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)

15 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase Ib trial tests the safety, side effects, and best dose of a enasidenib in combination with cobimetinib in treating patients with acute myeloid leukemia that has come back (relapsed) or does not respond to treatment (refractory). Enasidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Cobimetinib is used in patients whose cancer has a mutated (changed) form of a gene called BRAF. It is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells. Giving enasidenib and cobimetinib may kill more cancer cells in patients with relapsed or refractory acute myeloid leukemia.

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.

What data supports the effectiveness of the drug Enasidenib for treating acute myeloid leukemia?

Enasidenib has shown promising results in treating acute myeloid leukemia with IDH2 mutations, with studies indicating it can improve survival and induce remissions in some patients. In a study, enasidenib alone achieved a complete response rate of 46% in newly diagnosed patients, demonstrating its potential effectiveness. ^{1 2 3 4 5}

Is the combination of Enasidenib and Cobimetinib safe for humans?

Enasidenib has been studied and approved for use in patients with certain types of acute myeloid leukemia, and it has been found to be generally safe, although it may have some side effects. However, there is no specific safety data available for the combination of Enasidenib and Cobimetinib. ^{1 3 4 6 7}

What makes the drug combination of Enasidenib and Cobimetinib unique for treating acute myeloid leukemia?

The combination of Enasidenib and Cobimetinib is unique because Enasidenib specifically targets and inhibits mutant IDH2 proteins, which are involved in the development of acute myeloid leukemia, while Cobimetinib is a MEK inhibitor that may enhance the effectiveness of Enasidenib. This combination aims to improve treatment outcomes by addressing different pathways involved in the disease. ^{1 3 5 6 7}

Research Team

Brian Ball, MD

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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 (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]

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]

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]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Modeling and simulation of the endogenous CYP3A induction marker 4β-hydroxycholesterol during enasidenib treatment. [2022]

2. United States 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. [2022]

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

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

4. United States 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. [2023]

5. England pubmed.ncbi.nlm.nih.gov

An evaluation of enasidenib for the treatment of acute myeloid leukemia. [2019]

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

Positive First Trial of Enasidenib for AML. [2022]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Enasidenib: First Global Approval. [2022]