral Neoplasm
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Immune Checkpoint Inhibitor In High Risk Oral Premalignant Lesions
  • Official Title: Phase II Trial, Open Label, Single-arm, of Immune Checkpoint Inhibitor In High Risk Oral Premalignant Lesions

Clinical Trial IDs

  • ORG STUDY ID: IMPEDE
  • NCT ID: NCT04504552

Conditions

  • Oral Premalignant Lesions

Interventions

DrugSynonymsArms
AvelumabBavencioSingle Arm Avelumab

Purpose

This trial is designed as a prospective, multi-centre, open-label, single-arm, phase II study. Oral Premalignant Lesions (OPL) may be considered the equilibrium phase of the immunoediting concept, i.e. a dynamic process between the tumour cells and the immune system including surveillance by the immune system or tumour progression. Thus, an imbalance in immunosuppressive microenvironment is a possible key in malignant transformation. In this regard, the activation of the PD-1/PD-L1 pathway has a central role, witnessed by the expression of PD-L1 by multiple cell types within the microenvironment of OPL (tumour-associated macrophages, fibroblasts, lymphocytes) and by the fact that PD-L1 expression in epithelial and subepithelial cells is associated with malignant transformation. The use of checkpoint inhibitors in this setting seems to be justified by this rationale. Employing intermediate end-point markers during preventive strategies against OPL may allow the conduction of smaller trials, able to give insights for designing larger studies and to better select the population receiving benefit from the treatment. In this regard, the evaluation of phenotypic changes (reduction in size or in grade of dysplasia) may not be enough to assess the potential benefit of an intervention. Modulation of molecular markers may be more precise indicator of oral cancer risk in patients with OPL. Thus, the change in LOH at critical loci may be considered intermediate end-point biomarkers of prevention as well as predictors of cancer risk at baseline. Previous experience with anti-EGFR agents showed the feasibility of such measures in a prevention trial.

Detailed Description

      OPL represent the most common oral precancerous condition, with a potential of malignant
      transformation varying from 1% to 47% in different studies. Among molecular markers, the most
      effective in predicting oral cancer risk is loss of heterozygosity (LOH), which may appear in
      tissues with different histological grade of dysplasia. Patients carrying OPL with LOH at
      3p14 and/or 9p21 plus LOH at another locus have an expected 3-year risk of developing oral
      cancer of 35%. This chromosomal profile is found in about 28% of OPL. Moreover, when a
      patient has previously suffered from oral cavity cancer, the 3-year risk of malignant
      transformation for OPL with such a chromosomal profile reaches 69%. The presence of tumour
      suppressor genes (TSGs) at these chromosomal loci explains the potential for cancer
      development in the presence of such alterations.

      The clinical management of small OPL is excision by a cold knife or laser. However, treatment
      is not effective to prevent oral cancer in patients. Lesions recur frequently and transform
      subsequently, and tumours develop in the same or adjacent anatomical region. For larger OPL
      the clinical management is limited to lifelong surveillance. To improve clinical management
      of OPLs, the arsenal of treatments should be expanded.

      Therefore, this study is aimed at treating high-risk OPL with a short course of immunotherapy
      (avelumab)
    

Trial Arms

NameTypeDescriptionInterventions
Single Arm AvelumabExperimentalAvelumab monotherapy on the Day 1 (± 2 days) of a 2-week treatment cycle for 4 administrations.
  • Avelumab

Eligibility Criteria

        Inclusion Criteria:

          1. Signed written informed consent;

          2. Male or female > 18 years of age;

          3. ECOG Performance status (PS) 0-1;

          4. Clinical and histological evidence of OPL with high risk of malignant transformation
             as defined by LOH at 3p14 and/or 9p21 plus at least at one additional chromosomal site
             (4q, 8p,11p,13q, or 17p) or patients with a prior oral cancer history and LOH at 3p14
             and/or 9p21 (LOH defined according to EPOC trial). These conditions define "LOH
             positivity";

          5. OPL with a histological definition of dysplasia and a minimum diameter of at least 20
             mm;

          6. Be willing to provide tissue from newly obtained oral biopsies;

          7. Not receiving chronic systemic steroidal therapy or any immunosuppressive therapy
             within 7 days prior to the first treatment; absence of active autoimmune disease that
             required systemic treatment in the past 2 years, except the following:

               -  Intranasal, inhaled, topical steroids, or local steroid injections (e.g.
                  intra-articular injection);

               -  Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or
                  equivalent;

               -  Steroids as premedication for hypersensitivity reactions (e.g. CT scan
                  premedication);

          8. Adequate bone marrow function: neutrophils > 1.5 x 109/L, platelets > 100 x 109/L,
             haemoglobin > 9 g/dL;

          9. Adequate liver function: bilirubin < 2 X upper normal limit (except known medical
             reason not interfering with liver function, such as Gilbert disease), SGOT, SGPT, AP,
             GGT < 3 x ULN;

         10. Adequate renal function: calculated or analysed creatinine clearance > 60 mL/min;

         11. If of childbearing potential, willingness to use effective contraceptive method (Pearl
             Index < 1; e.g. oral contraceptive (pill), hormone spiral, hormone implant,
             transdermal patch, a combination of two barrier methods (condom and diaphragm),
             sterilization, sexual abstinence for the study duration and 2 months post-dosing.

        Exclusion Criteria:

          1. Previous immunotherapy (anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody or any
             other antibody or drug specifically targeting T-cell co-stimulation or immune
             checkpoint receptors);

          2. Oral lesions due to lichen planus;

          3. Diagnosis of prior immunodeficiency or organ transplant requiring immunosuppressive
             therapy, or known human immunodeficiency virus (HIV) or acquired immunodeficiency
             syndrome (AIDS)-related illness;

          4. Any test for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating acute or
             chronic infection;

          5. Vaccination within 4 weeks of the first dose of avelumab and while on trial is
             prohibited except for the administration of inactivated vaccines (for example,
             inactivated influenza vaccines);

          6. Clinically significant cardiovascular disease, e.g. cardiac failure of New York Heart
             Association classes III-IV, uncontrolled coronary artery disease, cardiomyopathy,
             uncontrolled arrhythmia, uncontrolled hypertension, or history of myocardial
             infarction in the last 12 months;

          7. Significant neurologic or psychiatric disorders including dementia or seizures;

          8. Active uncontrolled infection (requiring IV antibiotics) or active tuberculosis;

          9. Active disseminated intravascular coagulation;

         10. Other serious underlying medical conditions which could impair the ability of the
             patient to participate into the study;

         11. Having participated in another clinical trial or having received any investigational
             agent in the preceding 30 days before study entry;

         12. Known allergic/hypersensitivity reaction to any of the components of the treatment;

         13. Pregnancy (absence confirmed by serum/urine beta HCG) or breastfeeding;

         14. Other active malignancy within 3 years, with the exception of a history of a previous,
             adequately treated:

               -  basal cell carcinoma of the skin

               -  pre-invasive carcinoma of the cervix

               -  superficial bladder cancer

               -  carcinoma in situ of the prostate, cervix or breast,

               -  head and neck squamous cell carcinoma, surgically treated (radiotherapy treatment
                  not allowed);

         15. Legal incapacity or limited legal capacity;

         16. Medical, psychological or socio-geographical condition or situation which in the
             opinion of the investigator would not permit the patient to complete the study or sign
             meaningful informed consent;

         17. Active, known or suspected autoimmune disease. Patients with vitiligo, type I diabetes
             mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone
             replacement, psoriasis not requiring systemic treatment, or conditions not expected to
             recur in the absence of an external trigger are permitted to be enrolled;

         18. Conditions requiring systemic treatment with either corticosteroids (> 10 mg daily
             prednisone equivalents) or other immunosuppressive medications within 7 days of study
             drug administration. Inhaled or topical steroids, steroids as premedication for
             hypersensitivity reactions and adrenal replacement doses > 10 mg daily prednisone
             equivalents are permitted in the absence of active autoimmune disease.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recurrence-free survival or malignant transformation-free survival
Time Frame:Every 2 weeks for the first 6 months, then every month for 1 year, then every 3 months for 30 months
Safety Issue:
Description:Recurrence or malignancy-free survival since immunotherapy start, for which the events of interest are the recurrence of OPL with LOH or malignant transformation of OPL

Secondary Outcome Measures

Measure:Safety of immunotherapy in the treatment of OPL
Time Frame:Through study completion, an average of 5 years
Safety Issue:
Description:Grade 3-5 adverse events or any treatment interruption due to toxicities (safety)
Measure:Grading of OPL
Time Frame:6 months
Safety Issue:
Description:Change of histological grading of OPL
Measure:Multi-omic signatures
Time Frame:6 months and through study completion, an average of 5 years
Safety Issue:
Description:Identification of multi-omic signatures associated with response to immunotherapy

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia

Last Updated

August 5, 2020