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.|
|ClinicalTrials.gov Identifier: NCT04504552|
Recruitment Status : Not yet recruiting
First Posted : August 7, 2020
Last Update Posted : August 7, 2020
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.
|Condition or disease||Intervention/treatment||Phase|
|Oral Premalignant Lesions||Drug: Avelumab||Phase 2|
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 :||Interventional (Clinical Trial)|
|Estimated Enrollment :||240 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase II Trial, Open Label, Single-arm, of Immune Checkpoint Inhibitor In High Risk Oral Premalignant Lesions|
|Estimated Study Start Date :||September 16, 2020|
|Estimated Primary Completion Date :||October 31, 2023|
|Estimated Study Completion Date :||March 31, 2024|
Experimental: Single Arm Avelumab
Avelumab monotherapy on the Day 1 (± 2 days) of a 2-week treatment cycle for 4 administrations.
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
- 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
- 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