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

Last updated: June 5, 2025
Sponsor: National Cancer Institute (NCI)
Overall Status: Active - Recruiting

Phase

2

Condition

Lung Cancer

Mesothelioma

Treatment

Decitabine/cedazuridine

Clinical Study ID

NCT05960773
10001549
001549-C
  • Ages 18-120
  • All Genders

Study 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.

Eligibility Criteria

Inclusion

  • INCLUSION CRITERIA:

  • Participants with history of germline BRCA1-Associated Protein-1 (BAP1) mutations.

  • Histologically confirmed by NCI LP subclinical, early-stage (Tx-T1) mesotheliomas.

  • Participants with other early-stage BAP1-associated malignancies in addition tosubclinical, early-stage mesotheliomas are eligible for study.

  • The extent of the disease (Tx by radiographic imaging) must be insufficient towarrant approved front-line therapies (surgery, chemotherapy, immunotherapy) perstandard of care (SOC). Participants with cT1 tumors may be eligible for study ifthey have been offered and have refused front-line SOC treatment.

  • Age >= 18 years.

  • Evaluable disease as confirmed by minimally invasive (videoscopic) assessment (thoracoscopy and/or laparoscopy) performed at screening (within 8 weeks prior totreatment initiation).

  • Willingness to undergo pre- and post-treatment minimally invasive thoracoscopyand/or laparoscopy to assess treatment response.

  • Willingness to co-enroll on 20C0106 (Prospective Evaluation of High Resolution DualEnergy Computed Tomographic Imaging, Noninvasive (Liquid) Biopsies, and MinimallyInvasive Surgical Surveillance for Early Detection of Mesotheliomas in Patients withBAP1 Tumor Predisposition Syndrome) and/or 06C0014 (Prospective Evaluation ofGenetic and Epigenetic Alterations in Patients with Thoracic Malignancies) to enablecollection/processing of tumor, blood and normal pleura if applicable per PI.

  • ECOG performance status 0 - 1

  • Adequate pulmonary reserve evidenced by FEV1 and DLCO >= 35% predicted on screeningpulmonary function testing (PFTs).

  • Oxygen saturation >= 92% on room air by pulse oximetry at screening.

  • Adequate renal, hepatic, and hematopoietic function at screening as defined below:

  • leukocytes >= 3,000/microL

  • absolute neutrophil count >= 1,500/microL (without transfusion or cytokinesupport within 2 months prior to study treatment initiation)

  • absolute lymphocyte count > 800/microL

  • platelets >=100,000/microL and < 1,200,000/microL

  • prothrombin time (PT) <=2 seconds above the upper limit of normal (ULN)

  • total bilirubin < 1.5 X institutional upper limit of normal OR direct bilirubin <= 1 ULN for participants with total bilirubin > 1.5 ULN

  • serum albumin >= 2.0 mg/dL

  • aspartate aminotransferase (AST) / alanine aminotransferase (ALT) <= 2.5 Xinstitutional ULN

  • creatinine <= 1.6 mg/ml OR creatinine clearance (eGFR) >= 60 mL/min/1.73 m^2for participants with creatinine levels above institutional normal.

  • Individuals of child-bearing potential (IOCBP) and those that can father childrenmust agree to use an effective method of contraception (barrier, hormonal,intrauterine device (IUD), surgical sterilization) from the study entry and up to 6months (IOCBP) or 3 months (those that can father children) after the last dose ofthe decitabine/cedazuridine.

  • Nursing (including breastfeeding) participants must be willing to discontinuenursing from study treatment initiation through 2 weeks after the last dose of thestudy drug.

  • The ability of a participant to understand and the willingness to sign a writteninformed consent document.

Exclusion

EXCLUSION CRITERIA:

  • Participants with cancers requiring frontline standard of care treatment.

  • Clinically significant cardiovascular/cerebrovascular disease as follows: cerebralvascular accident/stroke (< 6 months prior to study treatment initiation),myocardial infarction (< 6 months prior to study treatment initiation), unstableangina, congestive heart failure (New York Heart Association Classification Class >=II, serious cardiac arrhythmia, clinically significant bleeding or clinicallysignificant pulmonary embolism.

  • Therapeutic anticoagulation within 2 weeks prior to study treatment initiation.

  • Active Hepatitis A (HAV), Hepatitis B (HBV) (e.g., HBsAg reactive), or Hepatitis C (HCV) (e.g., HCV RNA [qualitative] is detected) at screening.

  • History of human immunodeficiency virus (HIV) infection or acquired immunodeficiencysyndrome (AIDS)-related illness.

  • Other active infections requiring systemic therapy.

  • Active COVID infection.

  • Major surgery within 4 weeks prior to study treatment initiation.

  • Immunosuppressive medications within 4 weeks prior to study treatment initiationexcept non-systemic corticosteroids.

  • History of prior treatment with a DNA demethylating agent.

  • Pregnancy (confirmed with beta human chorionic gonadotropin (beta-HCG) serum orurine pregnancy test performed in IOCBP at screening).

  • Uncontrolled intercurrent illness or situation that would limit compliance withstudy requirements.

Study Design

Total Participants: 15
Treatment Group(s): 1
Primary Treatment: Decitabine/cedazuridine
Phase: 2
Study Start date:
January 31, 2024
Estimated Completion Date:
December 01, 2026

Study 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.

Connect with a study center

  • National Institutes of Health Clinical Center

    Bethesda, Maryland 20892
    United States

    Active - Recruiting

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