Decitabine + FLAG-Ida for Myeloid Malignancies

Overseen By Naveed Ali, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Fred Hutchinson Cancer Center

Must not be taking: Anti-leukemia agents

Disqualifiers: Active CNS disease, Infections, Pregnancy, others

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

Compensation: Varies

Number of Visits: 8

36 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This phase I/II trial studies the safety, side effects, and best dose of decitabine in combination with fludarabine, cytarabine, filgrastim, and idarubicin (FLAG-Ida) and total body irradiation (TBI) followed by a donor stem cell transplant in treating adult patients with cancers of blood-forming cells of the bone marrow (myeloid malignancies) that are at high risk of coming back after treatment (relapse). Cancers eligible for this trial are acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic myelomonocytic leukemia (CMML). Decitabine is in a class of medications called hypomethylation agents. It works by helping the bone marrow produce normal blood cells and by killing abnormal cells in the bone marrow. The FLAG-Ida regimen consists of the following drugs: fludarabine, cytarabine, filgrastim, and idarubicin. These are chemotherapy drugs that 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. Filgrastim is in a class of medications called colony-stimulating factors. It works by helping the body make more neutrophils, a type of white blood cell. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. TBI is radiation therapy to the entire body. Giving chemotherapy and TBI before a donor peripheral blood stem cell (PBSC) transplant helps kill cancer cells in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. When the healthy stem cells from a donor are infused into a patient, they may help the patient's bone marrow make more healthy cells and platelets. Giving decitabine in combination with FLAG-Ida and TBI before donor PBSC transplant may work better than FLAG-Ida and TBI alone in treating adult patients with myeloid malignancies at high risk of relapse.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot be on any other approved or investigational anti-leukemia treatments while participating in this trial.

Is the Decitabine + FLAG-Ida treatment generally safe for humans?

The Decitabine + FLAG-Ida treatment, which includes drugs like cytarabine, idarubicin, and filgrastim, has been studied for safety in people with myeloid malignancies. Common side effects include infections, especially in the lungs, and conditions like mucositis (painful inflammation and ulceration of the mucous membranes) and pulmonary toxicity (lung damage). While some patients experienced severe side effects, the overall safety profile is considered acceptable for high-risk patients. ^{1 2 3 4 5}

How is the drug Decitabine + FLAG-Ida unique for treating myeloid malignancies?

The combination of Decitabine with FLAG-Ida is unique because it uses Decitabine as an 'epigenetic priming' agent, which means it helps make cancer cells more sensitive to chemotherapy by altering gene expression. This approach is particularly useful for patients with acute myeloid leukemia (AML) who have not responded to other treatments, offering a new option for those with difficult-to-treat cases. ^{6 7 8 9 10}

What data supports the effectiveness of the Decitabine + FLAG-Ida treatment for myeloid malignancies?

Research shows that the combination of Decitabine with FLAG-Ida has been effective in treating acute myeloid leukemia (AML), with studies reporting complete remission rates of over 50% in patients with relapsed or refractory AML. This suggests that the treatment can be effective in managing difficult cases of AML. ^{2 4 6 10 11}

Who Is on the Research Team?

Naveed Ali, MD

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Are You a Good Fit for This Trial?

Adults with high-risk myeloid malignancies, such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic myelomonocytic leukemia (CMML) who are candidates for a stem cell transplant. Participants should not have other health conditions that could interfere with the trial.

Inclusion Criteria

My heart, liver, lungs, and kidneys are functioning well.

I had a stem cell transplant and my condition worsened more than 6 months after.

I am mostly independent and active.

Exclusion Criteria

I do not have any uncontrolled infections.

HAPLOIDENTICAL DONOR: Patients with anti-donor-specific antibodies (anti-DSA) MFI < 5000 after desensitization treatment

Pregnancy or lactation

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Chemotherapy and Radiation

Participants receive decitabine, FLAG-Ida regimen, and total body irradiation before donor stem cell transplantation

3 weeks

Daily visits for treatment administration

Transplantation

Participants undergo hematopoietic cell transplantation (HCT) with donor peripheral blood stem cells

1 day

1 visit (in-patient)

Follow-up

Participants are monitored for safety, effectiveness, and disease response after treatment

Up to 2 years

Regular follow-up visits at 6 months, 1 year, and 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Cytarabine
• Decitabine
• Filgrastim
• Idarubicin

Trial Overview The trial is testing the effectiveness of decitabine combined with FLAG-Ida chemotherapy and total-body irradiation before a donor stem cell transplant. The goal is to see if this combination works better than standard treatments in preventing cancer relapse.

How Is the Trial Designed?

Group I: Treatment (decitabine, FLAG-Ida, HCT) Experimental Treatment 14 Interventions

DONORS: Participants undergo apheresis for collection of PBSCs on study. PATIENTS: Patients receive decitabine IV daily over 1 hour on days -12 to -10, -14 to -10, -16 to -10, or -19 to -10, filgrastim SC daily on days -9 to -4, idarubicin IV over 60 minutes daily on days -8 to -6, fludarabine IV over 30 minutes daily on days -8 to -4, cytarabine IV over 2 hours daily on days -8 to -4, and undergo TBI BID on day -1 or 0 OR daily on days -1 and 0 in the absence of disease progression or unacceptable toxicity. Patients then undergo HCT (receive donor PBSCs via infusion) on day 0. Patients also undergo MUGA scan or ECHO during screening, chest X-rays and bone marrow aspiration and/or biopsy during screening and as clinically indicated, and collection of blood samples throughout the study.

Who Is Running the Clinical Trial?

Fred Hutchinson Cancer Center

Lead Sponsor

Trials

583

Recruited

1,341,000+

Published Research Related to This Trial

In a phase I trial involving 37 pediatric patients with relapsed/refractory acute myeloid leukemia (R/R AML), the combination of decitabine, vorinostat, and FLAG chemotherapy showed a promising overall response rate of 54%, with 16 patients achieving complete response (CR).

The treatment was well-tolerated with no dose-limiting toxicities, and among those who responded, 90% achieved minimal residual disease (MRD) negativity, leading to a significantly higher two-year overall survival rate of 75.6% for MRD-negative patients compared to 17.9% for those with residual disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine and vorinostat with FLAG chemotherapy in pediatric relapsed/refractory AML: Report from the therapeutic advances in childhood leukemia and lymphoma (TACL) consortium. Pommert, L., Schafer, ES., Malvar, J., et al.[2023]

In a study of 21 patients with refractory or recurrent acute myeloid leukemia (R/R AML), the triple therapy of decitabine, idarubicin, and cytarabine (D-IA) resulted in a 47.6% complete remission rate after one treatment cycle, indicating significant efficacy.

The treatment was generally well tolerated, with no treatment-related mortalities reported, although common side effects included hematological toxicity and infections, suggesting a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Management of Decitabine prior to Full-Dose Idarubicin and Cytarabine in the Treatment of Refractory/Recurrent Acute Myeloid Leukemia. Zhao, H., Xu, L., Yang, Y., et al.[2018]

In a study of 42 adult patients with relapsed or refractory acute myeloid leukemia (AML) treated with the FLAG ± Ida chemotherapy regimen, the complete remission (CR) rate was 47.6%, which aligns with historical rates of 52% to 63%.

The median overall survival (OS) for patients achieving CR was not reached, with an estimated 48-month survival rate of 56%, indicating that FLAG ± Ida remains an effective salvage treatment for R/R AML, despite common adverse effects like pancytopenia and infection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Analysis of Adult Patients With Relapsed/Refractory Acute Myeloid Leukemia Treated with FLAG at a Comprehensive Cancer Center. Tenold, ME., Moskoff, BN., Krishnan, R., et al.[2022]

In a study of 45 patients with high-risk myeloid malignancies, the FLAG-IDA treatment regimen resulted in a 53% complete remission rate, demonstrating its effectiveness against these aggressive cancers.

Despite some serious side effects, including pulmonary toxicity and mucositis, the FLAG-IDA regimen showed an overall survival rate of 40% at 12 months, indicating it has an acceptable safety profile for high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FLAG-IDA regimen (fludarabine, cytarabine, idarubicin and G-CSF) in the treatment of patients with high-risk myeloid malignancies. de la Rubia, J., Regadera, A., Martín, G., et al.[2019]

The FLAG-IDA chemotherapy regimen was administered to seven children with refractory acute myeloid leukemia (AML), and while it was tolerable with no early deaths, the efficacy remains uncertain due to high relapse rates and limited patient numbers.

Hematological toxicity was common among patients, with one case of severe non-hematological toxicity (bacterial meningitis), highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin for relapsed childhood acute myeloid leukemia. Nakayama, H., Tomizawa, D., Tanaka, S., et al.[2018]

In a study of 44 patients with relapsed/refractory acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), the combination of decitabine with the EIAG regimen resulted in a higher modified composite complete response (mCRc) rate of 72.7% compared to 40.9% in the CAG regimen group, indicating improved efficacy.

Both treatment regimens led to significant myelosuppression as a common adverse effect, but there was no increase in non-hematological toxicities, suggesting that decitabine combined with EIAG is a safe option that enhances remission rates without adding extra risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[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]. Mao, JP., Xue, LG., Zhu, YX., et al.[2023]

Decitabine is an effective hypomethylating agent for treating acute myeloid leukemia (AML), significantly improving overall survival and response rates compared to standard care, based on results from the phase 3 DACO-016 trial with adult patients who are not eligible for standard chemotherapy.

The treatment is generally well tolerated and remains effective even in patients with adverse-risk karyotypes or TP53 mutations, making it a valuable option for those unfit for more intensive therapies, with potential for future combination treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Clinical Value of Decitabine Monotherapy in Patients with Acute Myeloid Leukemia. Santini, V., Lübbert, M., Wierzbowska, A., et al.[2022]

Citations

1. United States pubmed.ncbi.nlm.nih.gov

FLAG salvage therapy combined with idarubicin in relapsed/refractory acute myeloid leukemia. [2020]

2. England pubmed.ncbi.nlm.nih.gov

IDA-FLAG (idarubicin, fludarabine, cytarabine, G-CSF), an effective remission-induction therapy for poor-prognosis AML of childhood prior to allogeneic or autologous bone marrow transplantation: experiences of a phase II trial. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Decitabine and vorinostat with FLAG chemotherapy in pediatric relapsed/refractory AML: Report from the therapeutic advances in childhood leukemia and lymphoma (TACL) consortium. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Successful Management of Decitabine prior to Full-Dose Idarubicin and Cytarabine in the Treatment of Refractory/Recurrent Acute Myeloid Leukemia. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

Retrospective Analysis of Adult Patients With Relapsed/Refractory Acute Myeloid Leukemia Treated with FLAG at a Comprehensive Cancer Center. [2022]

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

FLAG-IDA regimen (fludarabine, cytarabine, idarubicin and G-CSF) in the treatment of patients with high-risk myeloid malignancies. [2019]

7. Australia pubmed.ncbi.nlm.nih.gov

Fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin for relapsed childhood acute myeloid leukemia. [2018]

8. Germany pubmed.ncbi.nlm.nih.gov

Phase-II trial of idarubicin, fludarabine, cytosine arabinoside, and filgrastim (Ida-FLAG) for treatment of refractory, relapsed, and secondary AML. [2019]

9. Germany pubmed.ncbi.nlm.nih.gov

A multicenter, randomized study of decitabine as epigenetic priming with induction chemotherapy in children with AML. [2018]

10. China pubmed.ncbi.nlm.nih.gov

[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]

11. United States pubmed.ncbi.nlm.nih.gov

The Clinical Value of Decitabine Monotherapy in Patients with Acute Myeloid Leukemia. [2022]