NCT05960773

Decitabine/Cedazuridine (INQOVI), an Oral DNA Demethylating Agent, in Subjects With BAP1 Cancer Predisposition Syndrome and Subclinical, Early-Stage Mesothelioma

Phase II Evaluation of Decitabine/Cedazuridine (INQOVI), an Oral DNA Demethylating Agent in Subjects With BAP1 Cancer Predisposition Syndrome and Subclinical, Early-Stage Mesothelioma

• Status: Suspended
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 9 (actual)
• Sponsor: National Cancer Institute (NCI) · NIH
• Sex: All
• Age: 18 Years – 120 Years
• Healthy volunteers: Not accepted

Summary

This is a Phase II study to determine the rate of stabilization or disease improvement from investigational decitabine/cedazuridine (INQOVI) treatment in subjects with BRCA1-Associated Protein-1 (BAP1) Cancer Predisposition Syndrome (CPDS) and subclinical, early-stage mesothelioma. Progression-free survival (PFS) will also be determined for treated subjects, and the treatment safety (toxicity) evaluated.

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 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.

Conditions

• Mesothelioma
• Malignant Mesothelioma (MM)
• Early-stage Mesothelioma
• Subclinical Mesothelioma
• BRCA1-Associated Protein-1 (BAP1) Mutations
• Early-stage BAP1-associated Malignancies

Interventions

Type	Name	Description
DRUG	Decitabine/cedazuridine	Decitabine/cedazuridine (INQOVI) oral tablet (35 mg decitabine and 100 mg cedazuridine) taken 3 consecutive days during the first week of every cycle (1 cycle=28-days) for 6 cycles (i.e., 1 course). Additional 6 cycles (i.e., Course 2) for subjects with stable disease or disease regression. Max (total) of 2 treatment courses.

Timeline

• Start date: 2024-01-31
• Primary completion: 2026-12-01
• Completion: 2027-12-01
• First posted: 2023-07-27
• Last updated: 2026-04-17

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study