Decitabine + Cedazuridine for Solid Tumors

Recruiting at 1 trial location

Overseen By Danielle Wendler

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must not be taking: Investigational agents

Disqualifiers: Hepatitis B, Hepatitis C, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle, up to 2 years

35 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a phase 1 study of the combination of cedazuridine with decitabine in patients with solid tumors. At least 6 patients will be enrolled per treatment level to assess optimal hypomethylation and toxicity (up to 35 patients total).

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, you cannot be on any other investigational agents and must not have had chemotherapy or radiotherapy within the last 3 weeks.

What data supports the effectiveness of the drug Decitabine + Cedazuridine for solid tumors?

The combination of Decitabine and Cedazuridine has been shown to be effective in treating myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), with clinical responses observed in 60% of patients, including 21% achieving complete response. This suggests potential effectiveness in other cancers, including solid tumors, although specific data for solid tumors is still being studied. ^{1 2 3 4 5}

Is the combination of Decitabine and Cedazuridine safe for humans?

The combination of Decitabine and Cedazuridine has been studied in patients with certain blood disorders, and common serious side effects included low white blood cell counts, low platelet counts, and fever with low white blood cell counts. These side effects are similar to those seen with Decitabine alone. ^{4 5 6 7 8}

How is the drug Decitabine + Cedazuridine unique for treating solid tumors?

Decitabine + Cedazuridine is unique because it combines decitabine, a drug that inhibits DNA methylation (a process that can turn off genes), with cedazuridine, which helps increase the amount of decitabine that can be absorbed when taken by mouth. This oral combination makes it easier for patients to take compared to traditional intravenous administration. ^{4 5 8 9 10}

Research Team

Nilofer S. Azad

Principal Investigator

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Eligibility Criteria

This trial is for adults with advanced solid tumors who've tried at least two treatments without success or declined other beneficial therapies. They must be in good physical condition (ECOG <1), able to swallow pills, and have measurable tumor growth. People can't join if they have recent ulcers, bowel blockages, chemotherapy or radiotherapy within the last 3 weeks, are on other experimental drugs, or have active hepatitis B/C or symptomatic ascites.

Inclusion Criteria

I can swallow pills.

My cancer is advanced, cannot be surgically removed, and has spread.

I am fully active and can carry on all my pre-disease activities without restriction.

Exclusion Criteria

I have an active hepatitis B or C infection.

I have had fluid build-up in my abdomen causing discomfort in the last 4 weeks.

Participants may not be receiving any other investigational agents

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a combination of cedazuridine and decitabine on an outpatient basis. Cycle length is 28 days.

28 days per cycle, up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 2 years

Treatment Details

Interventions

• Cedazuridine
• Decitabine

Trial Overview The study tests different doses of Cedazuridine combined with Decitabine in patients with solid tumors to find the best dose that modifies DNA methylation without causing too much toxicity. At least six people will be tested per dose level up to a total of thirty participants.

Participant Groups

Group I: Decitabine and Cedazuridine Experimental Treatment 2 Interventions

Treatment will be administered on an outpatient basis. Cycle length is 28 days. The dose of cedazuridine is fixed at 100mg and the dose and duration of decitabine will vary depending on when a patient enters the study.

Cedazuridine is already approved in United States for the following indications:

Approved in United States as ASTX727 for:

• Acute Myeloid Leukemia (AML)

Who Is Running the Clinical Trial?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

Astex Pharmaceuticals, Inc.

Industry Sponsor

Trials

97

Recruited

7,400+

Dr. Harren Jhoti

Astex Pharmaceuticals, Inc.

Chief Executive Officer since 2007

PhD in Biochemistry from Birkbeck College, London

Dr. Harold N. Keer

Astex Pharmaceuticals, Inc.

Chief Medical Officer since 2020

MD

Findings from Research

The D-CAG regimen, which combines decitabine with a modified chemotherapy approach, achieved a complete remission (CR) rate of 69.4% in 59 elderly patients (≥70 years) with newly diagnosed acute myeloid leukemia (AML), indicating its efficacy in this age group.

The treatment was found to be safe, with major adverse reactions including grade 3-4 myelosuppression and infections, but it significantly improved overall survival (OS) and event-free survival (EFS) for patients who achieved CR, with median OS of 19.8 months compared to 6.4 months for those who did not respond.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and Safety of Decitabine Combined with Modified CAG Regimen in Patients Aged ≥ 70 Years with Newly Diagnosed Acute Myeloid Leukemia]. Cao, L., Jiang, ZQ., Liu, WJ., et al.[2023]

In a study of 44 patients with relapsed/refractory acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), the combination of decitabine with the EIAG regimen resulted in a higher modified composite complete response (mCRc) rate of 72.7% compared to 40.9% in the CAG regimen group, indicating improved efficacy.

Both treatment regimens led to significant myelosuppression as a common adverse effect, but there was no increase in non-hematological toxicities, suggesting that decitabine combined with EIAG is a safe option that enhances remission rates without adding extra risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and Safety of Decitabine Combined with Modified EIAG Regimen in the Treatment of Patients with Relapsed/Refractory Acute Myeloid Leukemia and High-risk Myelodysplastic Syndrome]. Mao, JP., Xue, LG., Zhu, YX., et al.[2023]

In a study of 45 elderly patients (average age 68.5) with high-risk MDS and MDS-transformed AML, the decitabine combined with CEG regimen (DCEG) showed a significantly higher overall response rate (86.4%) compared to the decitabine combined with CAG regimen (47.8%).

Patients treated with the DCEG regimen also experienced longer overall survival (10 months) and progression-free survival (9 months) compared to those on the CAG regimen, indicating that DCEG may be a more effective treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Comparison of the Curative Efficacy of Elderly Patients with High-Risk MDS and MDS-Transformed AML between Decitabine Combined with Low-Dose CEG Regimen and Decitabine Combined with Low-Dose CAG Regimen]. Wu, M., Ma, IX., Xie, YH., 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]

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 study of 8 geriatric patients with acute myeloid leukemia, treatment with decitabine, with or without low-dose cytarabine, resulted in a 50% overall response rate, with 25% achieving complete remission and 25% achieving partial remission.

The treatment showed a median overall survival time of 9.5 months, with some patients surviving over a year, although it was associated with significant side effects, including severe myelosuppression in 87.5% of patients and pneumonia in 50%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Efficacy of Decitabine Combined with or without Cytarabine-based Low Dose Regimen for Senile patients with Acute Myeloid Leukemia]. Zhou, HW., Zhou, MH., Wang, ZH., et al.[2019]

Oral azacitidine (CC-486) has been shown to improve overall survival as maintenance therapy for older patients with acute myeloid leukemia who are in complete remission, highlighting its efficacy in this specific patient population.

The combination of decitabine and cedazuridine (ASTX727) is approved for treating adult patients with myelodysplastic syndromes and chronic myelomonocytic leukemia, particularly those with intermediate-1 or higher risk, indicating its targeted therapeutic application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The path to approval for oral hypomethylating agents in acute myeloid leukemia and myelodysplastic syndromes. Kipp, D., H Wei, A.[2022]

Decitabine, administered at a dose of 20 mg/m² for 5 consecutive days, has been approved for older patients (≥65 years) with acute myeloid leukaemia (AML) who cannot undergo standard treatment, showing clinically meaningful improvements in overall survival after extended follow-up.

In a pivotal phase III trial, decitabine demonstrated significantly higher complete remission rates compared to standard treatment options like cytarabine, with a safety profile similar to cytarabine, including common side effects like fever and low blood cell counts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine: a review of its use in older patients with acute myeloid leukaemia. Curran, MP.[2021]

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]

Decitabine is a DNA methyltransferase inhibitor with a long history of antileukemic efficacy, particularly effective in treating acute myeloid leukemia in older patients or those unable to undergo intensive therapy.

The current dosing regimen of decitabine (20 mg/m² for 5 days) has been refined to minimize nonhematologic toxicity, making it a promising option for patients who may not tolerate more aggressive treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine for acute myeloid leukemia. Marks, PW.[2018]

References

1. China pubmed.ncbi.nlm.nih.gov

[Efficacy and Safety of Decitabine Combined with Modified CAG Regimen in Patients Aged ≥ 70 Years with Newly Diagnosed Acute Myeloid Leukemia]. [2023]

2. China pubmed.ncbi.nlm.nih.gov

[Efficacy and Safety of Decitabine Combined with Modified EIAG Regimen in the Treatment of Patients with Relapsed/Refractory Acute Myeloid Leukemia and High-risk Myelodysplastic Syndrome]. [2023]

3. China pubmed.ncbi.nlm.nih.gov

[Comparison of the Curative Efficacy of Elderly Patients with High-Risk MDS and MDS-Transformed AML between Decitabine Combined with Low-Dose CEG Regimen and Decitabine Combined with Low-Dose CAG Regimen]. [2022]

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

Decitabine/Cedazuridine: First Approval. [2021]

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

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

6. China pubmed.ncbi.nlm.nih.gov

[Clinical Efficacy of Decitabine Combined with or without Cytarabine-based Low Dose Regimen for Senile patients with Acute Myeloid Leukemia]. [2019]

7. England pubmed.ncbi.nlm.nih.gov

The path to approval for oral hypomethylating agents in acute myeloid leukemia and myelodysplastic syndromes. [2022]

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

Decitabine: a review of its use in older patients with acute myeloid leukaemia. [2021]

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

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

10. England pubmed.ncbi.nlm.nih.gov

Decitabine for acute myeloid leukemia. [2018]