Background:
* Mutations involving BRCA1-Associated Protein-1 (BAP1), a nuclear deubiquitinase involved in epigenetic regulation of gene expression, DNA repair, and cellular energetics, have emerged as one of the most common somatic mutations in malignant mesotheliomas.
* Germline mutations involving BAP1 predispose individuals to mesotheliomas and a variety of other malignancies including melanomas, as well as lung, renal, gastric, breast, and hepatobiliary carcinomas.
* The cancer penetrance of germline BAP1 mutations is nearly 100%, and most patients develop multiple synchronous or metachronous neoplasms.
* Mesotheliomas are the most common malignancies diagnosed in subjects with BAP1 Cancer Predisposition Syndrome (CPDS).
* Although clinically evident mesotheliomas arising in the context of germline BAP1 mutations tend to be more indolent than more common, sporadic mesotheliomas, the natural history of early-stage mesotheliomas in subjects with BAP1 CPDS is unknown.
* Presently there are no established guidelines for the treatment of subclinical malignancies in subjects with BAP1 CPDS.
* Epigenetic aberrations including those related to the up regulation of DNA methyltransferases (DNMT) induce genomic instability and enhance the growth and invasion of mesothelioma cells.
* Over-expression of DNMT1 also promotes the development of an immunosuppressive tumor micro-environment (TME).
* Up-regulation of DNMT1 is an early event during mesothelioma development, and levels of DNMT1 over-expression are associated with poor survival in mesothelioma patients.
* Genetic or pharmacologic inhibition of DNMT1 activity induces growth arrest, genomic stress, and apoptosis of mesothelioma cells.
* DNMT1 inhibition can reprogram TMEs thereby promoting more effective antitumor immune responses.
* Decitabine/cedazuridine is an oral DNMT inhibitor which is FDA approved for patients with myelodysplastic syndromes (MDS).
* Conceivably decitabine/cedazuridine therapy can arrest or delay the progression of subclinical/early-stage mesotheliomas in subjects with BAP1 CPDS.
Objective:
-To determine stabilization or disease improvement rates in participants with early-stage mesotheliomas arising in the context of BAP1 CPDS following decitabine/cedazuridine treatment.
Eligibility:
* Participants with history of germline BAP1 mutations and histologically confirmed subclinical, early-stage mesotheliomas, with or without other early-stage BAP1-associated malignancies.
* The extent of the disease insufficient to warrant approved front-line therapies (surgery, chemotherapy, immunotherapy).
* Age \>= 18 years.
* Eastern Cooperative Oncology Group (ECOG) performance status 0 - 1.
* Willingness to undergo pre- and post-treatment, minimally invasive thoracoscopy, and/or laparoscopy to assess treatment response.
* Adequate cardiac, renal, hepatic, and hematopoietic function.
Design:
* Participants with subclinical, early-stage mesotheliomas will undergo baseline imaging studies followed by minimally invasive thoracoscopy and/or laparoscopy to document the extent of the disease and obtain biopsies for pharmacodynamic (PD) endpoints.
* Participants will then begin oral decitabine/cedazuridine at a fixed dose and schedule (one capsule taken per day for three consecutive days during the first week of each four-week cycle) and will continue this regimen for six cycles.
* Participants will then undergo repeat imaging and minimally invasive thoracoscopy and/or laparoscopy to determine treatment response and obtain tissue for response endpoints.
* Participants who experience disease progression or unacceptable toxicities will be removed from the study.
* Participants with stable disease or disease regression will be offered an additional 6 months of decitabine/cedazuridine treatment.
* Approximately 13 participants will receive study drug on this trial.
