LY3214996 for Acute Myeloid Leukemia

Overseen By Rahul Vedula, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Dana-Farber Cancer Institute

Must be taking: Antifungal agents

Must not be taking: Tyrosine kinase inhibitors

Disqualifiers: Chemotherapy, Major surgery, CNS leukemia, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 21 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new oral medication, LY3214996 (Temuterkib), to determine its effectiveness in treating acute myeloid leukemia (AML) that has returned or resisted standard treatments. It examines two groups: one taking the medication without antifungal drugs and another with antifungal drugs that might interact with the treatment. Individuals diagnosed with AML that hasn't improved with previous treatments and who can swallow pills might be suitable for this trial. As a Phase 1 trial, the research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop all current medications, but it does mention that you cannot take certain antifungal medications if they are moderate or strong CYP3A4 inhibitors, unless specified in the trial arm. Additionally, you should not have had chemotherapy, investigational therapy, immunotherapy, or radiotherapy within 2 weeks before starting the trial.

Is there any evidence suggesting that LY3214996 is likely to be safe for humans?

Research shows that LY3214996 is under study as a treatment for acute myeloid leukemia (AML). Other research has found LY3214996 to be safe when given to patients with different conditions. It has also been well-tolerated when combined with another drug, abemaciclib, in various types of cancer.

This trial is in the early stages, focusing on determining the right dose and assessing the safety of LY3214996 for people with AML. Although specific information on side effects for AML patients is not yet available, its use in other studies suggests it might be safe for most people. However, like any new treatment, unknown side effects may still occur. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for AML?

Most treatments for acute myeloid leukemia (AML) involve chemotherapy, which can be tough on the body and may not be effective for everyone. However, LY3214996 is unique because it targets a specific enzyme in cancer cells known as ERK, which plays a crucial role in cell division and survival. By blocking this enzyme, LY3214996 aims to stop the cancer cells from growing and spreading. Researchers are excited about this approach because it offers a more targeted therapy, potentially leading to fewer side effects and better outcomes for patients with AML. Additionally, LY3214996 is taken orally, making it more convenient compared to traditional intravenous treatments.

What evidence suggests that LY3214996 might be an effective treatment for acute myeloid leukemia?

Research suggests that LY3214996 might help treat acute myeloid leukemia (AML). Studies have shown that this treatment blocks the MAPK pathway, which aids cancer cell growth. In lab tests, LY3214996 stopped AML cells from growing and spreading. Further research found that this drug could slow leukemia cell growth in different models. In this trial, participants will receive LY3214996 in one of two arms: Arm A focuses on dose expansion, while Arm B focuses on dose escalation. These findings indicate that LY3214996 may be a promising option for patients whose AML has returned or hasn't responded to standard treatments. ^{1 5 6 7 8}

Who Is on the Research Team?

Rahul Vedula, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

Adults with acute myeloid leukemia (AML) that has returned or is unresponsive to standard treatments can join this trial. They must be able to sign consent, not have had a stem cell transplant recently, and agree to use contraception. Those on certain antifungal drugs affecting liver enzyme activity are included in specific arms of the study.

Inclusion Criteria

Ability to understand and the willingness to sign a written informed consent document.

I can take care of myself but might not be able to do heavy physical work.

I can swallow and keep down pills.

Exclusion Criteria

I have not had major surgery in the last 4 weeks.

I do not have any severe illnesses that could interfere with the study.

I am not pregnant, not breastfeeding, and if capable of becoming pregnant, I have a negative pregnancy test.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive LY3214996 by mouth once daily continuously throughout each treatment cycle

21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• LY3214996

Trial Overview The trial is testing LY3214996, a targeted therapy for AML patients who haven't responded well to other treatments. It's designed to see if this drug can help where others haven't by blocking cancer growth signals.

How Is the Trial Designed?

Group I: Arm B: Dose Escalation LY3214996 Experimental Treatment 1 Intervention

-LY3214996 will be administered by mouth once daily continuously throughout each treatment cycle for patients with inhibitors for fungal prophylaxis/treatment

Group II: Arm A: Dose Expansion LY3214996 Experimental Treatment 1 Intervention

-LY3214996 will be administered by mouth once daily continuously throughout each treatment cycle for patients without inhibitors for fungal prophylaxis/treatment

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Eli Lilly and Company

Industry Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Published Research Related to This Trial

AMG 232, an investigational drug for relapsed/refractory acute myeloid leukemia (AML), was found to have acceptable safety and pharmacokinetics, with no dose-limiting toxicities at doses up to 360 mg when used alone, although gastrointestinal side effects were noted at higher doses.

In terms of efficacy, 1 out of 30 evaluable patients achieved complete remission, and 31% of patients with wild-type TP53 responded to treatment, indicating potential effectiveness, especially in specific patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in relapsed/refractory acute myeloid leukemia. Erba, HP., Becker, PS., Shami, PJ., et al.[2023]

A comprehensive review of 397 phase II trials and 28 phase III trials from 2000 to 2020 revealed that targeted therapies for acute myeloid leukemia (AML) have limited success, with only eight drugs receiving FDA approval, and three of those not demonstrating overall survival benefits.

Repurposed drugs were less likely to progress in clinical trials compared to those specifically designed for AML, highlighting the need for future research to focus on both targeted and non-targeted therapies, as well as endpoints that assess patient quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two decades of targeted therapies in acute myeloid leukemia. Cucchi, DGJ., Polak, TB., Ossenkoppele, GJ., et al.[2021]

Recent advancements in genomics and molecular biology have significantly enhanced our understanding of acute myeloid leukemia (AML), a disease known for its clinical and genetic diversity and poor prognosis.

Since 2017, there have been new drug approvals for AML, particularly focusing on epigenetic-targeted therapies that are currently in pre-clinical and clinical development, marking a significant shift in treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent advances in the understanding and treatment of acute myeloid leukemia. Watts, J., Nimer, S.[2023]

The study evaluated MK-8242 in 26 subjects with refractory/recurrent acute myeloid leukemia (AML), finding that a 7on/14off dosing regimen (210mg or 300mg BID) had a more favorable safety profile compared to the 7on/7off regimen, with no dose-limiting toxicities observed in the higher doses.

Efficacy was demonstrated with responses including one partial response and one complete response in patients, suggesting that MK-8242, an HDM2 inhibitor, warrants further investigation for treating AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of the human double minute 2 inhibitor (MK-8242) in patients with refractory/recurrent acute myelogenous leukemia (AML). Ravandi, F., Gojo, I., Patnaik, MM., et al.[2018]

Recent advancements in targeted therapies for acute myeloid leukemia (AML) include novel agents like pinometostat, KO-539, SYNDX-5613, and APR-246, which specifically target mutations associated with AML, showing promise in early-phase clinical trials.

In addition to mutation-specific therapies, new drug classes such as BET inhibitors, polo-like kinase inhibitors, and MDM2 inhibitors are being explored, offering potential treatments for AML cases without targetable mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel Targeted Therapeutics in Acute Myeloid Leukemia: an Embarrassment of Riches. Grieselhuber, NR., Mims, AS.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7852028/

Evaluation of ERK as a therapeutic target in acute ... Taken together, these data suggest that LY3214996 is a potentially effective AML therapeutic, with targeted inhibition of MAPK-mediated ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04081259

NCT04081259 | LY3214996 in Patients With AML Who Are ... This research study is evaluating a targeted therapy as a possible treatment for acute myeloid leukemia (AML) that has returned or not responded to standard ...

3. researchgate.net researchgate.net/figure/Anti-leukemic-effects-of-LY3214996-in-vitro-and-in-vivo-against-human-AML-cell-lines_fig2_335438131

Anti-leukemic effects of LY3214996 in vitro and in vivo ... b LY3214996 inhibits growth of primary AML cells and in vivo growth of AML cells. First figure on the left: Proliferation study: 3-day treatment of a mutant RAS ...

4. researchgate.net researchgate.net/publication/386394587_Effects_of_ERK12_Inhibitors_on_the_Growth_of_Acute_Leukemia_Cells

(PDF) Effects of ERK1/2 Inhibitors on the Growth of Acute ... Results: The inhibitors suppressed the growth of three leukemia cell lines (OCI/AML3, HL-60, and THP-1) harboring neuroblastoma rat sarcoma ...

5. biorxiv.org biorxiv.org/content/10.1101/2023.05.25.542238v2.full.pdf

Designing patient-oriented combination therapies for acute ... Acute myeloid leukemia (AML), a heterogeneous and aggressive blood cancer, does not. 17 respond well to single-drug therapy.

6. medchemexpress.com medchemexpress.com/LY3214996.html?srsltid=AfmBOoowIbEXb7PTPpH_NcuO-BFMvFiPv0xFFGZx7D7yevUyCDSKKlkg

Temuterkib (LY3214996) | ERK1/ERK2 Inhibitor Combination treatment of Temuterkib and CDK4/6 inhibitor abemaciclib is well tolerated and results in potent tumor growth inhibition or regression in multiple ...

7. withpower.com withpower.com/trial/phase-1-leukemia-myeloid-acute-6-2020-fb8da

LY3214996 for Acute Myeloid Leukemia · Info for Participants AMG 232, an investigational drug for relapsed/refractory acute myeloid leukemia (AML), was found to have acceptable safety and pharmacokinetics, with no ...

8. por-journal.com por-journal.com/journals/pathology-and-oncology-research/articles/10.3389/pore.2024.1611747/full

The roles of phosphorylation of signaling proteins in ... Acute myeloid leukemia (AML) is characterized by clonal malignant proliferation of immature myeloid blast cells. AML may develop by ...