Cedazuridine + Azacitidine for Leukemia

(AZTOUND Trial)

Recruiting at 73 trial locations

Overseen By Taiho Oncology, Inc.

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Astex Pharmaceuticals, Inc.

Must be taking: Azacitidine

Must not be taking: Decitabine, Guadecitabine

Disqualifiers: HIV, Hepatitis B/C, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

236 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two drugs, azacitidine (Vidaza or 5-azacytidine) and cedazuridine (ASTX727), to determine their effectiveness in treating certain blood cancers like leukemia. Researchers compare different administration methods, such as oral and injection, and explore a combination with another drug, venetoclax. The trial seeks participants with specific blood conditions like myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) who have not responded well to standard treatments. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering a chance to explore new treatment possibilities.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the combination of cedazuridine and azacitidine is generally well-tolerated by patients. In past studies, individuals with conditions like MDS (a type of blood cancer) and AML (acute myeloid leukemia) who took this combination experienced positive safety outcomes. For instance, a study with 208 patients closely monitored the safety of using cedazuridine and azacitidine together. The treatment did not cause any unexpected or severe side effects beyond those typically associated with these drugs, suggesting that most patients can handle the combination well.

Azacitidine has already received FDA approval for treating certain blood cancers, indicating its safety is well-established. When combined with cedazuridine, the aim is to enhance its effectiveness while maintaining safety. Overall, these findings support the idea that this treatment is safe for use in clinical trials. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatment combining Cedazuridine and Azacitidine for leukemia because it introduces a novel way of delivering these drugs. Unlike standard treatments that often rely on injections, this combination allows for oral administration, making it more convenient for patients. Additionally, Cedazuridine acts to enhance the effectiveness of Azacitidine by inhibiting the enzyme that breaks down the drug, potentially increasing its availability and efficacy in the body. This dual approach not only simplifies the treatment regimen but also holds promise for better outcomes in managing leukemia.

What evidence suggests that this trial's treatments could be effective for leukemia?

Studies have shown that azacitidine effectively treats certain blood cancers, such as acute myeloid leukemia (AML), and the FDA has approved it for this purpose. In this trial, some participants will receive a combination of cedazuridine with azacitidine. Research suggests this combination allows azacitidine to be taken as a pill while maintaining the effectiveness of the injection form. Early results indicate that this combination can sustain similar drug levels in the body as the standard treatment, making it easier to take. This could be a promising option for patients who prefer oral medication over injections. ^{1 2 3 5 6}

Are You a Good Fit for This Trial?

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

I haven't had chemotherapy in the last 4 weeks.

I can swallow several pills within 10 minutes and fast for 4 hours.

My liver function tests are within the required range.

Exclusion Criteria

I have had more than one cycle of specific chemotherapy treatments.

I have MDS/MPN and can feel swelling in my liver or spleen.

I do not have any severe illnesses or conditions that could risk my safety in the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1: Dose Escalation

Open-label dose escalation stage using multiple cohorts at escalating dose levels of oral cedazuridine and azacitidine

28 days per cycle

Multiple visits per cycle

Phase 1: Dose Expansion

Dose expansion stage with oral azacitidine followed by SC azacitidine, ASTX030, and oral cedazuridine

28 days per cycle

Multiple visits per cycle

Phase 2: Randomized Crossover

Randomized, open-label crossover study comparing oral ASTX030 to SC azacitidine

28 days per cycle

Multiple visits per cycle

Phase 3: Randomized Crossover

Randomized open-label crossover study comparing the final oral ASTX030 dose to SC azacitidine

28 days per cycle

Multiple visits per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 36 months

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Cedazuridine

Trial Overview 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.

How Is the Trial Designed?

Group I: Phase 3 Monotherapy, Sequence A & B Experimental Treatment 2 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 Monotherapy, Part B, Sequence A & B Experimental Treatment 2 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 Monotherapy, Stage B (Dose Expansion) Experimental Treatment 3 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 Monotherapy , Stage A (Dose Escalation) Experimental Treatment 3 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.

Group V: Phase 1 Combination Therapy Experimental Treatment 3 Interventions

Treatment Arm 1: Participants will receive oral dose of ASTX030 along with ramp-up oral dosing of venetoclax in Cycle 1 (cycle length = 28 days); participants will receive ASTX030 along with venetoclax on a specific dosing schedule in subsequent cycles (Cycles ≥2). Treatment Arm 2: Participants will receive SC azacitidine along with ramp-up oral dosing of venetoclax in Cycle 1 (cycle length = 28 days); participants will receive SC azacitidine along with oral dose of venetoclax on a specific dosing schedule in subsequent cycles (Cycles ≥2). At the beginning of Cycle 5, Arm 2 patients may be permitted to cross over to Arm 1.

Azacitidine is already approved in European Union, United States, Canada, Japan 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

Who Is Running the Clinical Trial?

Astex Pharmaceuticals, Inc.

Lead Sponsor

Trials

97

Recruited

7,400+

Dr. Harren Jhoti

Astex Pharmaceuticals, Inc.

Chief Executive Officer since 2007

PhD in Biochemistry from Birkbeck College, London

Dr. Harold N. Keer

Astex Pharmaceuticals, Inc.

Chief Medical Officer since 2020

MD

Taiho Oncology, Inc.

Lead 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

Published Research Related to This Trial

Azacitidine (Vidaza) is the only drug approved in the EU that significantly prolongs survival in adults with high-risk myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), making it a crucial treatment option for patients not eligible for stem cell transplantation.

The treatment is associated with a lower risk of AML progression and higher rates of remission and blood transfusion independence, while maintaining an acceptable safety profile, with peripheral cytopenias being the most common side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine: a review of its use in higher-risk myelodysplastic syndromes/acute myeloid leukaemia. Keating, GM.[2021]

5-Azacytidine has shown a 36% overall response rate and 20% complete remission in patients with acute myelogenous leukemia (AML) who have previously been treated, indicating its potential effectiveness in this specific cancer.

While the drug has dose-limiting toxicities such as nausea, vomiting, and leukopenia, it has low incidence of thrombocytopenia and varying degrees of hepatic toxicity, suggesting that its safety profile needs careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

5-Azacytidine. A new anticancer drug with effectiveness in acute myelogenous leukemia. Von Hoff, DD., Slavik, M., Muggia, FM.[2019]

Azacitidine (AZA) significantly prolonged overall survival by 3.9 months compared to conventional care regimens in older patients (≥65 years) with acute myeloid leukemia (AML).

Patients treated with AZA experienced lower rates of treatment-emergent adverse events (TEAEs) and related hospitalizations compared to those receiving best supportive care, suggesting that AZA is a safer option for older patients who cannot tolerate intensive therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Seymour, JF., Döhner, H., Minden, MD., et al.[2019]

The ROMAZA trial established that the maximum tolerated dose of the combination therapy of romidepsin (ROM) and azacitidine (AZA) for treating acute myeloid leukaemia (AML) is ROM 12 mg/m2 on Days 8 and 15, along with AZA 75 mg/m2 for a 7/28 day cycle.

Out of 38 patients treated at this maximum tolerated dose, 23.7% achieved a response by Cycle 6, with 7 patients reaching complete remission and 2 achieving partial response, indicating the potential efficacy of this combination therapy in AML patients who cannot undergo intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination romidepsin and azacitidine therapy is well tolerated and clinically active in adults with high-risk acute myeloid leukaemia ineligible for intensive chemotherapy. Loke, J., Metzner, M., Boucher, R., et al.[2022]

Azacitidine significantly improves response rates and overall survival in patients with myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), with a median survival increase of 9.4 months compared to conventional care in higher-risk patients.

The treatment is generally well tolerated, with peripheral cytopenias being the most common side effect, along with gastrointestinal issues and injection-site reactions, making it a viable option for elderly patients as well.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine: a review of its use in the management of myelodysplastic syndromes/acute myeloid leukaemia. Keating, GM.[2022]

Azacitidine is an effective and well-tolerated treatment for patients with higher-risk myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), including older patients who are ineligible for stem cell transplants, as demonstrated in pivotal phase 3 trials.

It is the only approved hypomethylating agent that has been shown to prolong overall survival compared to conventional care, making it the recommended first-line treatment for most patients with higher-risk MDS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine: A Review in Myelodysplastic Syndromes and Acute Myeloid Leukaemia. Scott, LJ.[2022]

In a real-life study of 49 patients with myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and chronic myelomonocytic leukaemia (CMML), azacitidine demonstrated a clinically acceptable safety profile, with 67.3% of patients experiencing treatment-related adverse events.

Efficacy results showed that 41.4% of MDS and CMML patients achieved a complete or partial response, and 43.8% of transfusion-dependent patients became transfusion-independent, with a median overall survival of 490 days.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Beguin, Y., Selleslag, D., Meers, S., et al.[2015]

The Vidaza Access Program in Belgium successfully facilitated access to azacitidine treatment for 175 patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML) by streamlining the approval process for patient dossiers.

Out of the 175 patient dossiers submitted, 163 were approved by Celgene, demonstrating the program's effectiveness in ensuring timely treatment initiation without financial risk to hospitals, which is crucial for patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine access program for Belgian patients with myelodysplastic syndromes, acute myeloid leukemia or chronic myelomonocytic leukemia. Meers, S., Selleslag, D., Potier, H., et al.[2018]

In a study of 1406 patients receiving azacitidine, the most common severe adverse events were hematologic, with grade 3-4 anemia occurring in 43.4% of patients, which was higher than reported in clinical trials.

Despite the high frequency of adverse events, treatment discontinuation due to these events was low (5.1%), indicating that with proper management, azacitidine can be safely administered to most patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Leisch, M., Pfeilstöcker, M., Stauder, R., et al.[2022]

Azacitidine is effective for treating adult patients with acute myeloid leukemia (AML) who have 20%-30% blasts and multilineage dysplasia, significantly prolonging median overall survival compared to conventional care, as shown in the AZA-001 phase III trial.

The review also highlights the potential benefits of combining azacitidine with other treatments for AML, suggesting it may enhance patient outcomes further.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine for the treatment of patients with acute myeloid leukemia with 20%-30% blasts and multilineage dysplasia. Font, P.[2017]

Citations

1. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/3245/502685/Development-of-Oral-Azacitidine-with-Cedazuridine

Development of Oral Azacitidine with Cedazuridine for ... This Phase I trial is designed to determine the dose combination for oral AZA plus CED to replicate SC AZA AUC exposures in subjects with MDS and MDS/MPN, ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0006497123098476

Development of Oral Azacitidine with Cedazuridine for ... Hypomethylating agents (HMAs) such as azacitidine (AZA) and decitabine (DEC) are FDA-approved for patients with MDS/CMML and acute myeloid leukemia (AML).

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04256317

A Multi-phase Study of ASTX030 (Azacitidine and ... A Multi-phase Study of ASTX030 (Azacitidine and Cedazuridine) in Myeloid Neoplasm Alone or in Combination With Venetoclax in AML (AZTOUND Study) (AZTOUND).

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.6551

Phase II trial of 10-day ASTX727 (decitabine/cedazuridine ... In this prospective clinical trial, we investigate the efficacy of a novel 10-day induction regimen with fully oral combination therapy for pts with R/R AML.

5. ash.confex.com ash.confex.com/ash/2024/webprogram/Paper203569.html

Results from a Phase 1 Open-Label Dose ... Overall, 88 patients received a median of 6.0 (range, 1–32) ASTX030 treatment cycles (data cutoff: May 24, 2024). Median age was 72 years (range ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9378483/

FDA approval summary: decitabine and cedazuridine ... Safety was assessed in 208 patients (78 from ASTX727-01-B, 130 from ASTX727-02) with MDS or CMML treated with at least 1 dose of DEC-C tablets. Safety data ...