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

* INCLUSION CRITERIA:
* History of germline BRCA1-Associated Protein-1 (BAP1) mutations.
* Histologically confirmed by NCI Laboratory of Pathology (LP) subclinical/early-stage mesotheliomas.
* Participants with other early-stage BAP1-associated malignancies in addition to subclinical, early-stage mesotheliomas are eligible for the study.
* The extent of the disease (Tx by clinical staging criteria) must be insufficient to warrant approved front-line standard of care (SOC) therapies (surgery, chemotherapy, immunotherapy). Participants with clinical T1 tumors are eligible for protocol if they have been offered and have refused front-line SOC therapy.
* Age \>=18 years.
* Evaluable disease as confirmed by minimally invasive (videoscopic) assessment (thoracoscopy and/or laparoscopy with biopsy).
* Willingness to undergo pre- and post-treatment minimally invasive thoracoscopy and/orlaparoscopy to assess treatment response.
* Willingness to co-enroll on 20-C-0106 (Prospective Evaluation of High Resolution Dual Energy Computed Tomographic Imaging, Noninvasive (Liquid) Biopsies, and Minimally Invasive Surgical Surveillance for Early Detection of Mesotheliomas in Patients with BAP1 Tumor Predisposition Syndrome) and 06-C-0014 (Prospective Evaluation of Genetic and Epigenetic Alterations in Patients with Thoracic) to enable collection/processing of tumor, blood and normal pleura).
* ECOG performance status \<=1
* Adequate pulmonary reserve evidenced by forced expiratory volume (FEV)1 and diffusing capacity of the lungs for carbon monoxide (DLCO) \>=35% predicted on screening pulmonary function testing (PFTs).
* Oxygen saturation \>=92% on room air by pulse oximetry at screening.
* Adequate renal, hepatic, and hematopoietic function as defined below:

  * leukocytes \>= 3,000/micro L
  * absolute neutrophil count \>=1,500/micro L (without transfusion or cytokine support within 2 months prior to study treatment initiation)
  * absolute lymphocyte count \> 800/micro L
  * platelets \>= 100,000/micro L and \< 1,200,000/micro L
  * prothrombin time (PT) no more than 2 seconds above the upper limit of normal (ULN)
  * total bilirubin \< 1.5 X institutional ULN OR direct bilirubin \<= 1 ULN for participants with total bilirubin \>= 1.5 ULN serum albumin \>=2.0 mg/dL
  * aspartate aminotransferase (AST) \<=2.5 X institutional ULN
  * alanine aminotransferase (ALT) \<= 2.5 X institutional ULN
  * estimated glomerular filtration rate (eGFR) \>=60 mL/min/1.73 m2.
* Individuals of child-bearing potential (IOCBP) and those able to father a child must agree to use an effective method of contraception (barrier, hormonal, intrauterine device (IUD), surgical sterilization) from the study entry and up to 3 months after the last dose of APG-115.
* Nursing (i.e., breastfeeding/chest feeding) participants must be willing to discontinue nursing from study treatment initiation through 4 weeks after the last dose of the study drug.
* The ability of a participant to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

* Participants with any cancers requiring front-line standard of care treatment.
* Clinically significant cardiovascular/cerebrovascular disease as follows: cerebral vascular accident/stroke within 6 months prior to study treatment initiation, myocardial infarction within 6 months prior to study treatment initiation unless revascularized post infarction and cleared by cardiology consultants.
* Unstable angina, congestive heart failure (New York Heart Association Classification Class \>= II (https://manual.jointcommission.org/releases/TJC2016A/DataElem0439.html#:\~:text=Class%20II%20%2D%20Mild%20symptoms%20(mild,Class%20IV%20%2D%20Severe%20limitations.), serious cardiac arrhythmia, clinically significant bleeding or clinically significant pulmonary embolism at screening.
* QTcF interval \> than the 470 ms.
* Therapeutic anticoagulation within 2 weeks prior to study treatment initiation. Note: Oral agents and Lovenox, etc., are monitored by factor 10 levels, not PT or partial thromboplastin time (PTT).
* Participants receiving inhibitors or inducers of CYP3A4/3A5 as well as participants receiving P-glycoprotein inhibitors within 2 weeks prior to study treatment initiation treatment initiation

(https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm#table2-2,table3-3,table5-2,

* Positive Hepatitis A (HAV) serological test, positive Hepatitis B (HBV) serological test, or positive Hepatitis C (HCV) serological test with detected quantitative HCV RNA at screening.
* Participants seropositive for human immunodeficiency virus (HIV) infection.
* Active infections requiring systemic therapy.
* Immunosuppressive medications within 4 weeks prior to study treatment initiation except non-systemic corticosteroids.
* Positive beta human chorionic gonadotropin (beta-HCG) serum or urine pregnancy test performed in individuals of childbearing potential at screening.
* Uncontrolled intercurrent illness evaluated by medical history and physical exam or situation that is not stable (e.g., recent hospitalization, Emergency Room visit or undergoing medication changes) that would potentially increase in risk of participant.