Enasidenib + Cobimetinib for Acute Myeloid Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: CYP3A4 inducers/inhibitors, Immunosuppressants

Disqualifiers: Acute promyelocytic leukemia, Active CNS disease, Cardiac morbidities, others

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

Compensation: Varies

Number of Visits: 30

Duration: 12 cycles (28 days each)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two medications, enasidenib (Idhifa) and cobimetinib (Cotellic), to determine their safety and effectiveness in treating acute myeloid leukemia (AML) that is resistant to treatment or has recurred. Enasidenib blocks enzymes necessary for cancer cell growth, while cobimetinib prevents cancer cells from multiplying. This trial may suit individuals with AML unresponsive to other treatments, particularly those with specific gene mutations detectable through testing. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this potentially groundbreaking therapy.

Will I have to stop taking my current medications?

The trial requires that you stop using certain medications before starting, such as other investigational drugs, chemotherapy, and some immunosuppressive medications. You also need to avoid foods and supplements that affect certain enzymes, like grapefruit and St. John's wort, before and during the study.

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

Research has shown that using enasidenib and cobimetinib together might be safe for patients with acute myeloid leukemia (AML) that has returned or does not respond to treatment. This combination blocks substances that help cancer cells grow, aiming to slow or stop their spread.

As this is early research, detailed safety information remains limited. In the trial's early phase, researchers are determining the best dose and checking for side effects. They closely monitor patient reactions to ensure safety.

Both enasidenib and cobimetinib have been used for other conditions, providing some confidence in their safety. However, since this combination is new for AML, participants should be aware of possible side effects and report them to the study team. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for Acute Myeloid Leukemia (AML) typically involve chemotherapy or targeted therapies like FLT3 inhibitors. However, this new combination of enasidenib and cobimetinib is unique because it targets different pathways in leukemia cells. Enasidenib specifically targets mutated IDH2 enzymes, disrupting the cancer cells' metabolism, while cobimetinib inhibits the MEK pathway, which is crucial for cancer cell growth and survival. Researchers are excited about these treatments because they have the potential to work together, attacking the cancer on multiple fronts and potentially improving outcomes for patients with AML.

What evidence suggests that enasidenib and cobimetinib might be effective for acute myeloid leukemia?

Research has shown that enasidenib can help patients with acute myeloid leukemia (AML) when other treatments fail or the cancer returns. One study found that 12 out of 27 patients showed no signs of cancer after taking enasidenib. In lab studies with mice, combining enasidenib with cobimetinib improved blood counts and reduced spleen size, suggesting they might work well together. Cobimetinib blocks signals that help cancer cells grow, potentially preventing the cancer from spreading. This trial will evaluate the combination of enasidenib with cobimetinib, which could be promising for treating AML that has returned or is difficult to treat. ^{2 3 6 7 8}

Who Is on the Research Team?

Brian Ball, MD

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

Adults with relapsed or refractory acute myeloid leukemia (AML) who have specific IDH2 and RAS-pathway mutations can join this trial. They must be able to swallow pills, not be on high-dose steroids or immunosuppressants, and should not have other active cancers or serious heart conditions. Women of childbearing age need a negative pregnancy test and agree to use non-hormonal birth control.

Inclusion Criteria

I have an IDH2 mutation and was treated with enasidenib.

My cancer has specific IDH2 and RAS-pathway mutations.

I agree to use non-hormonal birth control or abstain from sex starting 4 weeks before and until 2 months after my last treatment dose.

Exclusion Criteria

Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

I have severe limitations due to heart problems.

History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive cobimetinib orally once daily on days 1-21 and enasidenib mesylate orally once daily on days 1-28 of each cycle. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.

12 cycles (28 days each)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days and every 3 months for 1 year.

1 year

Follow-up at 30 days, then every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Cobimetinib
• Enasidenib Mesylate

Trial Overview The trial is testing the combination of two drugs: Enasidenib, which blocks enzymes that cancer cells need to grow; and Cobimetinib, a kinase inhibitor that stops mutated proteins from multiplying cancer cells. The goal is to find the safest dose that effectively kills more AML cancer cells.

How Is the Trial Designed?

Group I: Treatment (cobimetinib, enasidenib mesylate) Experimental Treatment 2 Interventions

Patients receive cobimetinib PO QD on days 1-21 and enasidenib mesylate PO QD on days 1-28 of each cycle. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.

Cobimetinib is already approved in European Union, United States, Canada, Switzerland, Japan for the following indications:

Approved in European Union as Cotellic for:

• Melanoma

Approved in United States as Cotellic for:

• Melanoma

Approved in Canada as Cotellic for:

• Melanoma

Approved in Switzerland as Cotellic for:

• Melanoma

Approved in Japan as Cotellic for:

• Melanoma

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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 a targeted therapy approved by the FDA for patients with refractory or relapsed acute myeloid leukemia (AML) who have a specific mutation (IDH2).

The drug has shown the ability to induce remissions in some patients and may decrease the need for blood transfusions, although its approval was based on less supporting evidence than typically required.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enasidenib Approved for AML, but Best Uses Unclear. [2018]

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]

The investigational drug enasidenib, which targets IDH2 mutations, has shown a safety profile and potential to improve survival in patients with relapsed or refractory acute myeloid leukemia.

In a clinical trial, enasidenib induced responses in 40.3% of patients, leading to a median overall survival of 9.3 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Positive First Trial of Enasidenib for AML. [2022]

In a study involving 195 patients treated with enasidenib and 80 patients receiving standard of care (SoC), enasidenib was associated with a significant reduction in mortality risk, showing a hazard ratio of 0.67 after adjusting for covariates, indicating better survival outcomes for patients with relapsed/refractory acute myeloid leukemia (AML) and an IDH2 mutation.

The median overall survival for patients on enasidenib was 9.26 months compared to 4.76 months for those on SoC, highlighting enasidenib's potential as a more effective treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved survival with enasidenib versus standard of care in relapsed/refractory acute myeloid leukemia associated with IDH2 mutations using historical data and propensity score matching analysis. de Botton, S., Brandwein, JM., Wei, AH., et al.[2022]

Enasidenib (ENA) monotherapy showed a significant efficacy in treating newly diagnosed IDH2-mutant acute myeloid leukemia (AML) in patients aged 60 and older, achieving a composite complete response rate of 46% in a study of 60 evaluable patients.

For those who did not achieve complete remission with ENA alone, the addition of azacitidine in a phase 1b cohort resulted in a composite complete response rate of 41%, demonstrating the feasibility of a risk-adapted treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A study to assess the efficacy of enasidenib and risk-adapted addition of azacitidine in newly diagnosed IDH2-mutant AML. Cai, SF., Huang, Y., Lance, JR., et al.[2023]

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]

Citations

1. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124088724

Phase 1b Study of IDH Inhibition with Enasidenib and MEK ... In mice with co-occurring IDH2 and NRAS mutations, combined IDH2 and MEK inhibition led to a greater improvement in blood counts, decreased spleen weight and a ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36108427/

Real-world clinical outcomes with enasidenib in relapsed ... Results from this real-world study confirm the effectiveness of enasidenib among patients with IDH2-mutated RR AML and demonstrate that hospitalizations were ...

3. theoncologynurse.com theoncologynurse.com/issue-archive/2019/february-2019-vol-12-no-1/first-line-enasidenib-achieves-complete-remission-in-older-patients-with-acute-myeloid-leukemia-and-idh2-mutation

First-Line Enasidenib Achieves Complete Remission in ... Overall, 12 of 27 patients attained complete remission, including 2 patients who had incomplete hematologic recovery. No early deaths occurred, and the ...

4. mdpi.com mdpi.com/2072-6694/17/7/1141

Recent Developments in Differentiation Therapy of Acute ... Enasidenib improved the EFS and hematological parameters but failed to improve the OS compared to standard treatment; the OS could be confounded by early ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05441514

Study Details | NCT05441514 | Enasidenib in Combination ... Giving enasidenib and cobimetinib may kill more cancer cells in patients with relapsed or refractory acute myeloid leukemia. Detailed Description. PRIMARY ...

6. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/6043/527314/Phase-1b-Study-of-IDH-Inhibition-with-Enasidenib

Phase 1b Study of IDH Inhibition with Enasidenib and MEK ... We thus hypothesize that combined MEK inhibition with cobimetinib and IDH2 inhibition with enasidenib will be safe and overcome these mechanisms ...

7. ashpublications.org ashpublications.org/blood/article/140/Supplement%201/11761/488230/A-Phase-1b-Study-of-IDH-Inhibition-with-Enasidenib

A Phase 1b Study of IDH Inhibition with Enasidenib and MEK ... We designed a phase 1 study to evaluate combined targeting of IDH2 and MEK in patients with R/R AML.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12109363/

Advances in the Treatment of Acute Myeloid Leukemia These agents demonstrated improved OS compared to supportive care or low dose cytarabine (LDAC), and offered survival outcomes comparable to IC ...