IDH Inhibitors + Azacitidine/Venetoclax for Acute Myeloid Leukemia

Overseen By Molly Brandenburg

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Alice Mims

Disqualifiers: Acute promyelocytic leukemia, CNS involvement, uncontrolled infection, 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: 3

Duration: 28-day cycles, ongoing until treatment failure or completion

125 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests different treatment sequences for older patients with acute myeloid leukemia (AML) that has specific genetic changes (IDH1 or IDH2 mutations). Researchers aim to determine whether starting treatment with medications like ivosidenib or enasidenib (both IDH inhibitors) is more effective than starting with others, such as azacitidine and venetoclax. The goal is to identify which combination best slows or stops the cancer. This trial is suitable for those recently diagnosed with AML, who have IDH1 or IDH2 mutations, and are not opting for intensive chemotherapy. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that hydroxyurea can be used to manage white blood cell levels, which suggests some medications might be allowed. It's best to discuss your specific medications with the trial team.

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

A previous study found that the combination of ivosidenib and azacitidine helped patients with a specific type of acute myeloid leukemia (AML) live longer. Patients generally tolerated this combination well, experiencing few serious side effects.

Another study examined enasidenib and azacitidine for patients with a different mutation. This treatment was also well-tolerated and effective, especially for older patients, with many experiencing positive results.

Venetoclax and azacitidine proved effective but had known side effects such as constipation, nausea, and low white blood cell counts. However, most side effects were manageable, allowing doctors to help patients handle them.

Overall, earlier studies have shown these treatments to be safe, but like any treatment, they can have side effects. It's important to discuss with your doctor whether joining a trial is a good choice. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for acute myeloid leukemia (AML), which often involve chemotherapy, the investigational treatments in this trial target specific genetic mutations in the cancer cells. For instance, Ivosidenib and Enasidenib are IDH inhibitors that work by blocking abnormal IDH1 and IDH2 proteins, which are responsible for the growth of cancer cells. Meanwhile, Venetoclax is a BCL-2 inhibitor that promotes the death of cancer cells by disrupting their survival signals. Researchers are excited about these treatments because they offer a more targeted approach, potentially leading to better outcomes and fewer side effects compared to conventional therapies.

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

This trial will compare different treatment combinations for acute myeloid leukemia (AML) with specific genetic mutations. Research has shown that combining ivosidenib and azacitidine can greatly help patients with AML that has an IDH1 mutation. One study found that this combination increased survival rates, with patients living for an average of 29.3 months. In this trial, participants with IDH1 mutations will receive this combination in one of the treatment arms.

For patients with a different mutation, IDH2, combining enasidenib with azacitidine has also been effective, significantly improving response to treatment and duration without complications. Participants with IDH2 mutations will receive this combination in another treatment arm.

Additionally, venetoclax combined with azacitidine is more effective overall than azacitidine alone for treating AML. This combination will be tested in a separate arm of the trial. These treatments target specific proteins or enzymes that help cancer cells grow, offering promising options for managing AML in patients with certain genetic changes. ^{1 2 4 6 7}

Who Is on the Research Team?

Alice Mims

Principal Investigator

Ohio State University Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for older patients with a new diagnosis of acute myeloid leukemia (AML) that has specific genetic changes known as IDH mutations. They should not be candidates for intensive induction therapy, have decent organ function and performance status, and must agree to use contraception if applicable.

Inclusion Criteria

For female patients of childbearing potential, willingness to abstain from heterosexual intercourse or use a protocol-recommended method of contraception from the screening visit throughout the study treatment period and for 30 days following the last dose of either study drug. A serum pregnancy test will be done at screening. A serum or urine pregnancy test will be done on Day 1 of each cycle for women of childbearing potential. If the urine pregnancy test is positive, a serum pregnancy test must be performed per institutional standards.

Creatinine clearance > 40 ml/min

Total bilirubin < 1.5 x upper limit of normal (except for patients with Gilbert's disease)

Exclusion Criteria

I cannot take pills due to severe stomach or bowel problems.

Pregnancy or breast feeding

I do not have an uncontrolled infection with hepatitis C, B, or HIV.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive sequential treatment with either IDH inhibitor plus azacitidine or venetoclax plus azacitidine, depending on randomization

28-day cycles, ongoing until treatment failure or completion

Monthly visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

5 years

Every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Enasidenib
• Ivosidenib
• Venetoclax

Trial Overview The study compares two treatment sequences in AML patients: starting with ivosidenib or enasidenib followed by azacitidine plus venetoclax, versus beginning with azacitidine plus venetoclax then moving to ivosidenib or enasidenib. The goal is to find out which sequence works best.

How Is the Trial Designed?

Group I: Arm B (Ven+aza followed by IDHi+aza) Experimental Treatment 5 Interventions

For both IDH1 and IDH2 mutated AML patient randomized to first-line therapy with Ven+aza, patients will receive venetoclax dosing with the ramp-up and dosing per the FDA-label (based off of concurrent drug interactions). Azacitidine will be given intravenously at 75mg/m2 daily on days 1-7 of each 28-day cycle. Subsequent cycles after CR/CRi/CRh/MLFS achievement may be adjusted in timing and dosing.

Group II: Arm A (IDHi+Aza followed by Ven+aza) Experimental Treatment 5 Interventions

For IDH1 mutated AML patients randomized to first-line therapy with IDHi+aza, patients will receive Ivosidenib 500mg po orally daily on Days 1-28 of each 28 day cycle. For IDH2 mutated AML patients randomized to first-line therapy with IDHi+aza, patients will receive Enasidenib 100mg po orally daily on Days 1-28 of each 28 day cycle. Azacitidine will be given to both groups intravenously or subcutaneously at 75mg/m2 daily on days 1-7 or 1-5/8-9 of each 28 day cycle. Subsequent cycles after CR/CRi/CRh/MLFS achievement may be adjusted in timing and dosing.

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?

Alice Mims

Lead Sponsor

Trials

2

Recruited

150+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a phase 1/2 study involving six Japanese patients aged 60 and older with acute myeloid leukaemia, the combination of venetoclax and azacitidine demonstrated a high response rate, with 83% of patients achieving a response, including three complete remissions.

The treatment was generally well tolerated, with a median overall survival of 15.7 months, although some patients experienced serious adverse events, including grade 3 fungal pneumonia, which required treatment adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. Taniguchi, S., Yamauchi, T., Choi, I., et al.[2021]

In a study of nine AML patients with acquired resistance to venetoclax, the typical BCL2 mutation associated with resistance was not found, suggesting that this mutation is not necessary for developing resistance in AML.

The study identified that existing mutations, particularly the expansion of FLT3-ITD, were primarily responsible for venetoclax resistance, indicating that monitoring these mutations could help in developing strategies to prevent or overcome resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Not BCL2 mutation but dominant mutation conversation contributed to acquired venetoclax resistance in acute myeloid leukemia. Zhang, X., Qian, J., Wang, H., et al.[2022]

In a study of 13 patients with acute leukemia treated with venetoclax and azacitidine, 46% developed COVID-19, highlighting a significant risk associated with this treatment during the pandemic.

The study found that 33% of those who contracted COVID-19 died from the virus, indicating that COVID-19 can lead to severe outcomes in patients receiving AZA-VEN therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SARS-CoV-2 Infection in Patients Treated with Azacitidine and Venetoclax for Acute Leukemia: A Report of a Case Series Treated in a Single Institution. Drozd-Sokołowska, J., Mądry, K., Barankiewicz, J., et al.[2023]

The combination of the IDH1 inhibitor ivosidenib (IVO) with the BCL2 inhibitor venetoclax (VEN), with or without azacitidine (AZA), showed a high safety profile in 31 patients with IDH1-mutated myeloid malignancies, with 91% of adverse events being grade 1 or 2 and no maximum tolerated dose reached.

This combination therapy resulted in high remission rates, with 90% achieving composite complete remission and 63% attaining measurable residual disease (MRD)-negative remissions, suggesting it effectively overcomes resistance mechanisms associated with single-agent IDH inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase Ib/II Study of Ivosidenib with Venetoclax ± Azacitidine in IDH1-Mutated Myeloid Malignancies. Lachowiez, CA., Loghavi, S., Zeng, Z., et al.[2023]

In a network meta-analysis of 345 patients with acute myeloid leukemia (AML) and IDH1/IDH2 mutations, venetoclax plus azacitidine (Ven-Aza) significantly improved overall survival compared to enasidenib plus azacitidine (Ena-Aza) for IDH2 mutation patients, with a hazard ratio of 0.30.

Ven-Aza also showed a favorable trend in survival compared to ivosidenib plus azacitidine (Ivo-Aza) for IDH1 mutation patients, indicating that Ven-Aza could be a strong first-line treatment option for unfit newly diagnosed AML patients with these mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of venetoclax and ivosidenib/enasidenib for unfit newly diagnosed patients with acute myeloid leukemia and IDH1/2 mutation: a network meta-analysis. Wang, L., Song, J., Xiao, X., et al.[2023]

In a study of 44 patients with acute myeloid leukemia (AML) who had previously been treated with FLT3 or IDH1/2 inhibitors, venetoclax-based therapy showed an overall response rate of 56.8%, indicating its potential as an effective salvage treatment.

Patients with IDH1 mutations had a notably higher response rate to venetoclax after prior treatment with ivosidenib, while those with FLT3-ITD mutations had a lower response, suggesting that genetic factors may influence treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax-based salvage therapy in patients with relapsed/refractory acute myeloid leukemia previously treated with FLT3 or IDH1/2 inhibitors. Bewersdorf, JP., Shallis, RM., Derkach, A., et al.[2023]

The combination of venetoclax, azacitidine, and homoharringtonine (VAH) resulted in a high composite complete remission rate of 70.8% in patients with relapsed or refractory acute myeloid leukemia (R/R AML), indicating strong efficacy of this treatment regimen.

Patients treated with VAH had a median overall survival of 22.1 months and a 1-year overall survival rate of 61.5%, suggesting that this regimen not only effectively induces remission but also improves survival outcomes in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax Combined with Azacitidine and Homoharringtonine in Relapsed/Refractory AML: A Multicenter, Phase 2 Trial. Jin, H., Zhang, Y., Yu, S., et al.[2023]

In a study of 60 patients with acute myeloid leukemia (AML), the combination of venetoclax and azacitidine (Ven+AZA) demonstrated a high response rate, with 70.8% of previously untreated patients unfit for standard chemotherapy achieving complete remission (CR) or CR with incomplete hematological recovery (CRi) after one cycle.

Ven+AZA was found to be safe and tolerable, with some patients achieving minimal residual disease (MRD) negativity, particularly in those with favorable genetic mutations like NPM1, IDH1/IDH2, and TP53, indicating its potential effectiveness in specific patient subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Short-term efficacy of venetoclax combined with azacitidine in acute myeloid leukemia: a single-institution experience]. Yu, WJ., Jia, JS., Wang, J., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35078972/

Efficacy and safety of enasidenib and azacitidine ... ENA + AZA was a well-tolerated, and effective therapy for elderly pts with IDH2 mut ND AML as well as pts with R/R AML.

2. nature.com nature.com/articles/s41408-021-00604-2

Efficacy and safety of enasidenib and azacitidine ... ENA + AZA was a well-tolerated, and effective therapy for elderly pts with IDH2 mut ND AML as well as pts with R/R AML.

3. ashpublications.org ashpublications.org/ashclinicalnews/news/5940/Enasidenib-Plus-Azacitidine-Combo-Improved

Enasidenib Plus Azacitidine Combo Improved Response ... Patients with newly diagnosed, IDH2-mutated acute myeloid leukemia (AML) had significantly improved overall response rates (ORRs) with the combination of ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12552362/

Enasidenib as treatment for AML with IDH2 mutation Furthermore, combination of enasidenib with azacitidine as frontline also showed promising results CRR 50%, event-free survival (EFS) 17.2 ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03683433

Study Details | NCT03683433 | Enasidenib and Azacitidine ... This phase II trial studies how well enasidenib and azacitidine work in treating patients with IDH2 gene mutation and acute myeloid leukemia that has come back ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34672961/

a single-arm, phase 1b and randomised, phase 2 trial Combination enasidenib plus azacitidine was well tolerated and significantly improved overall response rates compared with azacitidine monotherapy.

7. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/159/502826/Final-Results-of-the-Phase-Ib-II-Study-Evaluating

Final Results of the Phase Ib/II Study Evaluating Enasidenib in ... Among 23 pts with R/R AML evaluable for response, the ORR was 70% (16/23), including 57% (13/23) CR ( Figure 1). In pts with R172 mut, the ORR ...