DEC-C Pre-emptive Therapy for Myelodysplastic Syndrome

Recruiting in Palo Alto (17 mi)

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

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Washington University School of Medicine

Must not be taking: Investigational agents, Cytidine deaminase

Disqualifiers: Pregnancy, Active infection, Cardiac arrhythmia, others

No Placebo Group

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

The investigators hypothesize that early measurable residual disease (MRD)-guided pre-emptive therapy with decitabine + cedazaridine (DEC-C) will decrease the risk of progression in post-transplant myelodysplastic syndromes (MDS) patients with persistent mutations (molecular MRD). To detect molecular MRD, the investigators will perform ultra-deep, error-corrected panel-based sequencing (MyeloSeq-HD) at Day 30 in post-transplant MDS patients. The investigators will treat patients with detectable molecular MRD with DEC-C to determine if pre-emptive, MRD-guided therapy with DEC-C decreases relapse rates and improves progression-free survival.

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.

What data supports the effectiveness of the drug DEC-C (Inqovi) for treating myelodysplastic syndrome?

The drug DEC-C (Inqovi), a combination of decitabine and cedazuridine, was shown to be effective in treating myelodysplastic syndromes (MDS) in clinical trials. In a phase III study, it demonstrated similar effectiveness to intravenous decitabine, with a complete remission rate of 21% and a median duration of remission of 7.5 months. ^{1 2 3 4 5}

Is DEC-C (decitabine/cedazuridine) safe for humans?

DEC-C, also known as Inqovi, has been approved by the FDA for treating myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), with safety data showing adverse reactions similar to those of intravenous decitabine. Postmarketing assessments are ongoing to further evaluate its safety in specific conditions like heart rhythm changes and liver or kidney issues. ^{1 2 3 4 6}

What makes the drug DEC-C unique for treating myelodysplastic syndrome?

DEC-C is unique because it combines decitabine with cedazuridine, allowing it to be taken orally instead of through an IV. Cedazuridine helps increase the amount of decitabine that stays in the body, making the oral form as effective as the IV form, which is more convenient for patients. ^{1 2 3 4 6}

Research Team

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

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• DEC-C (DNA Methyltransferase Inhibitor)
• MyeloSeq-HD (Procedure)

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.

Participant Groups

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 ≥ 0.5%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 ≥ 0.5%. 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 ≥ 0.5%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 ≥ 0.5%. 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 ≥ 0.5%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 ≥ 0.5%) 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

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

David H. Perlmutter

Washington University School of Medicine

Chief Executive Officer since 2015

MD from Washington University School of Medicine

Paul Scheel

Washington University School of Medicine

Chief Medical Officer since 2022

MD from Washington University School of Medicine

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

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]

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]

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]

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 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]

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]

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

Role of cedazuridine/decitabine in the management of myelodysplastic syndrome and chronic myelomonocytic leukemia. [2021]

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

Cedazuridine/decitabine: from preclinical to clinical development in myeloid malignancies. [2023]

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

Decitabine/Cedazuridine: First Approval. [2021]

5. China pubmed.ncbi.nlm.nih.gov

[Clinical Efficacy and Prognostic Factors of Decitabine for Treatment of Myelodysplastic Syndrome]. [2019]

6. 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]