Cedazuridine + Azacitidine for Leukemia
Recruiting in Palo Alto (17 mi)
+25 other locations
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2 & 3
Recruiting
Sponsor: Astex Pharmaceuticals, Inc.
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?This trial tests a new pill form of two drugs, cedazuridine and azacitidine, for patients needing azacitidine treatment. The goal is to see if the pill is as effective as the injection. Cedazuridine helps azacitidine work better by preventing its breakdown, and azacitidine stops cancer cells from growing.
Will I have to stop taking my current medications?
The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have had cytotoxic chemotherapy (except hydroxyurea) within 4 weeks before starting the study treatment, and you should not be on any investigational drugs or therapies within 2 weeks before the first dose.
What data supports the effectiveness of the drug Azacitidine for leukemia?
Azacitidine has been shown to significantly prolong survival in patients with higher-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) compared to conventional care. It also reduces the risk of AML progression and increases rates of complete and partial remission.
12345Is the combination of Cedazuridine and Azacitidine safe for humans?
Azacitidine, used in combination with Cedazuridine, has been studied for safety in patients with leukemia and related conditions. Common side effects include low blood cell counts, fatigue, and fever, but serious side effects leading to stopping treatment are rare. With proper management, it is generally considered safe for most patients.
12678What makes the drug Cedazuridine + Azacitidine unique for treating leukemia?
The combination of Cedazuridine and Azacitidine is unique because Cedazuridine helps increase the effectiveness of Azacitidine by preventing its breakdown in the body, allowing for oral administration instead of the usual subcutaneous (under the skin) injection, which can be more convenient for patients.
135910Eligibility Criteria
This trial is for adults with certain blood disorders like MDS, CMML, or AML who can benefit from azacitidine treatment. They should be physically stable (ECOG 0-1), expected to live at least 12 weeks, able to swallow pills and fast for 4 hours. Pregnant women can't join; participants need proper liver and kidney function and no recent major surgeries or chemotherapy.Inclusion Criteria
My liver function tests are within the required range.
I had a stem cell transplant without GVHD and haven't taken immunosuppressives for 2 weeks.
I can carry out all my daily activities without help.
My condition is a specific type of blood disorder according to certain classifications.
I am not pregnant or breastfeeding and my pregnancy test was negative.
My kidneys work well enough to clear waste from my blood.
Exclusion Criteria
I have MDS/MPN and can feel swelling in my liver or spleen.
I have other serious health issues or infections that are not under control.
I haven't taken any experimental drugs recently or have ongoing side effects from them.
I have an active stomach or upper small intestine ulcer that's not under control.
Participant Groups
The study tests ASTX030 (oral cedazuridine combined with azacitidine) against subcutaneous azacitidine alone in three phases: dose escalation, dose expansion, then a randomized comparison of the final oral dose versus the injection form over approximately four years.
4Treatment groups
Experimental Treatment
Group I: Phase 3, Sequence A & BExperimental Treatment2 Interventions
In Sequence A: Participants will receive ASTX030 in Cycle 1, followed by SC azacitidine in Cycle 2; all participants will receive ASTX030 in subsequent cycles (Cycles ≥3).
In Sequence B: Participants will receive SC azacitidine in Cycle 1 followed by ASTX030 in Cycle 2; all participants will receive ASTX030 in subsequent cycles (Cycles ≥3).
Group II: Phase 2, Part B, Sequence A & BExperimental Treatment2 Interventions
In Sequence A: Oral ASTX030 (cedazuridine + azacitidine) will be administered in Cycle 1, followed by SC azacitidine in Cycle 2; all participants will receive ASTX030 in subsequent cycles (Cycles ≥3).
In Sequence B: SC azacitidine will be administered in Cycle 1, followed by oral cedazuridine + azacitidine tablets/capsules in Cycle 2; all participants will receive ASTX030 in subsequent cycles (Cycles ≥3).
Group III: Phase 1, Stage B (Dose Expansion)Experimental Treatment3 Interventions
In Cycle 1 (28 days per cycle), single dose oral azacitidine will be administered, followed by SC azacitidine, ASTX030 and oral cedazuridine on a specific dosing schedule; in Cycle 2, oral ASTX030 (cedazuridine + azacitidine) will be administered. On Day 7 of Cycle 2 drug products will administered in a fed state and all other doses will be administered in fasted state.
Group IV: Phase 1, Stage A (Dose Escalation)Experimental Treatment3 Interventions
In Cycle 1 (28 days per cycle), single dose oral azacitidine will be administered, followed by subcutaneous (SC) azacitidine, ASTX030 and oral cedazuridine on a specific dosing schedule; in Cycle 2, oral ASTX030 (cedazuridine + azacitidine) will be administered.
Azacitidine is already approved in European Union, United States, Canada, Japan, Australia for the following indications:
🇪🇺 Approved in European Union as Vidaza for:
- Acute myeloid leukemia
- Chronic myelomonocytic leukemia
- Myelodysplastic syndromes
🇺🇸 Approved in United States as Vidaza for:
- Myelodysplastic syndromes
- Chronic myelomonocytic leukemia
🇨🇦 Approved in Canada as Vidaza for:
- Myelodysplastic syndromes
- Acute myeloid leukemia
🇯🇵 Approved in Japan as Vidaza for:
- Myelodysplastic syndromes
- Acute myeloid leukemia
🇦🇺 Approved in Australia as Vidaza for:
- Myelodysplastic syndromes
- Acute myeloid leukemia
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Dana-Farber Cancer InstituteBoston, MA
Eastern Health Sciences Centre - General HospitalSt. John's, Canada
Yale UniversityNew Haven, CT
MedStar Georgetown University HospitalWashington, United States
More Trial Locations
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Who is running the clinical trial?
Astex Pharmaceuticals, Inc.Lead Sponsor
Taiho Oncology, Inc.Lead Sponsor
References
Azacitidine access program for Belgian patients with myelodysplastic syndromes, acute myeloid leukemia or chronic myelomonocytic leukemia. [2018]Azacitidine (Vidaza *) is approved in Europe for treatment of myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) with 20-30% bone marrow (BM) blasts, and chronic myelomonocytic leukemia (CMML) with 10-29% BM blasts and no myeloproliferative syndrome (i.e.
Safety and efficacy of azacitidine in Belgian patients with high-risk myelodysplastic syndromes, acute myeloid leukaemia, or chronic myelomonocytic leukaemia: results of a real-life, non-interventional post-marketing survey. [2015]We evaluated azacitidine (Vidaza(®)) safety and efficacy in patients with myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and chronic myelomonocytic leukaemia (CMML), in a real-life setting. Treatment response, dose, and schedule were assessed.
Azacitidine: a review of its use in higher-risk myelodysplastic syndromes/acute myeloid leukaemia. [2021]Azacitidine (Vidaza) is a pyrimidine nucleoside analogue of cytidine. Subcutaneous azacitidine was recently approved in the EU for the treatment of adults who are not eligible for haematopoietic stem cell transplantation and who have intermediate-2-risk or high-risk myelodysplastic syndromes (MDS) [according to International Prognostic Scoring System (IPSS) criteria], chronic myelomonocytic leukaemia (CMML) with 10-29% marrow blasts without myeloproliferative disorder, or acute myeloid leukaemia (AML) with 20-30% blasts and multilineage dysplasia (according to the WHO classification). Subcutaneous azacitidine is the only drug shown to significantly prolong survival in patients with higher-risk MDS or WHO-defined AML, compared with conventional care (i.e. best supportive care, low-dose cytarabine or intensive chemotherapy). In addition, azacitidine is associated with a lower risk of AML progression and higher rates of complete remission, partial remission, haematological improvement and red blood cell (RBC) transfusion independence. Azacitidine has an acceptable tolerability profile; peripheral cytopenias are the most commonly occurring adverse event. Thus, azacitidine is a valuable option for the first-line treatment of patients with higher-risk MDS/AML.
Azacitidine for the treatment of patients with acute myeloid leukemia with 20%-30% blasts and multilineage dysplasia. [2017]Azacitidine is approved in the EU for the treatment of adult patients who are not candidates for allogeneic stem cell transplantation, and who have intermediate-2 risk or high-risk myelodysplastic syndromes, according to the International Prognostic Scoring System. The approval includes the treatment of patients with acute myeloid leukemia (AML) with 20%-30% blasts and multilineage dysplasia, according to the World Health Organization (WHO) classification. This review focuses on the outcomes with azacitidine in this latter group of patients, previously classified as refractory anemia with excess of blasts in transformation, as defined by the French-American-British classification criteria. The main clinical evidence is based on the results of two large phase III clinical trials (Cancer and Leukemia Group B 9221, and AZA-001). The AZA-001 trial shows azacitidine significantly prolongs median overall survival in older patients with low marrow blasts (20%-30%) according to WHO-defined AML, and significantly improved several patient morbidity measures, compared with conventional care regimens. In addition, the review examines the results of azacitidine in combination with other treatments currently used in AML.
Combination romidepsin and azacitidine therapy is well tolerated and clinically active in adults with high-risk acute myeloid leukaemia ineligible for intensive chemotherapy. [2022]Azacitidine (AZA) is important in the management of patients with acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy. Romidepsin (ROM) is a histone deacetylase inhibitor which synergises with AZA in vitro. The ROMAZA trial established the maximum tolerated dose (MTD) of combined ROM/AZA therapy in patients with AML, as ROM 12 mg/m2 on Days 8 and 15, with AZA 75 mg/m2 administered for 7/28 day cycle. Nine of the 38 (23·7%) patients treated at the MTD were classified as responders by Cycle 6 (best response: complete remission [CR]/incomplete CR n = 7, partial response n = 2). Correlative next-generation sequencing studies demonstrated important insights into therapy resistance.
Adverse Events in 1406 Patients Receiving 13,780 Cycles of Azacitidine within the Austrian Registry of Hypomethylating Agents-A Prospective Cohort Study of the AGMT Study-Group. [2022]Background: Azacitidine is the treatment backbone for patients with acute myeloid leukemia, myelodysplastic syndromes and chronic myelomonocytic leukemia who are considered unfit for intensive chemotherapy. Detailed reports on adverse events in a real-world setting are lacking. Aims: To analyze the frequency of adverse events in the Austrian Registry of Hypomethylating agents. To compare real-world data with that of published randomized clinical trials. Results: A total of 1406 patients uniformly treated with a total of 13,780 cycles of azacitidine were analyzed. Hematologic adverse events were the most common adverse events (grade 3-4 anemia 43.4%, grade 3-4 thrombopenia 36.8%, grade 3-4 neutropenia 36.1%). Grade 3-4 anemia was significantly more common in the Registry compared to published trials. Febrile neutropenia occurred in 33.4% of patients and was also more common in the Registry than in published reports. Other commonly reported adverse events included fatigue (33.4%), pain (29.2%), pyrexia (23.5%), and injection site reactions (23.2%). Treatment termination due to an adverse event was rare (5.1%). Conclusion: The safety profile of azacitidine in clinical trials is reproducible in a real-world setting. With the use of prophylactic and concomitant medications, adverse events can be mitigated and azacitidine can be safely administered to almost all patients with few treatment discontinuations.
Incidence rates of treatment-emergent adverse events and related hospitalization are reduced with azacitidine compared with conventional care regimens in older patients with acute myeloid leukemia. [2019]Relative risks of treatment-emergent adverse events (TEAEs) and related hospitalization is most accurate when accounting for treatment exposure. AZA-AML-001 showed azacitidine (AZA) prolonged overall survival versus conventional care regimens (CCR) in older patients (≥65 years) with acute myeloid leukemia (AML) by 3.9 months. Preselection of CCR before study randomization allows evaluation of AZA safety in patient subgroups with similar clinical features. Within preselection groups, AZA exposure was greater than each CCR. Incidence rates (IRs; numbers of events normalized for drug exposure time) of hospitalizations and days in hospital for TEAEs per patient-year of exposure were to varying degrees lower with AZA versus each CCR. Overall survival was significantly prolonged with AZA versus best supportive care (BSC) in AZA-AML-001; this analysis showed 55% and 41% reductions in IRs of TEAE-related hospitalization and days in hospital, respectively, with AZA versus BSC. Older patients with AML unable to tolerate intensive therapy should be offered active low-intensity treatment.
5-Azacytidine. A new anticancer drug with effectiveness in acute myelogenous leukemia. [2019]Clinical studies involving 5-azacytidine, a ring analogue of cytidine, began in Europe in 1967 and the United States in 1970, and we review available preclinical and clinical studies here. The drug possesses cytotoxic, antimicrobial, antineoplastic, abortive, and mutagenic activity in various biological systems. 5-Azacytidine is thought to exert its antineoplastic effect through interference with nucleic acid metabolism. The dose-limiting toxicities are nausea, vomiting, and leukopenia, while the incidence of thrombocytopenia is low. Hepatic toxicity ranges from abnormal findings in liver function tests to hepatic coma. Clinical results in solid tumors are not encouraging, but 5-azacytidine shows consistent antitumor activity in patients with acute myelogenous leukemia resistant to previous treatment. An overall response rate of 36%, with 20% complete remissions, was achieved in 200 previously treated patients with acute myelogenous leukemia. Further studies must define the role of 5-azacytidine alone and in combination for the first-line treatment of acute myelogenous leukemia.
Azacitidine: a review of its use in the management of myelodysplastic syndromes/acute myeloid leukaemia. [2022]Azacitidine (Vidaza®) is a pyrimidine nucleoside analogue of cytidine. This article reviews the clinical efficacy and tolerability of azacitidine in the treatment of patients with myelodysplastic syndromes (MDS)/acute myeloid leukaemia (AML), as well as summarizing its pharmacological properties. The randomized, multicentre Cancer and Leukemia Group B 9221 trial compared the efficacy of subcutaneous azacitidine with that of supportive care alone in patients with MDS fulfilling French-American-British (FAB) classification criteria. The overall response rate, the complete response rate and the complete plus partial response rate were significantly higher in patients receiving azacitidine than in those receiving supportive care alone. The randomized, open-label, multicentre AZA-001 trial compared the efficacy of subcutaneous azacitidine with that of conventional care in adults with higher-risk (i.e. International Prognostic Scoring System intermediate-2-risk or high-risk classification) MDS/AML. Prior to randomization, investigators preselected patients to the conventional care strategy considered most appropriate (i.e. best supportive care, low-dose cytarabine or intensive chemotherapy). The median duration of overall survival was significantly prolonged by 9.4 months in patients with higher-risk MDS receiving azacitidine versus those receiving conventional care. The survival benefit seen with azacitidine versus conventional care was maintained across various patient subgroups (e.g. in patients aged ≥75 years, in those who did not achieve complete remission and in patients with WHO-defined AML). The efficacy of subcutaneous or intravenous azacitidine was also shown in a noncomparative trial in Japanese patients with MDS fulfilling FAB classification criteria, and registry programmes in various countries support the efficacy of azacitidine in patients with MDS. Azacitidine was generally well tolerated in patients with MDS, including in the elderly. Across trials, peripheral cytopenias were the most commonly occurring adverse event in azacitidine recipients, with gastrointestinal adverse events (e.g. nausea, vomiting and diarrhoea) and injection-site reactions among the most commonly occurring non-haematological adverse events. In conclusion, azacitidine is an important agent for use in the treatment of patients with MDS/AML.
Azacitidine: A Review in Myelodysplastic Syndromes and Acute Myeloid Leukaemia. [2022]Azacitidine (Vidaza(®)) is a pyrimidine nucleoside analogue of cytidine and is approved in the EU for use in patients with higher-risk myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), including older patients (aged ≥65 years) with AML with >30 % bone marrow blasts (BMB) who are ineligible for haematopoietic stem cell transplant. This article reviews the clinical efficacy and tolerability of azacitidine in the treatment of these patient populations, as well as summarizing its pharmacological properties. In pivotal, international, phase 3 trials, subcutaneous azacitidine was an effective and well tolerated treatment in patients with higher-risk MDS or AML, including older patients with AML with >30 % BMB, with extensive evidence from the real-world setting confirming its efficacy and safety in these patient populations. Azacitidine is the only approved hypomethylating agent that has been shown to prolong overall survival compared with conventional care regimens and thus, it is recommended as the first-line hypomethylating agent for most patients with higher-risk MDS. Hence, azacitidine remains and important agent for use in the treatment of higher-risk MDS and AML, including in older patients with AML with >30 % BMB.