ASTX727 for Myelodysplastic Syndrome
Recruiting in Palo Alto (17 mi)
+14 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Taiho Oncology, Inc.
Must not be taking: Azacitidine, Lenalidomide, Cyclosporine, others
Disqualifiers: Uncontrolled infections, Heart disease, HIV, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This is a Phase 1b, multicenter, open-label, PK, and safety study of multiple oral doses of oral decitabine and cedazuridine (formerly known as ASTX727) as a fixed-dose combination of decitabine 35 milligrams (mg) and cedazuridine 100 mg in cancer participants with severe renal impairment and cancer participants with normal renal function as matched control participants. Adult participants with acute myeloid lymphoma (AML), myelodysplastic syndrome (MDS), or solid tumors who are candidates to receive oral decitabine and cedazuridine will be enrolled in this study. Study duration per participant is approximately up to 8 weeks.
Will I have to stop taking my current medications?
The trial requires that you stop taking certain medications, such as azacitidine or decitabine, at least 4 weeks before starting the study. Other investigational or targeted therapies should be stopped 2 weeks or 5 half-lives before the first dose. Some medications, like those that prolong the QT interval, may also need to be stopped.
What data supports the effectiveness of the drug ASTX727 (Oral Decitabine and Cedazuridine) for Myelodysplastic Syndrome?
Research shows that the combination of oral decitabine and cedazuridine is as effective as the intravenous form of decitabine for treating myelodysplastic syndromes, with similar drug exposure and clinical responses. This combination has been approved by the FDA for use in intermediate/high-risk myelodysplastic syndrome and chronic myelomonocytic leukemia.
12345Is ASTX727 (Oral Decitabine and Cedazuridine) safe for humans?
In clinical trials, the most common serious side effects of ASTX727 were low white blood cell counts (neutropenia), low platelet counts (thrombocytopenia), and fever with low white blood cell counts (febrile neutropenia). These side effects were similar to those seen with the intravenous form of decitabine.
12346How is the drug ASTX727 unique for treating myelodysplastic syndrome?
ASTX727 is unique because it combines decitabine with cedazuridine, allowing it to be taken orally rather than intravenously. Cedazuridine inhibits an enzyme that would otherwise break down decitabine in the body, improving its availability and making the treatment more convenient for patients.
12345Eligibility Criteria
This study is for adults with certain types of blood cancer or solid tumors that can't be removed or have spread, and who can't undergo standard treatments. They must understand the study and agree to its procedures, especially the PK assessment schedule. Participants should not be suitable for induction therapy if they are over 75 years old, have a performance status ≥2, severe lung issues, or high bilirubin levels.Inclusion Criteria
I haven't had major surgery in the last 30 days.
For participants with AML/MDS only: Cytologically or histologically confirmed diagnosis of AML (except M3 acute promyelocytic leukemia) or MDS according to the 2008 World Health Organization (WHO) classification, Participants with frontline MDS or treatment naïve AML not suitable for induction therapy (e.g., age >75 years, Eastern Cooperative Oncology Group [ECOG] performance ≥2, severe pulmonary disorder, total bilirubin 1.5 X upper limit of normal [ULN]), Platelet count ≥25,000/per microliter (μL), Absolute neutrophil count (ANC) ≥100 cells/μL.
Participants must have a body surface area (BSA)-adjusted CLcr using to the Cockcroft-Gault equation: Participants without renal impairment (Group B): ≥80 mL/min/1.73m², Participants with severe renal impairment (Group A): <30 mL/min/1.73m², not requiring dialysis, CLcr must be stable with <30% deviation allowed from Screening to Baseline (Day -1). Participants shifting outside the prospected renal function category (normal renal function or severe renal function) at Baseline need to be agreed by Taiho medical expert whether they are allowed to remain in the original category that was assessed at Screening.
+9 more
Exclusion Criteria
History of alcohol abuse or drug addiction (including soft drugs like cannabis products).
Known significant mental illness or other condition, such as active alcohol or other substance abuse or addiction, that in the opinion of the investigator predisposes the participants to high risk of noncompliance with the protocol.
I am not allergic to decitabine, cedazuridine, or their ingredients.
+17 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2 weeks
Treatment
Participants receive multiple oral doses of decitabine and cedazuridine for pharmacokinetic and safety evaluation
8 weeks
Multiple visits for dosing and monitoring
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The trial is testing ASTX727—a combination of oral decitabine (35 mg) and cedazuridine (100 mg)—in patients with severe renal impairment compared to those with normal kidney function. It's an open-label Phase 1b study focusing on how the body processes the drug and its safety over approximately eight weeks.
2Treatment groups
Experimental Treatment
Active Control
Group I: Group A: Severe Renal ImpairmentExperimental Treatment1 Intervention
Cancer participants with severe renal impairment not requiring dialysis (creatinine clearance \[CLcr\] \<30 mL/min/1.73m\^2)
Group II: Group B: Normal Renal FunctionActive Control1 Intervention
Cancer participants with normal renal function (CLcr ≥80 mL/min/1.73m\^2)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
MD AndersonHouston, TX
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Who Is Running the Clinical Trial?
Taiho Oncology, Inc.Lead Sponsor
Astex Pharmaceuticals, Inc.Lead Sponsor
References
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.
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.
Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. [2021]This phase 2 study was designed to compare systemic decitabine exposure, demethylation activity, and safety in the first 2 cycles with cedazuridine 100 mg/decitabine 35 mg vs standard decitabine 20 mg/m2 IV. Adults with International Prognostic Scoring System intermediate-1/2- or high-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) were randomized 1:1 to receive oral cedazuridine/decitabine or IV decitabine in cycle 1, followed by crossover to the other treatment in cycle 2. All patients received oral cedazuridine/decitabine in subsequent cycles. Cedazuridine and decitabine were given initially as separate capsules in a dose-confirmation stage and then as a single fixed-dose combination (FDC) tablet. Primary end points: mean decitabine systemic exposure (geometric least-squares mean [LSM]) of oral/IV 5-day area under curve from time 0 to last measurable concentration (AUClast), percentage long interspersed nuclear element 1 (LINE-1) DNA demethylation for oral cedazuridine/decitabine vs IV decitabine, and clinical response. Eighty patients were randomized and treated. Oral/IV ratios of geometric LSM 5-day AUClast (80% confidence interval) were 93.5% (82.1-106.5) and 97.6% (80.5-118.3) for the dose-confirmation and FDC stages, respectively. Differences in mean %LINE-1 demethylation between oral and IV were ≤1%. Clinical responses were observed in 48 patients (60%), including 17 (21%) with complete response. The most common grade ≥3 adverse events regardless of causality were neutropenia (46%), thrombocytopenia (38%), and febrile neutropenia (29%). Oral cedazuridine/decitabine (100/35 mg) produced similar systemic decitabine exposure, DNA demethylation, and safety vs decitabine 20 mg/m2 IV in the first 2 cycles, with similar efficacy. This study is registered at www.clinicaltrials.gov as #NCT02103478.
The role of decitabine in the treatment of myelodysplastic syndromes. [2019]Supportive care with red cell and platelet transfusions and use of growth factors has long been the standard of care for patients with myelodysplastic syndromes (MDS) ineligible for stem cell transplantation. Although these measures improve quality of life, their impact on the natural history of the disease is questionable. Recently, three new agents have been approved for the treatment of MDS. These include: 5-azacytidine, lenalidomide and, more recently, 5-aza-2 -deoxycytidine (decitabine). Decitabine is a hypomethylating agent that is incorporated into DNA and forms irreversible covalent adducts with DNA-methyltransferases. At high concentrations, this leads to cell death. At low concentrations, decitabine is considered to exert its anticancer effects by inducing DNA hypomethylation. This results in reactivation of epigenetically repressed genes, such as tumour suppressor genes and, potentially, cell differentiation. In a randomized, Phase III trial of decitabine versus best supportive care in patients with MDS, the overall response rate with decitabine was 17%, including 9% complete remissions. Patients at high risk had a statistically significant prolongation of time to acute myelogenous leukemia transformation or death. This experience has been followed by a study of low-dose decitabine using a five-times daily 1-h infusion schedule, with significant efficacy in patients with MDS observed. Ongoing studies are evaluating the activity and safety of the combination of decitabine with several histone deacetylase inhibitors and other indications. This article summarizes the experience in with decitabine in MDS.
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.