DEC-C Pre-emptive Therapy for Myelodysplastic Syndrome
Recruiting in Palo Alto (17 mi)
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.12345
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.12346
What makes the drug DEC-C unique for treating myelodysplastic syndrome?
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.
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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.
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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 OverviewThe 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
4Treatment groups
Experimental Treatment
Active Control
Group I: Phase II MRD Positive: DEC-CExperimental Treatment2 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-CExperimental Treatment2 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-CExperimental Treatment2 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 ArmActive Control1 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
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)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Washington University School of MedicineSaint Louis, MO
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Who Is Running the Clinical Trial?
Washington University School of MedicineLead Sponsor
Taiho Oncology, Inc.Industry Sponsor
References
FDA Approval Summary: Decitabine and Cedazuridine Tablets for Myelodysplastic Syndromes. [2023]On July 7, 2020, the Food and Drug Administration approved Inqovi (Otsuka Pharmaceutical Co.), an oral fixed-dose combination tablet comprising 35 mg decitabine, a hypomethylating agent, and 100 mg cedazuridine, a cytidine deaminase inhibitor (abbreviated DEC-C) for treatment of adult patients with myelodysplastic syndromes (MDS). Evidence of effectiveness of DEC-C was established in phase III ASTX727-02 (N = 133) in adults with MDS. The study involved a two-sequence crossover comparing DEC-C and intravenous (IV) decitabine 20 mg/m2 once daily for the first 5 days of each 28-day cycle in the first 2 cycles. From cycle 3 onward, patients received DEC-C. Five-day cumulative area under the curve (5-d AUC) of decitabine for DEC-C was similar to that of IV decitabine, with geometric mean ratio 0.99 (90% confidence interval: 0.93-1.06). Clinical benefit was supported by study ASTX727-02 and the similarly designed phase II study ASTX727-01-B (n = 80), with complete remission (CR) of 21% and 18% and median duration of CR 7.5 and 8.7 months, respectively. Adverse reactions were consistent with IV decitabine. Postmarketing assessments were issued to address the effect of cedazuridine on QT prolongation, food effect, moderate and severe hepatic impairment, and severe renal impairment on the pharmacokinetics and safety of DEC-C.
Role of cedazuridine/decitabine in the management of myelodysplastic syndrome and chronic myelomonocytic leukemia. [2021]Myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) are clonal hematopoietic stem cell disorders. Complex disease biology has posed significant challenge to the development of novel therapeutics. Despite myriad clinical trials, none have been superior to azacitidine and decitabine (DEC) therapy. These therapies present a substantial burden for patients with 5 and 7 days of parenteral treatment in an infusion clinic. To overcome this limitation, a fixed drug combination of oral DEC-cedazuridine (C-DEC), a cytidine deaminase inhibitor with documented safety profile was developed. This drug was recently approved by the US FDA, Australian TGA and Health Canada for newly diagnosed or previously treated intermediate or high risk by international prognostic scoring system, MDS and CMML. In this review, we detail the pharmacokinetic and clinical activity of C-DEC in the management of MDS and CMML.
Cedazuridine/decitabine: from preclinical to clinical development in myeloid malignancies. [2023]Since the US Food and Drug Administration (FDA) approvals of parenteral decitabine and azacitidine, DNA methyltransferase inhibitors, otherwise referred to as DNA hypomethylating agents (HMAs), have been a mainstay in the treatment of higher-risk myelodysplastic syndromes. The development of oral HMAs has been an area of active interest; however, oral bioavailability has been quite poor due to rapid metabolism by cytidine deaminase (CDA). This led to the development of the novel CDA inhibitor cedazuridine, which was combined with an oral formulation of decitabine. Preclinical work demonstrated a pharmacokinetic and pharmacodynamic profile approximate to parenteral decitabine, leading to early-phase clinical trials of oral cedazuridine-decitabine (C-DEC) in myelodysplastic syndromes and chronic myelomonocytic leukemia (CMML). A combination of oral decitabine 35 mg with oral cedazuridine 100 mg was established as the recommended phase 2 dose. Phase 2 data confirmed bioequivalence of C-DEC when compared with parenteral decitabine, and a larger phase 3 trial has demonstrated similar results, leading to the FDA approval of C-DEC for use in intermediate/high-risk myelodysplastic syndrome (MDS) and CMML. This review will focus upon the current role of HMA therapy in MDS/CMML, preclinical and clinical development of C-DEC, and potential roles of oral HMA therapy in myeloid malignancies moving forward.
Decitabine/Cedazuridine: First Approval. [2021]A fixed dose oral combination (FDC) of decitabine and cedazuridine (Inqovi®), is being developed by Astex Pharmaceuticals (a subsidiary of Otsuka Pharmaceuticals) for the treatment of various cancers like myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemia (AML), glioma and solid tumours. Decitabine, a DNA methyltransferase inhibitor approved for the treatment of MDS and CMML, is degraded by cytidine deaminase in the gastrointestinal tract and liver, thereby limiting oral bioavailability. Cedazuridine is a proprietary, patented cytidine deaminase inhibitor that, when added to decitabine, increases oral bioavailability of the drug. In July 2020, decitabine/cedazuridine received its first approval in the USA and Canada for the treatment of MDS and CMML. In the USA, it is indicated for use in adults with MDS and CMML, 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 blasts and CMML) and intermediate-1, intermediate-2 and high-risk International Prognostic Scoring System groups. Clinical studies for AML, glioma and solid tumours are underway in several countries worldwide. This article summarizes the milestones in the development of decitabine/cedazuridine leading to this first approval for the treatment of MDS and CMML.
[Clinical Efficacy and Prognostic Factors of Decitabine for Treatment of Myelodysplastic Syndrome]. [2019]To explore the clinical efficacy of decitabine for treatment of patients with myelodysplastic syndrome (MDS) and factors predicting the prognosis.
An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study. [2019]Decitabine, a DNA methyltransferase 1 inhibitor or DNA hypomethylating compound, is not readily orally bioavailable because of rapid clearance by cytidine deaminase (CDA) in the gut and liver. This dose-escalation study, guided by pharmacokinetic and pharmacodynamic observations, evaluated whether simultaneous oral administration with the novel CDA inhibitor cedazuridine increases decitabine bioavailability for the treatment of myelodysplastic syndromes.