Oral DNA Demethylating Agent for Mesothelioma

Overseen By Deneise C Francis, R.N.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Anticoagulants, Immunosuppressants

Disqualifiers: Cardiovascular disease, Hepatitis, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 8

Duration: 24 weeks

15 Participants Needed

Trial Summary

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. ^{1 2 3 4 5}

Is 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). ^{1 2 3 4 6}

How 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. ^{1 2 3 4 7}

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.

Research Team

David S Schrump, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility 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.

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.

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

Treatment Details

Interventions

• Decitabine/Cedazuridine (INQOVI)

Trial Overview 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.

Participant Groups

Group I: 1/ Arm 1 Experimental Treatment 1 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

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Inqovi, a combination of decitabine and cedazuridine, was approved by the FDA for treating myelodysplastic syndromes (MDS) based on a phase III study involving 133 adults, showing similar effectiveness to intravenous decitabine.

The treatment demonstrated a complete remission rate of 21% in one study and 18% in another, with a median duration of remission lasting around 7.5 to 8.7 months, while adverse reactions were consistent with those seen in IV decitabine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Decitabine and Cedazuridine Tablets for Myelodysplastic Syndromes. Kim, N., Norsworthy, KJ., Subramaniam, S., et al.[2023]

The phase 2 study found that oral cedazuridine/decitabine (100 mg/35 mg) provided similar systemic exposure and DNA demethylation compared to standard IV decitabine (20 mg/m2) in patients with myelodysplastic syndromes or chronic myelomonocytic leukemia, indicating comparable efficacy.

Clinical responses were observed in 60% of patients, with 21% achieving a complete response, while the most common serious side effects included neutropenia (46%) and thrombocytopenia (38%), highlighting the treatment's safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Garcia-Manero, G., Griffiths, EA., Steensma, DP., et al.[2021]

In a phase 1 study involving 44 patients with myelodysplastic syndromes or chronic myelomonocytic leukaemia, the combination of oral decitabine and the CDA inhibitor cedazuridine successfully increased the bioavailability of decitabine, achieving pharmacokinetics similar to intravenous administration without increasing toxicity.

The study demonstrated that oral decitabine combined with cedazuridine produced effective dose-dependent demethylation and clinical responses comparable to intravenous decitabine, suggesting it could be a viable alternative treatment for myeloid disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study. Savona, MR., Odenike, O., Amrein, PC., et al.[2019]

The fixed-dose oral combination of decitabine and cedazuridine (Inqovi®) has been approved for treating myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML), enhancing the oral bioavailability of decitabine through the inhibition of cytidine deaminase by cedazuridine.

Decitabine is already an established treatment for MDS and CMML, and the combination therapy has shown promise in ongoing clinical studies for other cancers like acute myeloid leukaemia (AML), glioma, and solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine/Cedazuridine: First Approval. Dhillon, S.[2021]

In a phase I/II clinical study involving 21 patients with relapsed/refractory ovarian cancer, low dose decitabine combined with taxol and platinum chemotherapy was well-tolerated, with no severe adverse events observed, although common side effects included nausea (77.8%) and neutropenia (66.7%).

The treatment showed a clinical benefit rate of 70.6%, with significant decreases in serum CA125 levels in many patients, suggesting that CA125 levels could be a potential predictor of clinical response to this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low Dose Decitabine Combined with Taxol and Platinum Chemotherapy to Treat Refractory/Recurrent Ovarian Cancer: An Open-Label, Single-Arm, Phase I/II Study. Fu, X., Zhang, Y., Wang, X., et al.[2019]

Treatment with the DNA hypomethylating agent guadecitabine, either alone or in combination with other epigenetic drugs, significantly enhances the expression of immune-related molecules in malignant pleural mesothelioma (MPM) cell lines, suggesting a potential strategy to improve immunotherapy efficacy.

Guadecitabine treatment particularly activated immune-related genes in the sarcomatoid subtype of MPM, indicating that epigenetic therapies could be tailored to specific histological subtypes for better therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epigenetic Immune Remodeling of Mesothelioma Cells: A New Strategy to Improve the Efficacy of Immunotherapy. Lofiego, MF., Cannito, S., Fazio, C., et al.[2022]

In a study of 99 patients with myelodysplastic syndromes (MDS), decitabine administered at a higher dose of 20 mg/m² daily for 5 days every 4 weeks resulted in a 32% overall response rate, indicating significant efficacy in treating MDS.

The outpatient regimen of decitabine not only provided comparable efficacy to the FDA-approved inpatient schedule but also allowed for more than half of the patients to show clinical improvement, suggesting a safe and effective alternative treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Steensma, DP., Baer, MR., Slack, JL., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Decitabine and Cedazuridine Tablets for Myelodysplastic Syndromes. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. [2021]

3. England pubmed.ncbi.nlm.nih.gov

An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study. [2019]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Decitabine/Cedazuridine: First Approval. [2021]

5. United Arab Emirates pubmed.ncbi.nlm.nih.gov

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]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Epigenetic Immune Remodeling of Mesothelioma Cells: A New Strategy to Improve the Efficacy of Immunotherapy. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

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]