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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new oral treatment, decitabine/cedazuridine (INQOVI), to determine if it can stabilize or improve early-stage mesothelioma, a cancer linked to specific genetic mutations. The trial aims to assess the treatment's effectiveness in halting disease progression and to identify any side effects. Suitable candidates for this trial include individuals with a history of BRCA1-Associated Protein-1 (BAP1) mutations and early-stage mesothelioma who have not undergone standard therapies or have opted not to pursue them. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

A previous study found that the oral treatment decitabine/cedazuridine (INQOVI) was generally well-tolerated by patients. The ASCERTAIN trial showed that this pill form had a safety profile similar to the injectable version. Most patients experienced mild to moderate side effects, such as low blood cell counts, which are common with many cancer treatments. Serious side effects, like infections due to low white blood cell counts, were less common but did occur.

Since the FDA has already approved INQOVI for other conditions, it has a known safety record. While every treatment carries risks, the drug's approval for use in other cancers provides some reassurance about its safety. Always discuss potential risks and benefits with the clinical trial team to make an informed decision. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for mesothelioma, which often involve chemotherapy and surgery, Decitabine/Cedazuridine (INQOVI) offers a fresh approach. This treatment works as an oral DNA demethylating agent, which means it can potentially modify the way cancer cells read their genetic code, possibly stopping their growth. Researchers are excited because it targets mesothelioma at the genetic level, which could lead to more personalized and effective treatment options with potentially fewer side effects. Plus, being an oral medication, it offers a more convenient option compared to traditional intravenous treatments.

What evidence suggests that this treatment might be an effective treatment for mesothelioma?

Research has shown that the drug decitabine/cedazuridine (INQOVI) can effectively treat certain blood disorders, such as myelodysplastic syndromes (MDS). In these cases, about 70% of patients experienced some level of improvement, either fully or partially. This treatment alters DNA modification, which can help stop cancer cells from growing. Although approved for MDS, this trial is investigating its potential for treating mesothelioma. The researchers aim to determine if it can stabilize or improve early-stage mesothelioma, particularly in patients with specific genetic traits. Participants in this trial will receive decitabine/cedazuridine as part of the study's single treatment arm. ^{1 3 4 6 7}

Who Is on the Research Team?

David S Schrump, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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]

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]

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]

Citations

1. withpower.com withpower.com/trial/phase-2-mesothelioma-6-2023-d9bee

Oral DNA Demethylating Agent for Mesothelioma The drug Decitabine/Cedazuridine (INQOVI) has been shown to be effective in treating myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), ...

2. inqovi.com inqovi.com/hcp/efficacy-and-safety

Efficacy & Safety | INQOVI® (decitabine and cedazuridine) ... 70 percent. 70% of MDS patients experienced a clinical response, showing improvements like complete or partial response, complete marrow response, and ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40524338/

Efficacy and safety of oral decitabine/cedazuridine in the ... The overall response rate was 76%, with 21% (n = 7) of patients achieving a complete response. Nearly half of the 11 patients who were red blood ...

4. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-06113

Decitabine/Cedazuridine (INQOVI), an Oral DNA ... This is a Phase II study to determine the rate of stabilization or disease improvement from investigational decitabine/cedazuridine (INQOVI) treatment.

5. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-approves-oral-combination-decitabine-and-cedazuridine-myelodysplastic-syndromes

FDA approves oral combination of decitabine and ... The 01-B trial demonstrated a complete response (CR) rate of 18% (95% CI: 10, 28) and median duration of CR was 8.7 months (range: 1.1, 18.2).

6. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/decitabine-and-cedazuridine?pn=1

Clinical Trials Using Decitabine and Cedazuridine - NCI Review the clinical trials studying decitabine and cedazuridine on this list and use the filters to refine the results by age and location.

7. taihooncology.com taihooncology.com/us/news/2024-01-23_taiho_oncology_ascertain_publication/

2024-01-23_Taiho_Oncology_ASCERTAIN_Publication The ASCERTAIN study has demonstrated that the orally delivered fixed dose combination of decitabine and cedazuridine is an alternative option to parenteral ...