DEC-C + Thioguanine for AML

Overseen By Research Nurse Navigator

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Joseph Jurcic

Must not be taking: Thioguanine

Disqualifiers: CNS involvement, HIV, Hepatitis, 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

Compensation: Varies

Number of Visits: Unknown

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop any anti-leukemic therapy, including investigational therapies, at least 14 days before starting the study treatment. However, you can continue using hydroxyurea to control blood counts during the induction cycles.

What data supports the effectiveness of the drug DEC-C + Thioguanine for AML?

The drug DEC-C (Decitabine-Cedazuridine) has shown effectiveness in treating myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), with clinical studies indicating complete remission rates of 21% and 18% in MDS patients. Additionally, Decitabine, a component of DEC-C, has demonstrated activity in AML when used in combination with other agents like gemtuzumab ozogamicin, achieving a complete response in 42% of patients in a small study. ^{1 2 3 4 5}

Is the combination of DEC-C and Thioguanine safe for humans?

The safety data for DEC-C (Decitabine-Cedazuridine) and Thioguanine specifically is not available in the provided research articles. However, Gemtuzumab ozogamicin, a related treatment, has been associated with risks like myelosuppression (reduced bone marrow activity) and veno-occlusive disease (a liver condition) when used in certain combinations for acute myeloid leukemia (AML). ^{5 6 7 8 9}

What makes the drug DEC-C + Thioguanine unique for treating AML?

The drug DEC-C + Thioguanine is unique for treating AML because it combines Decitabine-Cedazuridine, which helps modify DNA to stop cancer cell growth, with Thioguanine, which interferes with DNA replication. This combination may offer a novel approach by potentially enhancing the effectiveness of treatment through different mechanisms of action. ^{3 10 11 12 13}

What is the purpose of this trial?

The purpose of this study is to find out if oral decitabine-cedazuridine (Inqovi®) is effective, safe, and able to be tolerated without severe side effects when given with thioguanine (Tabloid®) in patients with acute myeloid leukemia (AML) whose disease has returned or did not respond to treatment (relapsed or refractory). This is a "phase II trial with a safety lead-in." The goal of the lead-in portion of the study is to make sure participants are getting the highest dose of medications that are safe. If too many serious side effects are seen with the dose previously studied, some additional patients may be treated with a lower dose to make sure that this dose is safe.

Research Team

Joseph Jurcic

Principal Investigator

Columbia University

Eligibility Criteria

This trial is for patients with acute myeloid leukemia (AML) whose disease has returned or hasn't responded to previous treatments. The study aims to ensure participants can handle the highest safe dose of medications.

Inclusion Criteria

Able to provide informed consent

My organs are functioning well.

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5x the upper limit of normal (ULN)

Exclusion Criteria

Known hypersensitivity to DEC-C or thioguanine

Significant medical diseases or comorbidities, in the opinion of the investigator, that would preclude the safe participation in the study

I currently have an infection that isn't under control.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Lead-In

Participants receive different doses of thioguanine and decitabine-cedazuridine to identify the highest safe doses

8-12 weeks

Phase II Treatment

Participants receive the maximum tolerated dose of the drug combination to explore anti-leukemia activity and safety

Up to 3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Treatment Details

Interventions

• Decitabine-Cedazuridine
• Thioguanine

Trial Overview The study tests if oral decitabine-cedazuridine (Inqovi®) combined with thioguanine (Tabloid®) is effective and tolerable for AML patients. It's a phase II trial that starts by confirming the safety of the maximum dose before proceeding.

Participant Groups

Group I: Safety Lead-In Experimental Treatment 2 Interventions

Groups of participants will receive different doses of thioguanine and decitabine-cedazuridine to identify the highest doses that can be given safely. The highest doses that are safe will then be used in the phase II portion of the clinical trial. If no dose is found to be safe, the study will be stopped. A phase II expansion cohort will be enrolled to further explore the combination's anti-leukemia activity and safety and will proceed at the maximum tolerated dose defined in the initial Safety Cohort.

Decitabine-Cedazuridine is already approved in United States, European Union for the following indications:

Approved in United States as Inqovi for:

• Myelodysplastic syndromes (MDS)
• Chronic myelomonocytic leukemia (CMML)

Approved in European Union as Inqovi for:

• Adult patients with myelodysplastic syndromes (MDS), 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 of blasts, refractory anaemia with excess of blasts in transformation to acute myeloid leukaemia), and intermediate-1, intermediate-2 and high-risk International Prognostic Scoring System groups.

Who Is Running the Clinical Trial?

Joseph Jurcic

Lead Sponsor

Trials

3

Recruited

2+

Columbia University

Lead Sponsor

Trials

1,529

Recruited

2,832,000+

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]

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]

In a study of 12 patients with relapsed or refractory acute myeloid leukemia (AML), a combination of decitabine and gemtuzumab ozogamicin resulted in a 42% complete response rate, with five patients achieving complete remission and undergoing stem cell transplantation.

The treatment was well tolerated, with only mild nonhematologic toxicity observed, suggesting that this regimen could be a promising option for further investigation in larger controlled trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine combined with fractionated gemtuzumab ozogamicin therapy in patients with relapsed or refractory acute myeloid leukemia. Chowdhury, S., Seropian, S., Marks, PW.[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 study of 90 patients with acute myeloid leukemia (AML) in first relapse, combining gemtuzumab ozogamycin (GO) with intermediate- to high-dose cytarabine (IHDAraC) resulted in a significantly higher response rate (68% vs 45%) and improved overall survival (median 35 months vs 6 months) compared to IHDAraC alone.

The benefits of the IHDAraC + GO combination were particularly evident in patients with low- or intermediate-risk cytogenetics, suggesting that this treatment strategy could be more effective for these specific patient groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved outcome of patients with low- and intermediate-risk cytogenetics acute myeloid leukemia (AML) in first relapse with gemtuzumab and cytarabine versus cytarabine: results of a retrospective comparative study. Prebet, T., Etienne, A., Devillier, R., et al.[2019]

Gemtuzumab ozogamicin (GO) combined with standard-dose cytarabine shows promise for treating newly diagnosed acute myeloid leukemia (AML) in elderly patients, with preliminary results indicating its effectiveness, especially in patients with favorable and intermediate cytogenetic risk.

The combination of GO with high-dose cytarabine has been found to be safe and more effective for treating refractory AML compared to previous treatments, and initial data suggest that allogeneic stem cell transplantation is feasible after GO therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemtuzumab ozogamicin (mylotarg) for the treatment of acute myeloid leukemia--ongoing trials. Gleissner, B., Schlenk, R., Bornhäuser, M., et al.[2019]

In a study of 62 patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS), those who received the monoclonal antibody gemtuzumab ozogamicin (GO) prior to stem cell transplantation had a significantly higher risk of developing venoocclusive disease (VOD), with 64% of GO-exposed patients affected compared to only 8% of those without GO exposure.

The study found that the timing of stem cell transplantation after GO administration is critical; 90% of patients who underwent transplantation within 3.5 months of receiving GO developed VOD, highlighting the importance of monitoring and timing in treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation. Wadleigh, M., Richardson, PG., Zahrieh, D., et al.[2022]

In a phase I study involving 20 adult patients with relapsed or refractory acute myeloid leukemia (AML), the combination of clofarabine and gemtuzumab ozogamicin (GO) showed an overall response rate of 42%, indicating potential effectiveness in this difficult-to-treat population.

The maximum tolerated dose (MTD) of clofarabine was determined to be 20 mg/m², but the high rate of dose-limiting toxicities (38%) such as prolonged myelosuppression and hepatotoxicity suggests that further studies should explore lower doses of GO to improve safety while preserving efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I dose-escalation study of clofarabine in combination with fractionated gemtuzumab ozogamicin in patients with refractory or relapsed acute myeloid leukemia. Foster, MC., Amin, C., Voorhees, PM., et al.[2019]

Gemtuzumab ozogamicin (GO) combined with cytarabine showed promising results in two pediatric patients with relapsed acute myeloid leukemia (AML), significantly reducing minimal residual disease to unprecedented levels.

The treatment had a relatively mild toxicity profile, although it did cause severe but manageable myelosuppression, indicating a need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular response in two children with relapsed acute myeloid leukemia treated with a combination of gemtuzumab ozogamicin and cytarabine. Brethon, B., Auvrignon, A., Cayuela, JM., et al.[2019]

Cytarabine and thioguanine therapy successfully achieved complete remission of acute myelocytic leukemia in a 22-year-old pregnant woman, demonstrating their efficacy in treating this type of leukemia.

The treatment was initiated during the 26th week of pregnancy and resulted in the delivery of a healthy infant without chromosomal abnormalities, suggesting that this therapy can be safely administered to pregnant patients after the first trimester.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of acute leukemia during pregnancy. Raich, PC., Curet, LB.[2019]

In a Phase II trial involving 35 elderly patients (ages 51 to 80) with acute myelogenous leukemia (AML), a new chemotherapy regimen (V-TAD) achieved a complete remission rate of 42%, with a median remission duration of 6 months.

Despite being tolerated well, the V-TAD regimen did not improve overall survival rates compared to previous treatments, largely due to a high rate of resistant and recurrent leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of acute myelogenous leukemia in patients over 50 years of age with V-TAD: a Southwest Oncology Group study. Bigelow, CL., Kopecky, K., Files, JC., et al.[2019]

Decitabine (DAC) and arsenic trioxide (As2O3) both effectively inhibit the proliferation of human acute myeloid leukemia (AML) MV4-11 cells in a dose-dependent manner, with IC50 values of 2.409 µmol/L for DAC and 2.364 µmol/L for As2O3.

The combination of DAC and As2O3 significantly enhances the inhibition of cell proliferation and induces a much higher apoptotic rate (51.13%) compared to either drug alone, indicating a synergistic effect that could be beneficial for treating AML with MLL rearrangements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of Decitabine in Combination with Arsenic Trioxide on Prolife-ration and Apoptosis of Human Acute Myeloid Leukemia MV4-11 Cells]. Chen, SS., Zhao, YP., Wu, WZ., et al.[2018]

Thioguanine was tested as a primary therapy in seven patients with chronic granulocytic leukaemia (C.G.L.), but it did not lead to prolonged remission or conversion to Philadelphia chromosome negativity in any patient.

Despite inducing neutropenia in some cases, thioguanine was found to be at least as effective as busulphan for initial treatment and offered the benefit of quick recovery from blood cell suppression when treatment was stopped, suggesting it deserves further study for managing C.G.L. in its chronic phase.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thioguanine as primary treatment for chronic granulocytic leukaemia. Spiers, AS., Galton, DA., Kaur, J., et al.[2019]

References

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

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

2. England pubmed.ncbi.nlm.nih.gov

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

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

Decitabine combined with fractionated gemtuzumab ozogamicin therapy in patients with relapsed or refractory acute myeloid leukemia. [2019]

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

Decitabine/Cedazuridine: First Approval. [2021]

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

Improved outcome of patients with low- and intermediate-risk cytogenetics acute myeloid leukemia (AML) in first relapse with gemtuzumab and cytarabine versus cytarabine: results of a retrospective comparative study. [2019]

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

Gemtuzumab ozogamicin (mylotarg) for the treatment of acute myeloid leukemia--ongoing trials. [2019]

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

Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation. [2022]

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

A phase I dose-escalation study of clofarabine in combination with fractionated gemtuzumab ozogamicin in patients with refractory or relapsed acute myeloid leukemia. [2019]

9. Italy pubmed.ncbi.nlm.nih.gov

Molecular response in two children with relapsed acute myeloid leukemia treated with a combination of gemtuzumab ozogamicin and cytarabine. [2019]

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

Treatment of acute leukemia during pregnancy. [2019]

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

Treatment of acute myelogenous leukemia in patients over 50 years of age with V-TAD: a Southwest Oncology Group study. [2019]

12. China pubmed.ncbi.nlm.nih.gov

[Effect of Decitabine in Combination with Arsenic Trioxide on Prolife-ration and Apoptosis of Human Acute Myeloid Leukemia MV4-11 Cells]. [2018]

13. England pubmed.ncbi.nlm.nih.gov

Thioguanine as primary treatment for chronic granulocytic leukaemia. [2019]