Decitabine + Cedazuridine for Solid Tumors
Recruiting in Palo Alto (17 mi)
+1 other location
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Must not be taking: Investigational agents
Disqualifiers: Hepatitis B, Hepatitis C, others
No Placebo Group
Trial Summary
What is the purpose of this trial?
This is a phase 1 study of the combination of cedazuridine with decitabine in patients with solid tumors. At least 6 patients will be enrolled per treatment level to assess optimal hypomethylation and toxicity (up to 35 patients total).
Will I have to stop taking my current medications?
The trial protocol does not specify whether you need to stop taking your current medications. However, you cannot be on any other investigational agents and must not have had chemotherapy or radiotherapy within the last 3 weeks.
What data supports the effectiveness of the drug Decitabine + Cedazuridine for solid tumors?
The combination of Decitabine and Cedazuridine has been shown to be effective in treating myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), with clinical responses observed in 60% of patients, including 21% achieving complete response. This suggests potential effectiveness in other cancers, including solid tumors, although specific data for solid tumors is still being studied.12345
Is the combination of Decitabine and Cedazuridine safe for humans?
The combination of Decitabine and Cedazuridine has been studied in patients with certain blood disorders, and common serious side effects included low white blood cell counts, low platelet counts, and fever with low white blood cell counts. These side effects are similar to those seen with Decitabine alone.45678
How is the drug Decitabine + Cedazuridine unique for treating solid tumors?
Decitabine + Cedazuridine is unique because it combines decitabine, a drug that inhibits DNA methylation (a process that can turn off genes), with cedazuridine, which helps increase the amount of decitabine that can be absorbed when taken by mouth. This oral combination makes it easier for patients to take compared to traditional intravenous administration.458910
Eligibility Criteria
This trial is for adults with advanced solid tumors who've tried at least two treatments without success or declined other beneficial therapies. They must be in good physical condition (ECOG <1), able to swallow pills, and have measurable tumor growth. People can't join if they have recent ulcers, bowel blockages, chemotherapy or radiotherapy within the last 3 weeks, are on other experimental drugs, or have active hepatitis B/C or symptomatic ascites.Inclusion Criteria
I can swallow pills.
My cancer is advanced, cannot be surgically removed, and has spread.
I am fully active and can carry on all my pre-disease activities without restriction.
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Exclusion Criteria
I have an active hepatitis B or C infection.
I have had fluid build-up in my abdomen causing discomfort in the last 4 weeks.
Participants may not be receiving any other investigational agents
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Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive a combination of cedazuridine and decitabine on an outpatient basis. Cycle length is 28 days.
28 days per cycle, up to 2 years
Follow-up
Participants are monitored for safety and effectiveness after treatment
up to 2 years
Treatment Details
Interventions
- Cedazuridine (Cytidine Deaminase Inhibitor)
- Decitabine (Anti-metabolites)
Trial OverviewThe study tests different doses of Cedazuridine combined with Decitabine in patients with solid tumors to find the best dose that modifies DNA methylation without causing too much toxicity. At least six people will be tested per dose level up to a total of thirty participants.
Participant Groups
1Treatment groups
Experimental Treatment
Group I: Decitabine and CedazuridineExperimental Treatment2 Interventions
Treatment will be administered on an outpatient basis. Cycle length is 28 days. The dose of cedazuridine is fixed at 100mg and the dose and duration of decitabine will vary depending on when a patient enters the study.
Cedazuridine is already approved in United States for the following indications:
🇺🇸 Approved in United States as ASTX727 for:
- Acute Myeloid Leukemia (AML)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
USC Norris Comprehensive Cancer CenterLos Angeles, CA
Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimore, MD
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Who Is Running the Clinical Trial?
Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsLead Sponsor
Astex Pharmaceuticals, Inc.Industry Sponsor
References
[Efficacy and Safety of Decitabine Combined with Modified CAG Regimen in Patients Aged ≥ 70 Years with Newly Diagnosed Acute Myeloid Leukemia]. [2023]To evaluate the clinical efficacy and safety of decitabine combined with modified CAG regimen (D-CAG regimen) in patients aged ≥70 years with newly diagnosed acute myeloid leukemia (AML).
[Efficacy and Safety of Decitabine Combined with Modified EIAG Regimen in the Treatment of Patients with Relapsed/Refractory Acute Myeloid Leukemia and High-risk Myelodysplastic Syndrome]. [2023]To investigate the efficacy, prognosis and safety of decitabine combined with modified EIAG regimen in the treatment of patients with relapsed/refractory acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS).
[Comparison of the Curative Efficacy of Elderly Patients with High-Risk MDS and MDS-Transformed AML between Decitabine Combined with Low-Dose CEG Regimen and Decitabine Combined with Low-Dose CAG Regimen]. [2022]To evaluate the efficacy of decitabine combined with low-dose CEG regimen (DCEG) and decitabine combined with low-dose CAG regimen (DCAG) in the treatment of elderly patients with MDS and MDS-transformed acute myeloid leukemia (AML).
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.
[Clinical Efficacy of Decitabine Combined with or without Cytarabine-based Low Dose Regimen for Senile patients with Acute Myeloid Leukemia]. [2019]To investigate the therapeutic effectiveness and side effects of decitabine combined with or without cytarabine-based low dose regimen for acute myeloid leukemia in geratic patients.
The path to approval for oral hypomethylating agents in acute myeloid leukemia and myelodysplastic syndromes. [2022]Two oral hypomethylating agents, oral azacitidine (CC-486) and decitabine/cedazuridine (ASTX727), have recently entered the clinical domain. CC-486 has been shown to improve overall survival as maintenance therapy for older patients with acute myeloid leukemia in complete remission, whereas the combination of decitabine with cedazuridine, a cytidine deaminase inhibitor, is indicated for the treatment of adult patients with myelodysplastic syndromes and chronic myelomonocytic leukemia with intermediate-1, or higher, International Prognostic Scoring System risk. This article briefly summarizes the clinical development of both drugs, the pivotal studies that led to their approval and some of the issues faced in extending the use of these drugs to other indications.
Decitabine: a review of its use in older patients with acute myeloid leukaemia. [2021]Decitabine (Dacogen(®)) is a deoxynucleoside analogue of cytidine that selectively inhibits DNA methyltransferases. Decitabine administered at a dose of 20 mg/m(2) by a 1-h intravenous infusion for 5 consecutive days of a 4-week cycle has been approved by the European Medicines Agency (EMA) for use in adult patients aged ≥65 years with de novo or secondary acute myeloid leukaemia (AML) who are not candidates for standard induction therapy. Decitabine, compared with treatment choice (cytarabine or supportive care), did not result in a statistically significant improvement in median overall survival (OS) in older patients with AML at the pre-specified primary endpoint of a pivotal phase III trial. However, the improvement in OS was considered by the EMA to be clinically meaningful. After a further year of follow-up, an analysis of the mature survival data demonstrated a statistical significance in median OS in favour of decitabine over treatment choice. Complete remission (CR) rates in the phase III trial were significantly improved with decitabine versus treatment choice. The overall safety profile of decitabine in older patients with AML was generally similar to that of cytarabine, with pyrexia, thrombocytopenia and anaemia being the most commonly reported adverse events. In conclusion, low-dose decitabine may be considered as an effective and generally well tolerated alternative treatment to cytarabine or supportive care in older patients with AML who are not candidates for standard induction therapy.
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.
Decitabine for acute myeloid leukemia. [2018]Decitabine (Dacogen(®), Eisai Inc., NJ, USA) is a nucleoside analogue DNA methyltransferase inhibitor first synthesized and documented to have antileukemic efficacy over 40 years ago. Over the years, the dosing of decitabine has been refined, such that for acute myeloid leukemia, a 5-day schedule of 20 mg/m(2) is now commonly utilized. Owing to its relatively modest nonhematologic toxicity when administered in this manner, single agent decitabine has shown the greatest promise in antileukemic efficacy for the management of older individuals and others who are not candidates for more intensive therapy. Whether or not single-agent decitabine is more safe and effective than existing therapies for older individuals, which markers best predict for response, and what drugs combine most effectively with decitabine, are all areas of active investigation at this time.