Azacitidine + Quizartinib for Myelodysplastic Syndrome

Overseen By Guillermo M. Bravo

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CYP3A4 inducers, QT prolongers

Disqualifiers: Heart disease, Infections, Hepatitis, others

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

Compensation: Varies

Number of Visits: 6

Duration: 28 days per cycle

58 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I/II trial studies the side effects and best dose of quizartinib when given with azacitidine and to see how well they work in treating patients with myelodysplastic syndrome or myelodysplastic/myeloproliferative neoplasm with FLT3 or CBL mutations. Chemotherapy drugs, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Quizartinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving azacitidine and quizartinib may help to control myelodysplastic syndrome or myelodysplastic/myeloproliferative neoplasm.

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 take strong CYP3A4 inducers or drugs that prolong the QT/QTc interval, except for certain essential medications like antibiotics or antiemetics. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What data supports the effectiveness of the drug Azacitidine for treating myelodysplastic syndrome?

Azacitidine has been shown to significantly prolong survival in patients with higher-risk myelodysplastic syndromes compared to conventional care, and it is associated with higher rates of complete and partial remission, as well as improved blood cell counts. ^{1 2 3 4 5}

Is the combination of Azacitidine and Quizartinib safe for humans?

Azacitidine (also known as Vidaza or 5-azacytidine) has been used safely in patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML). Common side effects include nausea, vomiting, diarrhea, and low blood cell counts, but it generally has a favorable safety profile. Quizartinib (Vanflyta) is not mentioned in the provided research, so specific safety data for the combination with Azacitidine is not available. ^{1 2 3 6 7}

How is the drug Azacitidine + Quizartinib unique for treating myelodysplastic syndrome?

Azacitidine is a drug that has been shown to prolong survival in patients with higher-risk myelodysplastic syndromes (MDS) and is the only approved hypomethylating agent for this purpose. Combining it with Quizartinib, which is not typically used for MDS, may offer a novel approach by potentially enhancing treatment effectiveness, although specific details on this combination's uniqueness for MDS are not provided in the research. ^{1 2 3 6 8}

Research Team

Guillermo M. Bravo

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with myelodysplastic syndrome or related conditions, who have specific FLT3 or CBL mutations. It's open to those new to treatment and those who didn't respond to previous therapies. Participants should be in decent health otherwise, with acceptable organ function and no severe heart issues.

Inclusion Criteria

Patient (or patient's legally authorized representative) must have signed an informed consent document indicating that the patient understands the purpose of and procedures required for the study and is willing to participate in the study

I have used medications like hydroxyurea or growth factors for blood cell control.

I have not used hypomethylating agents and my blood cancer is classified as intermediate-2 or higher, or I have specific genetic mutations.

Exclusion Criteria

Sustained heart rate of < 50/minute on screening ECG

I have a serious heart rhythm problem but have a pacemaker.

Complete left bundle branch block

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive azacitidine subcutaneously or intravenously on days 1-5 and quizartinib orally once daily on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle

5 visits (in-person) per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

4 weeks

1 visit (in-person)

Long-term follow-up

Participants are monitored for relapse-free survival, overall survival, and other outcomes

Up to 2 years

Treatment Details

Interventions

• Azacitidine
• Quizartinib

Trial Overview The trial is testing the combination of two drugs: Azacitidine, a chemotherapy drug that stops cancer cells from growing, and Quizartinib, which blocks enzymes needed by cancer cells. The study aims to find the best dose and see how well these drugs work together against certain blood disorders.

Participant Groups

Group I: Treatment (azacitidine, quizartinib) Experimental Treatment 2 Interventions

Patients receive azacitidine SC or IV over about 30 minutes on days 1-5 and quizartinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

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]

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]

Azacitidine significantly improves overall survival in patients with myelodysplastic syndromes and related disorders, with a median survival of 24.5 months compared to 15 months for conventional care, based on a trial of 358 patients.

While azacitidine offers a viable treatment option when stem cell transplantation is not possible, it carries risks of severe toxicity and other side effects, highlighting the need for careful patient management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine. Poor-prognosis myelodysplasia: promising, but more data needed. [2013]

Azacitidine is the only approved hypomethylating agent in Europe for treating int-2-/high-risk myelodysplastic syndromes, significantly improving patient survival compared to conventional care.

Despite its effectiveness, many patients do not respond to azacitidine, and most responders experience relapse, highlighting the need for established treatment options after azacitidine failure and the importance of optimizing initial treatment and identifying biomarkers for monitoring response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Minimizing risk of hypomethylating agent failure in patients with higher-risk MDS and practical management recommendations. Santini, V., Prebet, T., Fenaux, P., et al.[2022]

In a study of 149 patients with higher-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML), azacitidine treatment resulted in a median progression-free survival (PFS) of 10.9 months and an overall survival (OS) of 14.1 months, demonstrating its effectiveness in a real-world clinical setting.

The safety profile of azacitidine was consistent with previous clinical trials, and factors such as Eastern Cooperative Oncology Group (ECOG) performance status and red blood cell transfusion prior to treatment were identified as predictive factors for better PFS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of performance status and transfusion dependency on outcome of patients with myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia treated with azacitidine (PIAZA study). Wehmeyer, J., Zaiss, M., Losem, C., et al.[2019]

Azacitidine was approved by the FDA for treating all subtypes of myelodysplastic syndrome (MDS) based on a randomized controlled trial showing a 16% overall response rate, with sustained responses lasting up to 17 months.

The treatment demonstrated a favorable safety profile, with no deaths attributed to azacitidine, although common side effects included gastrointestinal issues and hematologic complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Kaminskas, E., Farrell, AT., Wang, YC., et al.[2013]

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]

References

1. England 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. [2015]

2. New Zealand pubmed.ncbi.nlm.nih.gov

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

3. England pubmed.ncbi.nlm.nih.gov

Azacitidine access program for Belgian patients with myelodysplastic syndromes, acute myeloid leukemia or chronic myelomonocytic leukemia. [2018]

4. France pubmed.ncbi.nlm.nih.gov

Azacitidine. Poor-prognosis myelodysplasia: promising, but more data needed. [2013]

5. England pubmed.ncbi.nlm.nih.gov

Minimizing risk of hypomethylating agent failure in patients with higher-risk MDS and practical management recommendations. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Impact of performance status and transfusion dependency on outcome of patients with myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia treated with azacitidine (PIAZA study). [2019]

7. England pubmed.ncbi.nlm.nih.gov

FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. [2013]

8. New Zealand pubmed.ncbi.nlm.nih.gov

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