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

Mesothelioma Clinical Trial

Official title: 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 Recruiting

Clinical Trial 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.

Clinical Trial 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 (Bullet) 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 15 participants will be accrued to this trial. ;

Related Conditions & MeSH terms

• Disease Susceptibility
• Mesothelioma
• Mesothelioma, Malignant

• NCT number: NCT05960773
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Contact: Deneise Francis, R.N.
• Phone: (240) 858-3974
• Email: deneise.francis@nih.gov
• Status: Recruiting
• Phase: Phase 2
• Start date: January 31, 2024
• Completion date: December 1, 2026