What is the mechanism of action of this treatment?

The most common treatments for Acute Myeloid Leukemia (AML) often involve hypomethylating agents such as guadecitabine, azacitidine, and decitabine. These drugs inhibit DNA methyltransferases, leading to the hypomethylation of DNA and reactivation of tumor suppressor genes. This process can induce cell differentiation and apoptosis in leukemic cells. This mechanism is particularly important for AML patients as it targets the genetic and epigenetic abnormalities driving the disease, providing an effective treatment option, especially for those who may not tolerate traditional chemotherapy.

What side effects are associated with this type of intervention?

Common treatments for Acute Myeloid Leukemia (AML) include hypomethylating agents (HMAs) such as azacitidine and decitabine, IDH inhibitors like ivosidenib, and low-dose cytarabine (LDAC). Known side effects of HMAs include grade ≥3 adverse events such as febrile neutropenia, thrombocytopenia, pneumonia, and anemia. IDH inhibitors can cause QT interval prolongation, IDH differentiation syndrome, anemia, thrombocytopenia, and leukocytosis. LDAC is associated with mild toxicities, including cardiac issues, nausea/vomiting, and diarrhea, with a notable induction death rate. These treatments generally require careful monitoring and supportive care to manage side effects.

What prior FDA approvals exist?

The FDA has approved several hypomethylating agents for the treatment of Acute Myeloid Leukemia (AML), which function similarly to guadecitabine by inhibiting enzymes necessary for cancer cell growth. Notable approvals include azacitidine and decitabine, both of which have shown efficacy in extending survival and achieving hematologic responses in AML patients. Additionally, combinations of these HMAs with other agents like venetoclax and ivosidenib have been explored to enhance treatment outcomes. These drugs are particularly relevant for patients who are not candidates for intensive chemotherapy.

What other types of research exist?

Promising novel alternatives to Guadecitabine for AML patients include: 1) HMA plus venetoclax, which has shown improved outcomes compared to HMA monotherapy. 2) HMA plus ivosidenib, particularly for patients with IDH1 mutations. 3) Azacitidine plus gilteritinib, especially for patients with FLT3 mutations. These combinations have demonstrated efficacy in clinical trials and represent advanced treatment options for AML.

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DNA Methyltransferase Inhibitor

Guadecitabine + Donor Lymphocytes for Leukemia Relapse After Transplant

Phase 2

Waitlist Available

Led By Betul Oran, MD

Research Sponsored by M.D. Anderson Cancer Center

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Be able to start the drug therapy between 42 to 100 days following allogeneic SCT; No more than 1 prior allogeneic SCT; Post-transplant bone marrow consistent with complete remission with no evidence of minimal residual disease by flow-cytometry or cytogenetics or molecular testing; Adequate engraftment within 14 days prior to starting study drug: absolute neutrophil count (ANC) >= 1.0 x 10^9/L without daily use of myeloid growth factor; and, platelet >= 50 x 10^9/L without platelet transfusion within 1 week; Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2; Serum creatinine =< 1.5 mg/dL or creatinine clearance greater or equal than 40 cc/min as defined by the Cockcroft-Gault equation; Serum bilirubin =< 1.5 x upper limit of normal (ULN); Aspartate transaminase (AST) or alanine transaminase (ALT) =< 2.5 x ULN; Alkaline phosphatase =< 2.5 x upper limit (UL); No active bleeding; No uncontrolled graft versus host disease (GVHD); No clinical evidence of life-threatening infection; Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent; Human immunodeficiency virus (HIV) negative and hepatitis B surface antigen (HBs-Ag) negative; Negative serum or urine pregnancy test for women with reproductive potential; the only subjects who will be exempt from this criterion are postmenopausal women (defined as women who have been amenorrheic for > 12 months) or subjects who have been surgically sterilized or otherwise proven sterile

Diagnosis of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) according to WHO classification that underwent first allogeneic hematopoietic cell transplant (HSCT) with either peripheral blood or bone marrow as the source of the hematopoietic stem cells

Timeline

Screening 3 weeks

Treatment Varies

Follow Up at 1 year

Awards & highlights

No Placebo-Only Group

Summary

This trial studies how well guadecitabine works in patients with AML or MDS who relapsed after a stem cell transplant. Guadecitabine is a new type of treatment similar to other drugs that have been effective in treating these conditions. The treatment involves injections of guadecitabine and possibly additional help from donor cells. The drug aims to stop cancer growth and prevent harmful immune reactions, while the donor cells help the immune system fight cancer.

Who is the study for?

This trial is for patients with acute myeloid leukemia or myelodysplastic syndrome that's come back after a stem cell transplant. Participants must have a good match with their donor, be in specific stages of disease recovery or relapse, and have stable organ function without severe infections or active graft versus host disease. They can't join if they've had certain heart issues recently, uncontrolled infections, multiple transplants, or are HIV positive.

What is being tested?

The study tests guadecitabine's effectiveness in treating cancer recurrence post-transplant. It examines whether the drug can prevent growth of cancer cells and enhance the immune response against them when followed by an infusion of donor white blood cells (donor lymphocyte infusion).

What are the potential side effects?

Potential side effects may include reactions at the injection site, changes in blood counts leading to increased infection risk or bleeding tendencies, liver enzyme alterations suggesting liver stress, and possible worsening of graft versus host disease.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I have AML or MDS and had my first stem cell transplant using cells from blood or bone marrow.

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My donor and I have a maximum of one mismatch in our HLA markers.

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My cancer has returned or is still present after a stem cell transplant, even though it looks like I'm in remission.

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I am in complete remission from AML or MDS after a stem cell transplant, with no signs of the disease.

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I have MDS with changes in my bone marrow or AML with a bone marrow blast count of 5% or more.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ at 1 year

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~at 1 year

This trial's timeline: 3 weeks for screening, Varies for treatment, and at 1 year for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Relapse free survival (RFS) (Cohort 3)

Secondary study objectives

Disease-free survival time (DFS)

Incidence of hematologic and non-hematologic toxicity

Overall survival (OS)

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

1Treatment groups

Experimental Treatment

Group I: Treatment (guadecitabine, DLI)Experimental Treatment3 Interventions

Patients receive guadecitabine SC QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive DLI IV over 10-30 minutes on day 6 of cycles 2, 4, and 6 in the absence of disease progression or unacceptable toxicity.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Donor Lymphocytes

2008

Completed Phase 2

~70

Guadecitabine

2014

Completed Phase 3

~730

0 / 6Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Acute Myeloid Leukemia (AML) often involve hypomethylating agents such as guadecitabine, azacitidine, and decitabine. These drugs inhibit DNA methyltransferases, leading to the hypomethylation of DNA and reactivation of tumor suppressor genes. This process can induce cell differentiation and apoptosis in leukemic cells. This mechanism is particularly important for AML patients as it targets the genetic and epigenetic abnormalities driving the disease, providing an effective treatment option, especially for those who may not tolerate traditional chemotherapy.

Progress in the problem of relapsed or refractory acute myeloid leukemia.Molecular targeting in acute myeloid leukemia.Targeting phosphatidylinositol 3-kinase signaling in acute myelogenous leukemia.