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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how two drugs, azacitidine and quizartinib, work together to treat myelodysplastic syndrome (MDS) or a related condition with certain genetic mutations. Azacitidine, a type of chemotherapy, can stop cancer cells from growing, while quizartinib may block enzymes that cancer cells need to grow. The trial aims to determine the best dose and assess the effectiveness of this combination. Individuals with MDS or a related disorder with specific mutations in their blood cells might be suitable candidates for this trial. As a Phase 1/Phase 2 trial, the research focuses on understanding the treatment's effects in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to early-stage treatment development.

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.

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

Research has shown that using azacitidine and quizartinib together is generally safe for individuals with certain genetic changes in blood disorders like myelodysplastic syndrome. Studies have found that patients with FLT3 or CBL mutations tolerate this treatment well.

Some patients experienced side effects, but these were manageable. This indicates that while the treatment might cause some discomfort, it is unlikely to cause serious harm. Ensuring safety remains a major focus of these studies, and determining the right dose is crucial for maximizing safety.

In summary, earlier studies suggest that the combination of azacitidine and quizartinib is a potentially safe option for those considering joining the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Azacitidine combined with quizartinib is unique because it offers a dual approach to treating myelodysplastic syndrome (MDS). While azacitidine is already used to help control abnormal blood cell production, quizartinib adds a novel twist by specifically targeting and inhibiting FLT3, a protein that can contribute to the growth of malignant cells. This combination could potentially enhance treatment efficacy compared to standard therapies like azacitidine alone. Researchers are excited about this treatment because it may improve patient outcomes by effectively slowing disease progression with a comprehensive strategy.

What evidence suggests that azacitidine and quizartinib might be an effective treatment for myelodysplastic syndrome?

This trial will evaluate the combination of azacitidine and quizartinib for treating myelodysplastic syndrome. Research has shown that this combination may be effective. One study reported that 83% of patients responded well, achieving an average survival time of 17.5 months. These drugs work together to kill cancer cells and prevent their growth. Overall, early results are promising, suggesting this treatment combination could be effective. ^{1 2 3 5 6}

Who Is on the Research Team?

Guillermo M. Bravo

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 (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]

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 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]

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]

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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04493138

Study Details | NCT04493138 | Azacitidine and Quizartinib ... Giving azacitidine and quizartinib may help to control myelodysplastic syndrome or myelodysplastic/myeloproliferative neoplasm. Detailed Description. PRIMARY ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12411709/

Novel small-molecule therapies for myelodysplastic ... The trial reported an ORR of 26% and stable disease in 52%, with a mDoR of 6.3 months. In the full cohort, the mOS was 8.5 months, with a 1-year ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0145212624000845

Phase 1 study of azacitidine in combination with quizartinib ... The overall response rate was 83 % with median relapse-free and overall survivals of 15.1 months (95 % CI 0.0–38.4 months) and 17.5 months (95 % CI NC-NC), ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33853292/

A phase I/II study of the combination of quizartinib ... - PubMed Seventy-three patients were treated (34 frontline, 39 first-salvage). Among previously untreated patients, composite response (CRc) was achieved ...

5. onclive.com onclive.com/view/azacitidine-quizartinib-combo-showcases-early-activity-in-mds-mds-mpn-with-flt3-or-cbl-mutations

Azacitidine/Quizartinib Combo Showcases Early Activity in ... Additional data showed that the combination resulted in a median OS of 17.35 months (95% CI, 6.8-28.3). Platelet recovery to more than 50 x 10 9 ...

6. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/3238/503750/Results-of-Phase-I-II-Study-of-Azacitidine-in

Results of Phase I/II Study of Azacitidine in Combination with ... The primary endpoint was to evaluate safety, tolerability and maximum tolerated dose of quizartinib. Responses were evaluated following 2006 ...