Enasidenib for Chronic Myelomonocytic Leukemia

Overseen By Veronica de Santiago

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Stanford University

Must not be taking: Erythropoietic agents

Disqualifiers: Cardiac disease, IDH2 mutations, infections, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether the drug enasidenib (also known as Idhifa) can safely and effectively aid individuals with certain blood conditions, specifically lower-risk myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML). The researchers aim to determine if enasidenib can improve anemia (a condition characterized by insufficient healthy red blood cells) and reduce the need for blood transfusions. Individuals diagnosed with these conditions who experience symptoms like fatigue or shortness of breath might be suitable candidates. Participants will take the medication orally each day to monitor improvements in their condition. As a Phase 1 trial, the research focuses on understanding how the treatment works in people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you cannot use certain erythropoietic agents (medications that help produce red blood cells) or G-CSF within 30 days of joining the study. It's best to discuss your specific medications with the study team.

Is there any evidence suggesting that enasidenib is likely to be safe for humans?

Research has shown that enasidenib is generally well-tolerated, with most participants in earlier studies not experiencing severe issues. It has a safety profile manageable for patients with certain blood disorders. Specifically, studies involving patients with high-risk myelodysplastic syndromes (MDS) and a specific IDH2 mutation found enasidenib to be acceptably safe.

However, enasidenib can cause side effects, including differentiation syndrome, which may lead to symptoms like fever, shortness of breath, and swelling. Prospective trial participants should discuss this with their doctor.

This trial tests enasidenib on patients without the IDH2 mutation, so safety may differ. Although enasidenib is approved for certain conditions, this trial explores its use in new patient groups. The results will clarify its safety for these patients. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for Chronic Myelomonocytic Leukemia, which typically include chemotherapy and hypomethylating agents, enasidenib offers a novel approach. Enasidenib works by specifically targeting and inhibiting the mutant IDH2 enzyme, which is often involved in the abnormal growth of leukemia cells. This targeted mechanism can potentially reduce the side effects associated with broader-acting treatments and offer a more personalized therapy option. Researchers are excited because this precision in targeting could lead to more effective management of the disease with potentially fewer adverse effects.

What evidence suggests that enasidenib might be an effective treatment for chronic myelomonocytic leukemia?

Research has shown that enasidenib can be effective for certain blood cancers, particularly in patients with IDH2 mutations. One study found that 53% of high-risk patients responded to enasidenib, with more than half showing improvement. These patients had an average survival time of 16.9 months. In this trial, participants will receive enasidenib to explore its potential benefits for conditions like chronic myelomonocytic leukemia (CMML) and myelodysplastic syndrome (MDS), even in patients without IDH2 mutations. Enasidenib alters how cells use energy, which might help improve anemia and reduce the need for blood transfusions. Although data for patients without IDH2 mutations is limited, early signs are encouraging. ^{2 6 7 8 9}

Who Is on the Research Team?

Tian Yi Zhang, MD

Principal Investigator

Stanford University

Are You a Good Fit for This Trial?

This trial is for adults with lower risk myelodysplastic syndrome (MDS) or nonproliferative chronic myelomonocytic leukemia (CMML), without IDH2 mutation, who have anemia symptoms like fatigue and shortness of breath. Participants must not have had certain therapies recently, be able to take oral meds, and use effective contraception if applicable. They can't join if they have other causes of anemia, significant heart disease, less than 3 months life expectancy, active infections including HIV or hepatitis B/C.

Inclusion Criteria

No disease-modifying therapy (HMA, hydrea) within 2 months of starting study

ECOG ≤ 3

Stated willingness to comply with all study procedures and availability for the duration of the study

Exclusion Criteria

You have anemia caused by factors like low levels of iron, vitamin B12, or folate, or nutritional issues related to certain surgeries, eating disorders, or excessive zinc intake. If these nutritional deficiencies can be fixed, you can be re-evaluated and potentially enrolled in the study if you are no longer deficient and still meet the other requirements.

You have used other medications that help produce red blood cells or boost the immune system within the past month.

Harbor IDH2 somatic mutations by NGS or PCR

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants self-administer enasidenib orally every day to assess safety and efficacy in improving anemia and decreasing transfusion needs

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

16 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Enasidenib

Trial Overview The study tests whether enasidenib mesylate can safely improve anemia and reduce the need for blood transfusions in MDS/CMML patients without the IDH2 mutation. It's a phase 1b/2 trial where everyone gets increasing doses of enasidenib to see how well it works and what effects it has on their body.

How Is the Trial Designed?

Group I: Enasidenib mesylat Experimental Treatment 1 Intervention

Participants will self administer the enasidenib orally everyday.

Enasidenib is already approved in United States, European Union for the following indications:

Approved in United States as Idhifa for:

• Relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation

Approved in European Union as Idhifa for:

• Acute myeloid leukaemia (AML) with an isocitrate dehydrogenase 2 (IDH2) mutation

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Tian Yi Zhang

Lead Sponsor

Trials

1

Recruited

20+

Celgene Corporation

Industry Sponsor

Trials

446

Recruited

58,500+

Mark Alles

Celgene Corporation

Chief Executive Officer since 2016

Bachelor's degree from Lock Haven University of Pennsylvania

Sol J. Barer

Celgene Corporation

Chief Medical Officer since 2006

PhD in Organic and Physical Chemistry from Rutgers University

Published Research Related to This Trial

Enasidenib is an effective oral treatment for acute myeloid leukemia (AML) that specifically targets IDH2 mutations, showing clinical improvement in 19.6% of patients and laboratory improvement in 38.8% of cases based on clinical trials.

While enasidenib is generally well-tolerated, it can cause differentiation syndrome, a serious side effect that requires careful monitoring by healthcare providers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An evaluation of enasidenib for the treatment of acute myeloid leukemia. Del Principe, MI., Paterno, G., Palmieri, R., et al.[2019]

Enasidenib is a targeted treatment for relapsed or refractory acute myeloid leukemia that effectively inhibits mutant IDH2 proteins, as shown in a Phase I/II study assessing its safety and efficacy in patients with IDH2 mutations.

The study revealed that enasidenib significantly induces CYP3A enzyme activity, which is important to consider when prescribing other medications that are metabolized by this pathway, due to the potential for drug interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modeling and simulation of the endogenous CYP3A induction marker 4β-hydroxycholesterol during enasidenib treatment. Li, Y., Connarn, JN., Chen, J., et al.[2022]

Enasidenib is an effective oral treatment for relapsed/refractory acute myeloid leukemia (AML) with IDH2 mutations, showing durable complete remissions in about 20% of patients and leading to improved survival in preclinical models.

The drug works by normalizing levels of the oncometabolite (R)-2-hydroxyglutarate, promoting differentiation of leukemic cells, and is generally well tolerated, although it can cause differentiation syndrome as a notable side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enasidenib. Krämer, A., Bochtler, T.[2019]

In a clinical trial involving 107 patients with newly diagnosed mutant-IDH2 acute myeloid leukaemia, the combination of enasidenib and azacitidine significantly improved overall response rates, with 74% of patients responding compared to 36% in the azacitidine-only group.

The combination treatment was well tolerated, with no treatment-related deaths reported, although some patients experienced common grade 3 or 4 adverse events like thrombocytopenia and neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial. DiNardo, CD., Schuh, AC., Stein, EM., et al.[2022]

Enasidenib (Idhifa®) is an oral medication that specifically inhibits the IDH2 enzyme and has been approved in the USA for treating adults with relapsed or refractory acute myeloid leukaemia (AML) with an IDH2 mutation.

The approval of enasidenib marks a significant milestone as it is the first global treatment option specifically targeting IDH2 mutations in AML, highlighting its potential efficacy in this specific patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enasidenib: First Global Approval. Kim, ES.[2022]

Citations

1. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2152265025017215

AML-751: Clinical Efficacy and Safety of Enasidenib in ... Enasidenib and enasidenib-based combination therapies demonstrated notable response rates in adult patients with ND IDH2-mutated AML. While promising, the ...

2. onclive.com onclive.com/view/enasidenib-elicits-clinical-efficacy-in-high-risk-idh2-mutated-mds

Enasidenib Elicits Clinical Efficacy in High-Risk, IDH2 ... Findings from the phase 1 AG221-C-001 study (NCT01915498) demonstrated a 53% response rate and a median overall survival (OS) of 16.9 months ...

3. stanfordhealthcare.org stanfordhealthcare.org/trials/e/NCT05282459.html

Enasidenib in MDS &Non-proliferative Chronic ... This is a phase 1b/2, open-label, single arm study to evaluate if enasidenib is safe and effective in improving anemia and decreasing transfusion needs in ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05282459

Study Details | NCT05282459 | Enasidenib in MDS &Non ... This is a phase 1b/2, open-label, single arm study to evaluate if enasidenib is safe and effective in improving anemia and decreasing transfusion needs in ...

5. link.springer.com link.springer.com/article/10.1007/s00277-025-06464-1

Enasidenib as treatment for AML with IDH2 mutation The median number of cycles administered was four, with an overall response rate (ORR) of 39.1% and a morphological complete remission (CR) rate ...

6. idhifapro.com idhifapro.com/safety

IDHIFA® (enasidenib) Safety Profile | For HCPs Learn about IDHIFA® (enasidenib) safety and side effects from the clinical trial. See Safety Information and Boxed WARNING on differentiation syndrome.

7. ashpublications.org ashpublications.org/ashclinicalnews/news/5689/Evaluating-Enasidenib-With-or-Without-Azacitidine

Evaluating Enasidenib, With or Without Azacitidine, in Patients with ... Enasidenib was had a tolerable safety profile and showed promising clinical activity in patients with IDH2-mutated, high-risk myelodysplastic syndromes ...

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

Enasidenib as treatment for AML with IDH2 mutation Despite the modest sample size, the observed safety profile, CR rates, and OS were consistent with the prior larger phase 2 study [16] and the ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10220255/

Targeted therapy with the mutant IDH2 inhibitor enasidenib ... Enasidenib, a selective inhibitor of mutant IDH2 enzyme, is an effective treatment option in patients with IDH2 mut MDS.