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

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Not yet recruiting

CT.gov ID

NCT05960773

Collaborator

(none)

Enrollment

Location

Arm

39.8

Anticipated Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Mesothelioma Malignant Mesothelioma (MM) Early-stage Mesothelioma Subclinical Mesothelioma BRCA1-Associated Protein-1 (BAP1) Mutations Early-stage BAP1-associated Malignancies	Drug: Decitabine/cedazuridine	Phase 2

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 with 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

15 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Anticipated Study Start Date :

Aug 7, 2023

Anticipated Primary Completion Date :

Dec 1, 2025

Anticipated Study Completion Date :

Dec 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1/ Arm 1 Decitabine/cedazuridine (35 mg decitabine and 100 mg cedazuridine; PO QD)	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.

Arm

Intervention/Treatment

Experimental: 1/ Arm 1

Decitabine/cedazuridine (35 mg decitabine and 100 mg cedazuridine; PO QD)

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.

Outcome Measures

Primary Outcome Measures

To determine stabilization or disease improvement rates in participants with early-stage mesotheliomas arising in the context of BAP1 CPDS following decitabine/cedazuridine treatment [baseline, before each cycle, after every 6 treatment cycles (Course 1 and Course 2), and at the safety visit]
Assessment of thoracoscopy and/or laparoscopy findings demonstrating stability of evaluable disease or improvement compared to baseline

Secondary Outcome Measures

To evaluate the safety of decitabine/cedazuridine [before each cycle, after every 6 treatment cycles (Course 1 and Course 2), and at the safety visit]
Assessment of safety and tolerability as determined by the frequency and severity of adverse events
To determine PFS in participants receiving decitabine/cedazuridine [baseline, after every 6 treatment cycles (Course 1 and Course 2), and until date of progression or last visit ending at the time of the safety visit]
Progression free survival (PFS) determined by RECIST using the Kaplan-Meier method

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 120 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 to subclinical, early-stage mesotheliomas may be eligible for study.
The extent of the disease (Tx by radiographic imaging) must be insufficient to warrant approved front-line therapies (surgery, chemotherapy, immunotherapy) per standard of care (SOC). Participants with T1 tumors may be eligible for study if they 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).
Willingness to undergo pre- and post-treatment minimally invasive thoracoscopy and/or laparoscopy to assess treatment response.
Willingness to co-enroll on 20C0106 (Prospective Evaluation of High Resolution Dual Energy Computed Tomographic Imaging, Noninvasive (Liquid) Biopsies, and Minimally Invasive Surgical Surveillance for Early Detection of Mesotheliomas in Patients with BAP1 Tumor Predisposition Syndrome) and/or 06C0014 (Prospective Evaluation of Genetic and Epigenetic Alterations in Patients with Thoracic Malignancies) to enable collection/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 screening pulmonary function testing (PFTs).
Oxygen saturation >= 92% on room air by pulse oximetry or >= 92% by arterial blood gas (ABG) (ABG to be drawn if pulse oximetry < 90% on room air) 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 cytokine support 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 X institutional ULN
creatinine <= 1.6 mg/ml OR creatinine clearance (eGFR) >= 60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal.
Women of child-bearing potential (WOCBP) and men must agree to use an effective method of contraception (barrier, hormonal, intrauterine device (IUD), surgical sterilization) from the study entry and up to 6 months (women) or 3 months (men) after the last dose of the decitabine/cedazuridine.
Breastfeeding participants must be willing to discontinue breastfeeding from study treatment initiation through 2 weeks after the last dose of the study drug.
The ability of a participant to understand and the willingness to sign a written informed

consent document.

EXCLUSION CRITERIA:

Participants with cancers requiring frontline standard of care treatment.
Clinically significant cardiovascular/cerebrovascular disease as follows: cerebral vascular accident/stroke (< 6 months prior to study treatment initiation), myocardial infarction (< 6 months prior to study treatment initiation), unstable angina, congestive heart failure (New York Heart Association Classification Class >= II, serious cardiac arrhythmia, clinically significant bleeding or clinically significant pulmonary embolism.
Therapeutic anticoagulation (oral agents and Lovenox, etc., are monitored by factor 10 levels, not PT or partial thromboplastin time (PTT)) 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 immunodeficiency syndrome (AIDS)-related illness.
Other active infections requiring systemic therapy.
Immunosuppressive medications within 4 weeks prior to study treatment initiation except non-systemic corticosteroids.
History of prior treatment with a DNA demethylating agent.
Pregnancy (confirmed with beta human chorionic gonadotropin (beta-HCG) serum or urine pregnancy test performed in females of childbearing potential at screening).
Uncontrolled intercurrent illness or situation that would limit compliance with study requirements.