Oral DNA Demethylating Agent for Mesothelioma
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: National Cancer Institute (NCI)
Must not be taking: Anticoagulants, Immunosuppressants
Disqualifiers: Cardiovascular disease, Hepatitis, HIV, others
No Placebo Group
Prior Safety Data
Approved in 1 Jurisdiction
Trial Summary
What is the purpose of this trial?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.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications. However, you cannot be on therapeutic anticoagulation or immunosuppressive medications within 2 weeks and 4 weeks, respectively, before starting the study treatment.
What data supports the effectiveness of the drug Decitabine/Cedazuridine (INQOVI) for treating mesothelioma?
The drug Decitabine/Cedazuridine (INQOVI) has been shown to be effective in treating myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), with studies indicating similar effectiveness to intravenous decitabine. While specific data for mesothelioma is not available, the drug's ability to increase decitabine's bioavailability and its success in other cancers suggest potential effectiveness.
12345Is the oral DNA demethylating agent Decitabine/Cedazuridine safe for humans?
Decitabine/Cedazuridine (INQOVI) has been studied for safety in humans, primarily for conditions like myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Common serious side effects include low white blood cell counts (neutropenia), low platelet counts (thrombocytopenia), and fever with low white blood cell counts (febrile neutropenia).
12346How is the drug Decitabine/Cedazuridine (INQOVI) unique for treating mesothelioma?
Decitabine/Cedazuridine (INQOVI) is unique because it combines decitabine, a drug that modifies DNA to stop cancer growth, with cedazuridine, which helps the body absorb decitabine more effectively when taken by mouth. This oral administration is more convenient compared to traditional intravenous treatments.
12347Eligibility Criteria
This trial is for adults with BAP1 Cancer Predisposition Syndrome and early-stage mesothelioma who haven't received certain treatments. They must be able to perform daily activities with minimal assistance, agree to use contraception, and undergo specific procedures to assess treatment response. Excluded are those with recent significant cardiovascular events, active infections like COVID or hepatitis, HIV/AIDS-related illness, pregnancy, or on immunosuppressants.Inclusion Criteria
My lung function tests show I have enough breathing capacity.
I am breastfeeding but willing to stop from the start of the study until 2 weeks after the last dose.
My mesothelioma is in an early stage and confirmed by a biopsy.
+12 more
Exclusion Criteria
If you are a woman who could become pregnant, you have a positive pregnancy test.
I have a history of HIV or AIDS-related illness.
I haven't had a stroke, heart attack, severe chest pain, serious heart failure, dangerous irregular heartbeat, significant bleeding, or a serious blood clot in the lungs in the last 6 months.
+8 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Treatment
Participants receive oral decitabine/cedazuridine at a fixed dose for six cycles, with one capsule taken per day for three consecutive days during the first week of each four-week cycle
24 weeks
6 visits (in-person) for each cycle
Follow-up
Participants are monitored for safety and effectiveness after treatment, including repeat imaging and minimally invasive procedures to assess treatment response
4 weeks
1 visit (in-person)
Extension
Participants with stable disease or disease regression are offered an additional 6 months of decitabine/cedazuridine treatment
24 weeks
Participant Groups
The study tests the effectiveness of an oral medication called INQOVI (decitabine/cedazuridine) in stabilizing or improving subclinical mesothelioma in patients predisposed due to BAP1 mutations. It measures how long patients live without disease progression and evaluates the safety of this treatment.
1Treatment groups
Experimental Treatment
Group I: 1/ Arm 1Experimental Treatment1 Intervention
Decitabine/cedazuridine (35 mg decitabine and 100 mg cedazuridine; PO QD)
Decitabine/Cedazuridine (INQOVI) is already approved in United States for the following indications:
🇺🇸 Approved in United States as INQOVI for:
- Myelodysplastic syndromes (MDS), including previously treated and untreated, de novo and secondary MDS with specific French-American-British subtypes and International Prognostic Scoring System groups
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
National Institutes of Health Clinical CenterBethesda, MD
Loading ...
Who Is Running the Clinical Trial?
National Cancer Institute (NCI)Lead Sponsor
References
FDA Approval Summary: Decitabine and Cedazuridine Tablets for Myelodysplastic Syndromes. [2023]On July 7, 2020, the Food and Drug Administration approved Inqovi (Otsuka Pharmaceutical Co.), an oral fixed-dose combination tablet comprising 35 mg decitabine, a hypomethylating agent, and 100 mg cedazuridine, a cytidine deaminase inhibitor (abbreviated DEC-C) for treatment of adult patients with myelodysplastic syndromes (MDS). Evidence of effectiveness of DEC-C was established in phase III ASTX727-02 (N = 133) in adults with MDS. The study involved a two-sequence crossover comparing DEC-C and intravenous (IV) decitabine 20 mg/m2 once daily for the first 5 days of each 28-day cycle in the first 2 cycles. From cycle 3 onward, patients received DEC-C. Five-day cumulative area under the curve (5-d AUC) of decitabine for DEC-C was similar to that of IV decitabine, with geometric mean ratio 0.99 (90% confidence interval: 0.93-1.06). Clinical benefit was supported by study ASTX727-02 and the similarly designed phase II study ASTX727-01-B (n = 80), with complete remission (CR) of 21% and 18% and median duration of CR 7.5 and 8.7 months, respectively. Adverse reactions were consistent with IV decitabine. Postmarketing assessments were issued to address the effect of cedazuridine on QT prolongation, food effect, moderate and severe hepatic impairment, and severe renal impairment on the pharmacokinetics and safety of DEC-C.
Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. [2021]This phase 2 study was designed to compare systemic decitabine exposure, demethylation activity, and safety in the first 2 cycles with cedazuridine 100 mg/decitabine 35 mg vs standard decitabine 20 mg/m2 IV. Adults with International Prognostic Scoring System intermediate-1/2- or high-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) were randomized 1:1 to receive oral cedazuridine/decitabine or IV decitabine in cycle 1, followed by crossover to the other treatment in cycle 2. All patients received oral cedazuridine/decitabine in subsequent cycles. Cedazuridine and decitabine were given initially as separate capsules in a dose-confirmation stage and then as a single fixed-dose combination (FDC) tablet. Primary end points: mean decitabine systemic exposure (geometric least-squares mean [LSM]) of oral/IV 5-day area under curve from time 0 to last measurable concentration (AUClast), percentage long interspersed nuclear element 1 (LINE-1) DNA demethylation for oral cedazuridine/decitabine vs IV decitabine, and clinical response. Eighty patients were randomized and treated. Oral/IV ratios of geometric LSM 5-day AUClast (80% confidence interval) were 93.5% (82.1-106.5) and 97.6% (80.5-118.3) for the dose-confirmation and FDC stages, respectively. Differences in mean %LINE-1 demethylation between oral and IV were ≤1%. Clinical responses were observed in 48 patients (60%), including 17 (21%) with complete response. The most common grade ≥3 adverse events regardless of causality were neutropenia (46%), thrombocytopenia (38%), and febrile neutropenia (29%). Oral cedazuridine/decitabine (100/35 mg) produced similar systemic decitabine exposure, DNA demethylation, and safety vs decitabine 20 mg/m2 IV in the first 2 cycles, with similar efficacy. This study is registered at www.clinicaltrials.gov as #NCT02103478.
An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study. [2019]Decitabine, a DNA methyltransferase 1 inhibitor or DNA hypomethylating compound, is not readily orally bioavailable because of rapid clearance by cytidine deaminase (CDA) in the gut and liver. This dose-escalation study, guided by pharmacokinetic and pharmacodynamic observations, evaluated whether simultaneous oral administration with the novel CDA inhibitor cedazuridine increases decitabine bioavailability for the treatment of myelodysplastic syndromes.
Decitabine/Cedazuridine: First Approval. [2021]A fixed dose oral combination (FDC) of decitabine and cedazuridine (Inqovi®), is being developed by Astex Pharmaceuticals (a subsidiary of Otsuka Pharmaceuticals) for the treatment of various cancers like myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemia (AML), glioma and solid tumours. Decitabine, a DNA methyltransferase inhibitor approved for the treatment of MDS and CMML, is degraded by cytidine deaminase in the gastrointestinal tract and liver, thereby limiting oral bioavailability. Cedazuridine is a proprietary, patented cytidine deaminase inhibitor that, when added to decitabine, increases oral bioavailability of the drug. In July 2020, decitabine/cedazuridine received its first approval in the USA and Canada for the treatment of MDS and CMML. In the USA, it is indicated for use in adults with MDS and CMML, including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anaemia, refractory anaemia with ringed sideroblasts, refractory anaemia with excess blasts and CMML) and intermediate-1, intermediate-2 and high-risk International Prognostic Scoring System groups. Clinical studies for AML, glioma and solid tumours are underway in several countries worldwide. This article summarizes the milestones in the development of decitabine/cedazuridine leading to this first approval for the treatment of MDS and CMML.
Low Dose Decitabine Combined with Taxol and Platinum Chemotherapy to Treat Refractory/Recurrent Ovarian Cancer: An Open-Label, Single-Arm, Phase I/II Study. [2019]Previous research has proposed that the hypomethylating agent decitabine can sensitize ovarian cancer cells to chemical agents. In this open-label, phase I/II clinical study, we analyzed the toxicity and efficacy of low dose decitabine combined with taxol and platinum chemotherapy in treatment of refractory and recurrent ovarian cancer.
Epigenetic Immune Remodeling of Mesothelioma Cells: A New Strategy to Improve the Efficacy of Immunotherapy. [2022]Malignant pleural mesothelioma (MPM) is an aggressive malignancy with a severe prognosis, and with a long-standing need for more effective therapeutic approaches. However, treatment with immune checkpoint inhibitors is becoming an increasingly effective strategy for MPM patients. In this scenario, epigenetic modifications may negatively regulate the interplay between immune and malignant cells within the tumor microenvironment, thus contributing to the highly immunosuppressive contexture of MPM that may limit the efficacy of immunotherapy. Aiming to further improve prospectively the clinical efficacy of immunotherapeutic approaches in MPM, we investigated the immunomodulatory potential of different classes of epigenetic drugs (i.e., DNA hypomethylating agent (DHA) guadecitabine, histone deacetylase inhibitors VPA and SAHA, or EZH2 inhibitors EPZ-6438) in epithelioid, biphasic, and sarcomatoid MPM cell lines, by cytofluorimetric and real-time PCR analyses. We also characterized the effects of the DHA, guadecitabine, on the gene expression profiles (GEP) of the investigated MPM cell lines by the nCounter platform. Among investigated drugs, exposure of MPM cells to guadecitabine, either alone or in combination with VPA, SAHA and EPZ-6438 demonstrated to be the main driver of the induction/upregulation of immune molecules functionally crucial in host-tumor interaction (i.e., HLA class I, ICAM-1 and cancer testis antigens) in all three MPM subtypes investigated. Additionally, GEP demonstrated that treatment with guadecitabine led to the activation of genes involved in several immune-related functional classes mainly in the sarcomatoid subtype. Furthermore, among investigated MPM subtypes, DHA-induced CDH1 expression that contributes to restoring the epithelial phenotype was highest in sarcomatoid cells. Altogether, our results contribute to providing the rationale to develop new epigenetically-based immunotherapeutic approaches for MPM patients, potentially tailored to the specific histologic subtypes.
Multicenter study of decitabine administered daily for 5 days every 4 weeks to adults with myelodysplastic syndromes: the alternative dosing for outpatient treatment (ADOPT) trial. [2023]Decitabine, a DNA-targeted hypomethylating agent, is approved by the United States Food and Drug Administration for treatment of patients with myelodysplastic syndromes (MDS) on a schedule of 15 mg/m(2) administered via intravenous (IV) infusion every 8 hours for 3 days. This study assessed the efficacy and safety of an alternative dosing regimen administered on an outpatient basis in academic and community-based practices.