DEC-C Pre-emptive Therapy for Myelodysplastic Syndrome

Recruiting at 1 trial location

Overseen By Meagan Jacoby, M.D., Ph.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Washington University School of Medicine

Must not be taking: Investigational agents, Cytidine deaminase

Disqualifiers: Pregnancy, Active infection, Cardiac arrhythmia, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 5 cycles of 28 days each

209 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if DEC-C (also known as Inqovi or Decitabine/Cedazuridine, a type of chemotherapy) can prevent the return of myelodysplastic syndrome (MDS) after a transplant. The focus is on patients whose condition might worsen due to persistent mutations detected post-transplant. Those with myelodysplastic syndrome, who have undergone a transplant and possess specific genetic markers, might be suitable candidates. The trial evaluates DEC-C to see if it can lower relapse rates and improve survival without disease progression. As a Phase 1, Phase 2 trial, it seeks to understand how the treatment works in people and measure its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on any investigational drugs or drugs metabolized by cytidine deaminase. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of decitabine and cedazuridine (DEC-C) is generally safe for people. In studies involving 208 patients with myelodysplastic syndromes (MDS) who took DEC-C, doctors carefully monitored safety. Most patients experienced mild to moderate side effects, such as low blood cell counts, which are common in treatments for blood disorders. Serious side effects occurred less frequently.

The FDA has already approved DEC-C for treating MDS, indicating it has undergone safety testing in earlier studies. This approval provides some reassurance about its safety. However, like any treatment, side effects may occur, so discussing these with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about DEC-C for treating Myelodysplastic Syndrome (MDS) because it combines two drugs, decitabine and cedazuridine, which are taken orally. This is different from typical MDS treatments, like injectable hypomethylating agents, because it offers a more convenient pill form. DEC-C also targets minimal residual disease (MRD), potentially catching cancer cells early and preventing relapse. By offering a new delivery method and focusing on MRD, DEC-C could make managing MDS easier and more effective.

What evidence suggests that DEC-C might be an effective treatment for myelodysplastic syndrome?

Research has shown that the combination of decitabine and cedazuridine (DEC-C), which participants in this trial may receive, can be effective for patients with myelodysplastic syndromes (MDS). One study found that 70% of MDS patients experienced significant improvement, including complete or partial recovery and enhanced bone marrow function. Another study reported a 62% overall improvement rate, with patients living an average of 31.7 months. As an oral treatment, DEC-C is considered a breakthrough because it helps patients maintain their quality of life while managing their condition. ^{1 6 7 8 9}

Who Is on the Research Team?

Meagan Jacoby, M.D., Ph.D.

Principal Investigator

Washington University School of Medicine

Are You a Good Fit for This Trial?

Adults diagnosed with myelodysplastic syndromes who have had a stem cell transplant. They must have specific mutations detectable by MyeloSeq-HD, stable mild GVHD (if present), good kidney and liver function, and agree to use contraception. Excluded are pregnant or breastfeeding individuals, those on certain drugs, or with uncontrolled illnesses.

Inclusion Criteria

I have MDS and have undergone a stem cell transplant.

I have had gene testing showing a mutation relevant to my condition, not inherited.

Inclusion Criteria DEC-C Intervention Arm: One or more somatically acquired variants that were present prior to transplant detected by the MyeloSeq-HD panel at Day 30 post-transplant, with a variant allele frequency of ≥ 0.5% Within Days 42-100 post-transplant. Absolute neutrophil count (ANC) ≥ 1.0 X 109/L and platelets ≥ 50 X 109/L. Only patients with adequately controlled GVHD ≤ Grade 2 are eligible for the DEC-C intervention arm. Patients with active grade 3 or higher GVHD are ineligible for the DEC-C intervention arm. ECOG performance status ≤ 2 Adequate renal and hepatic function as described below: *Total bilirubin ≤ 1.5 x IULN *AST(SGOT)/ALT(SGPT) ≤ 3.0 IULN *Creatinine clearance ≥ 30 mL/min using Cockcroft-Gault Formula below: CrCl = [(140-age) x body weight in kg]/(serum creatinine in mg/dL x 72) x 0.85 if female *NOTE: If, in the opinion of the treating physician, bilirubin is elevated secondary to hemolysis or Gilbert's disease, the patient may be eligible after discussion with the Washington University PI Decitabine has been shown to be teratogenic in animal studies and use of IV decitabine in the first trimester of pregnancy has been associated with major birth defects. Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Men and women treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of the study, and 6 months after completion of the study.

Exclusion Criteria

You are currently taking part in another experimental treatment.

You have had an allergic reaction to drugs or chemicals similar to DEC-C or other medications used in this study.

I do not have any serious illnesses like heart failure or uncontrolled infections.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Initial Assessment

Bone marrow biopsy and MyeloSeq-HD sequencing to detect molecular MRD at Day 30 post-transplant

1 day

1 visit (in-person)

Treatment

MRD-positive patients receive up to 5 cycles of DEC-C prior to Day 180 evaluation

5 cycles of 28 days each

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year post-transplant

Every 3 months for 2 years, then every 6 months for 3 years

What Are the Treatments Tested in This Trial?

Interventions

• DEC-C
• MyeloSeq-HD

Trial Overview

The trial tests if early treatment with DEC-C can prevent disease progression in MDS patients post-transplant showing persistent mutations via MyeloSeq-HD testing. It aims to see if this approach lowers relapse rates and improves survival without the disease getting worse.

How Is the Trial Designed?

Group I: Phase II MRD Positive: DEC-C Experimental Treatment 2 Interventions

* 35 mg decitabine/100 mg cedazuridine taken by mouth once daily per the schedule determined in the Phase I portion of the study. Cycle 1 Day 1 may take place between Day 42 and Day 100 post-transplant. MRD-positive patients will receive up to 5 cycles of DEC-C prior to the Day 180 bone marrow evaluation. * Bone marrow biopsy with MyeloSeq-HD will be obtained on Day 180 post-transplant. If the Day 180 MyeloSeq-HD shows that MRD is still detectable in the opinion of the MGI board-certified molecular pathologist but below 0.5% and patient has tolerated initial treatment without toxicity, the patient may continue treatment. If it shows a lack of MRD, the patient will be moved to the post-treatment surveillance arm. If it shows any mutation detection prior to transplant that persists with a variant allele frequency of ≥ 0.2%VAF, the patient will receive up to an additional 6 cycles of DEC-C.

Group II: Phase I Dose Level 2: DEC-C Experimental Treatment 2 Interventions

* Bone marrow biopsy \& MyeloSeq-HD will be obtained on Day 30 post-transplant. MRD positivity is defined as the presence of at least one somatically acquired mutation detected prior to transplant that persists at Day 30 post-transplant with a variant allele frequency of ≥ 0.2%. MRD-positive patients will receive up to 5 cycles of DEC-C prior to the Day 180 bone marrow evaluation. If the Day 180 MyeloSeq-HD shows that MRD is still detectable in the opinion of the MGI board-certified molecular pathologist but below 0.5% and patient has tolerated initial treatment without toxicity, the patient may continue treatment. If it shows a lack of MRD, the patient will be moved to the post-treatment surveillance arm. If it shows any mutation detection prior to transplant that persists with a variant allele frequency of ≥ 0.2%VAF, the patient will receive up to an additional 6 cycles of DEC-C. * 35 mg decitabine/100 mg cedazuridine taken by mouth once daily on Days 1-4 of a 28 day cycle.

Group III: Phase I Dose Level 1: DEC-C Experimental Treatment 2 Interventions

* Bone marrow biopsy \& MyeloSeq-HD will be obtained on Day 30 post-transplant. MRD positivity is defined as the presence of at least one somatically acquired mutation detected prior to transplant that persists at Day 30 post-transplant with a variant allele frequency of ≥ 0.2%. MRD-positive patients will receive up to 5 cycles of DEC-C prior to the Day 180 bone marrow evaluation. If the Day 180 MyeloSeq-HD shows that MRD is still detectable in the opinion of the MGI board-certified molecular pathologist but below 0.5% and patient has tolerated initial treatment without toxicity, the patient may continue treatment. If it shows a lack of MRD, the patient will be moved to the post-treatment surveillance arm. If it shows any mutation detection prior to transplant that persists with a variant allele frequency of ≥ 0.2%VAF, the patient will receive up to an additional 6 cycles of DEC-C. * 35 mg decitabine/100 mg cedazuridine taken by mouth once daily on Days 1, 2, 3 of a 28 day cycle.

Group IV: Phase II MRD Negative: Observation Arm Active Control 1 Intervention

* In phase II, up to 77 patients who do not have MRD positivity on Day 30 post-transplant (i.e., the absence of at least one somatically acquired mutation detected prior to transplant that persists at Day 30 post-transplant with a variant allele frequency of ≥ 0.2%) will be placed on the observation arm and treated with standard of care. * Patients on the observation arm will be followed every 3 months for 2 years and every 6 months for 3 years for progression and survival

DEC-C is already approved in United States, European Union for the following indications:

Approved in United States as Inqovi for:

• Myelodysplastic syndromes (MDS)

Approved in European Union as Inqovi for:

• Myelodysplastic syndromes (MDS)

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Taiho Oncology, Inc.

Industry Sponsor

Trials

79

Recruited

12,700+

Tim Whitten

Taiho Oncology, Inc.

Chief Executive Officer since 2018

MBA and Pharmacy degree

Harold Keer

Taiho Oncology, Inc.

Chief Medical Officer

MD, PhD

Published Research Related to This Trial

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]

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 combination of oral cedazuridine and decitabine (C-DEC) has been shown to have a similar pharmacokinetic and pharmacodynamic profile to parenteral decitabine, making it a promising alternative for treating higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML).

Phase 2 and phase 3 clinical trials confirmed the bioequivalence of C-DEC to parenteral decitabine, leading to FDA approval for its use in intermediate/high-risk MDS and CMML, highlighting its efficacy and safety as an oral treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cedazuridine/decitabine: from preclinical to clinical development in myeloid malignancies. Patel, AA., Cahill, K., Saygin, C., et al.[2023]

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]

In a study of 87 patients with myelodysplastic syndrome (MDS) treated with decitabine, 58.6% showed therapeutic responses, indicating that decitabine is an effective treatment option for MDS.

Factors such as high hENT1 mRNA expression and TP53 gene mutations were identified as independent prognostic indicators for better treatment outcomes, suggesting that these molecular markers can help predict which patients are more likely to respond to decitabine therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Efficacy and Prognostic Factors of Decitabine for Treatment of Myelodysplastic Syndrome]. Bao, ZH., Zhao, HG., Yu, HE.[2019]

A new oral drug combination, DEC-cedazuridine (C-DEC), has been developed to provide a more convenient treatment option for patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML), which traditionally required lengthy parenteral therapies.

C-DEC has been approved by major health authorities, including the US FDA, for patients with newly diagnosed or previously treated intermediate or high-risk MDS and CMML, indicating its safety and potential efficacy in managing these complex disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of cedazuridine/decitabine in the management of myelodysplastic syndrome and chronic myelomonocytic leukemia. Thota, S., Oganesian, A., Azab, M., et al.[2021]

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INQOVI is indicated for treatment of adult patients with myelodysplastic syndromes (MDS). See full Safety Info.

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accessdata.fda.gov/drugsatfda_docs/label/2020/212576s000lbl.pdf

INQOVI® (decitabine and cedazuridine) tablets, for oral use

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