Alrizomadlin (APG-115) in Subjects With BAP1 Cancer Syndrome and Early-Stage Mesothelioma

Background: Mesothelioma is a rare cancer typically caused by exposure to asbestos and related fibers. Most people with mesothelioma survive less than 5 years after diagnosis. About 3000 people in the United States die from this disease each year. People with inherited mutations in the BAP1 gene \[called BAP1 Cancer Syndrome (BCS)\] are more likely to develop mesothelioma and other cancers such as melanomas and renal cell carcinomas without asbestos exposure. Almost all people with BCS develop multiple cancers, of which mesothelioma is the most commonly observed. Objective: To test a study drug (APG-115) in participants with BAP1 Cancer Syndrome (BCS) and early-stage mesothelioma. Eligibility: People aged 18 years and older with germline BAP1 mutations and early-stage mesothelioma that does not yet need standard treatment are eligible for protocol enrollment. Participants will be required to also enroll in NIH protocols 20-C-0106 and 06-C-0014 which allow for pre- and post-treatment biopsies and bloodwork to be obtained for additional research studies. Design: Participants will be screened. They will have a physical exam with blood tests. Their medical records will be reviewed. They will have imaging scans and tests of their heart and lung functions. A procedure using a flexible tube with a camera and light will be inserted into the participant s chest and abdomen through a small cut to look at the tumors and to collect a tissue sample (biopsy). APG-115 capsules are taken by mouth. Participants will take the drug at home every other day for the first 13 days of the 21-day treatment cycles. On the first day of each cycle, researchers will call or email participants to check on their health. Participants will have blood tests 2 times a week during the first 2 cycles; after that, the blood tests will be weekly. These blood tests can be done at a local medical facility or at the NIH Clinical Center. Participants may continue treatment for up to 16 cycles. Imaging scans, biopsy, and other tests will be repeated after 8 and 16 cycles.

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 Syndrome (BCS), previously known as 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 BCS is unknown. * Presently there are no established guidelines for the treatment of subclinical malignancies in subjects with BAP1 BCS. * Ubiquitin-like with plant homeodomain and ring finger domains 1 (UHRF1) is a master regulator of DNA methylation and genome integrity in normal cells. * Up-regulation of UHRF1 during malignant transformation induces widespread epigenomic perturbations including global DNA hypomethylation and paradoxical site-specific DNA hypermethylation of tumor suppressor genes. * Dysregulation of DNA methylation induces genomic instability and enhances growth as well as invasion and metastatic potential of cancer cells and promotes an immunosuppressive tumor micro-environment (TME). * Up-regulation of UHRF1 is an early event during mesothelioma development, and UHRF1 over-expression is associated with markedly decreased survival in mesothelioma patients. * Biochemical inhibition of UHRF1 expression inhibits the growth of mesothelioma cells invitro and in-vivo. * UHRF1 expression can be repressed by mdm2 inhibitors which activate p53 signaling. In addition to direct effects on cancer cells, mdm2 inhibitors can reprogram TMEs thereby promoting more effective antitumor immune responses. * APG-115 is an oral, highly potent, mdm2 inhibitor that is in clinical development. * Conceivably APG-115 therapy can arrest or delay the progression of subclinical/early stage mesotheliomas in subjects with BAP1 BCS. Objective: -To determine stabilization or disease improvement rates in participants with early-stage mesotheliomas arising in the context of BAP1 Cancer Syndrome (BCS) following APG-115 treatment Eligibility: * History of germline BRCA1-Associated Protein-1 (BAP1) mutations. * Histologically confirmed subclinical/early-stage mesotheliomas. * The extent of the disease must be insufficient to warrant approved front-line standard-of care therapies (surgery, chemotherapy, immunotherapy). * Age \>= 18 years. * Eastern Cooperative Oncology Group (ECOG) performance status \<=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 start oral APG-115 at a fixed dose and schedule (150 mg on Days 1, 3, 5,7, 9, 11, and 13 of a 21-day cycle) and will continue this regimen for 8 cycles. * After eight cycles, participants will undergo repeat imaging and minimally invasive thoracoscopy and/or laparoscopy to determine treatment response and obtain tissue for response endpoints. * Participants with stable disease or disease regression will be offered an additional 8 cycles of APG-115 treatment. * Approximately 13 participants will be administered investigational therapy on this protocol.