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

Description

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.