Ignite Creation Date:
2024-10-26 @ 3:43 PM
Last Modification Date:
2024-10-26 @ 3:43 PM
Study NCT ID:
NCT06654050
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-10-22
Brief Title:
Alrizomadlin APG-115 in Subjects With BAP1 Cancer Syndrome and Early-Stage Mesothelioma
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Phase II Study of Alrizomadlin APG-115 in Subjects With BAP1 Cancer Syndrome and Early-Stage Mesothelioma
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-10-18
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This is a phase II study to determine the rate of disease stabilization or improvement from investigational alrizomadlin APG-115 treatment in subjects with early-stage mesotheliomas arising in the context of BRCA1-Associated Protein-1 BAP1 Cancer Syndrome BCS previously known as BAP1 Cancer Predisposition Syndrome CPDS Safety toxicity of APG-115 will also be evaluated for treated subjects
Detailed 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 subclinicalearly 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 subclinicalearly-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 andor 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 andor 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 57 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 andor 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
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 subclinicalearly 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 subclinicalearly-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 andor 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 andor 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 57 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 andor 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None