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Immune Checkpoint Inhibitor In High Risk Oral Premalignant Lesions (IMPEDE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04504552
Recruitment Status : Recruiting
First Posted : August 7, 2020
Last Update Posted : December 1, 2020
Information provided by (Responsible Party):
Paolo Bossi, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia

Tracking Information
First Submitted Date  ICMJE August 3, 2020
First Posted Date  ICMJE August 7, 2020
Last Update Posted Date December 1, 2020
Actual Study Start Date  ICMJE July 16, 2020
Estimated Primary Completion Date October 31, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 5, 2020)
  • 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 ]
    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
  • Change in LOH status (positive to negative) of OPL [ Time Frame: 6 months ]
    Change in LOH status (positive to negative) of OPL after 6 months since the start of immunotherapy. This is defined as disappearance of any high-risk LOH (and the nonappearance of any other high-risk LOH) in the site of the OPL at the histological sample after immunotherapy treatment
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 5, 2020)
  • Safety of immunotherapy in the treatment of OPL [ Time Frame: Through study completion, an average of 5 years ]
    Grade 3-5 adverse events or any treatment interruption due to toxicities (safety)
  • Grading of OPL [ Time Frame: 6 months ]
    Change of histological grading of OPL
  • Multi-omic signatures [ Time Frame: 6 months and through study completion, an average of 5 years ]
    Identification of multi-omic signatures associated with response to immunotherapy
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Immune Checkpoint Inhibitor In High Risk Oral Premalignant Lesions
Official Title  ICMJE Phase II Trial, Open Label, Single-arm, of Immune Checkpoint Inhibitor In High Risk Oral Premalignant Lesions
Brief Summary

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)

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Oral Premalignant Lesions
Intervention  ICMJE Drug: Avelumab
Subjects will receive treatment with avelumab monotherapy 800 mg as a 60-minute IV infusion on the Day 1 (± 2 days) of a 2-week treatment cycle for 4 administrations.
Other Name: Bavencio
Study Arms  ICMJE Experimental: Single Arm Avelumab
Avelumab monotherapy on the Day 1 (± 2 days) of a 2-week treatment cycle for 4 administrations.
Intervention: Drug: Avelumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 5, 2020)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 31, 2024
Estimated Primary Completion Date October 31, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Paolo Bossi +390303996536
Contact: Mariarita Arenella +39 089 301545
Listed Location Countries  ICMJE Italy
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT04504552
Other Study ID Numbers  ICMJE IMPEDE
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: After the end of the trial, the genomic data of OPL will be made publicly available through GEO
Supporting Materials: Clinical Study Report (CSR)
Time Frame: 12 months after the end of the trial, for at least 1 year
Access Criteria: NS
Responsible Party Paolo Bossi, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
Study Sponsor  ICMJE Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP