LY3214996 + Cetuximab / Abemaciclib for Colorectal Cancer

Overseen By Christine M Parseghian

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must be taking: Anti-EGFR therapy

Must not be taking: CYP3A4 inhibitors/inducers

Disqualifiers: Brain metastasis, Cardiovascular disease, Infection, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 2

Duration: 28 days per cycle, repeated

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of two new drugs, LY3214996 (Temuterkib) and abemaciclib, in combination with cetuximab, against colorectal cancer that cannot be surgically removed or has metastasized. The goal is to determine the optimal dose and identify any side effects when using these drugs together. This trial may suit individuals with colorectal cancer that remains active after previous treatments, especially if the cancer has returned or spread. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive these new drugs.

Do I have to stop taking my current medications for the trial?

The trial requires a washout period (time without taking certain medications) of at least 21 days after the last chemotherapy dose and 14 days after the last radiotherapy session before starting the trial. Additionally, you cannot take medications that strongly affect the enzyme CYP3A4. Other current medications are not specifically mentioned, so it's best to discuss with the trial team.

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

Research has shown that using LY3214996 and cetuximab together, with or without abemaciclib, is generally safe. Studies have found no unexpected side effects when these treatments are combined. LY3214996 aims to stop tumor growth, and patients seem to tolerate it well when used with cetuximab. Abemaciclib, included in one part of the study, is already approved for other uses, indicating its well-known safety. This combination is being tested to determine the best dose and identify any side effects. Overall, the treatment appears well-tolerated so far. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for colorectal cancer because they combine innovative approaches to target the disease. Unlike standard treatments, which typically focus on chemotherapy or radiation, this trial explores the use of LY3214996, an ERK1/2 inhibitor, in combination with cetuximab and abemaciclib. LY3214996 targets specific proteins involved in cancer cell growth, potentially offering a more precise attack on cancer cells. Abemaciclib is a CDK4/6 inhibitor, which can interfere with cancer cell division. This multi-targeted approach may enhance effectiveness and possibly reduce the development of resistance, offering new hope for patients with colorectal cancer.

What evidence suggests that this trial's treatments could be effective for colorectal cancer?

Research has shown that using LY3214996 with cetuximab may help treat advanced colorectal cancer. In this trial, one group of participants will receive LY3214996 and cetuximab, which work together by blocking signals and targeting enzymes that cancer cells need to grow, potentially slowing tumor growth. Another group will also receive abemaciclib, another enzyme blocker, which could further enhance the treatment's ability to prevent cancer from spreading. Early trial results suggest these combinations can benefit patients with advanced colorectal cancer, with some experiencing tumor shrinkage. ^{1 6 7 8 9}

Who Is on the Research Team?

Christine M Parseghian, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with colorectal cancer that's spread and can't be removed by surgery. They must have tried at least one chemotherapy, recovered from its effects, and not have certain gene mutations. Participants need to be in good physical condition (ECOG <=1), able to take oral meds, and women must avoid pregnancy.

Inclusion Criteria

I can take pills by mouth.

Corrected QT (QTc) interval =< 480 ms (preferably the mean from triplicate electrocardiograms [ECGs])

I am a woman who cannot become pregnant or will take steps to prevent pregnancy during the study.

Exclusion Criteria

I am able to understand and follow the study's requirements.

I do not have any active infections or a history of chronic pancreatitis.

I do not have serious heart issues like heart failure or irregular heartbeat in the last 6 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ERK1/2 inhibitor LY3214996 and cetuximab, with or without abemaciclib, in 28-day cycles

28 days per cycle, repeated

2 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

30 days

What Are the Treatments Tested in This Trial?

Interventions

• Abemaciclib
• Cetuximab
• LY3214996

Trial Overview The study tests LY3214996 with cetuximab alone or combined with abemaciclib on unresectable/metastatic colorectal cancer. It aims to find the best dose of LY3214996, see how well these treatments work together, and understand their side effects.

How Is the Trial Designed?

Group I: Arm B (ERK1/2 inhibitor LY3214996, cetuximab, abemaciclib) Experimental Treatment 3 Interventions

Patients receive ERK1/2 inhibitor LY3214996 and cetuximab as in Arm A. Patients also receive abemaciclib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: Arm A (ERK1/2 inhibitor LY3214996, cetuximab) Experimental Treatment 2 Interventions

Patients receive ERK1/2 inhibitor LY3214996 PO QD on days 1-28 and cetuximab IV over 1-2 hours on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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

Approved in United States as Verzenio for:

• Hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer
• HR+, HER2- node-positive early breast cancer

Approved in European Union as Verzenio for:

• HR+, HER2- advanced or metastatic breast cancer
• HR+, HER2- node-positive early breast cancer

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Cetuximab and panitumumab are effective treatments for colorectal cancer, showing clinical activity as anti-EGFR monoclonal antibodies, and are generally well tolerated by patients.

While these medications have fewer severe adverse events compared to traditional cytotoxic agents, they can still cause issues like infusion reactions, skin toxicity, lung toxicity, and low magnesium levels, which need to be managed promptly to avoid treatment interruptions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Anti-epidermal growth factor receptor monoclonal antibodies induced adverse events]. Tsuji, Y., Kogawa, T., Abe, M.[2018]

Cetuximab monotherapy is a feasible treatment option for patients with metastatic colorectal cancer (MCRC) who are intolerant to irinotecan, with no severe adverse events reported in the study of 22 patients.

The efficacy of cetuximab was modest, with a response rate of only 9.1% and median overall survival of 3.5 months, indicating a need for more effective therapies for this patient group, especially since most had wild-type KRAS tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective analysis of cetuximab monotherapy for patients with irinotecan-intolerant metastatic colorectal cancer. Mizota, A., Shitara, K., Kondo, C., et al.[2021]

In the BEACON CRC study involving 216 patients with BRAFV600E-mutated metastatic colorectal cancer, the combination of encorafenib and cetuximab was generally well tolerated, with most adverse events being mild to moderate in severity and resolving quickly, typically within 1-2 weeks.

The most common adverse events included dermatological toxicity (75.5%), arthralgia/myalgia (56.0%), and fatigue/asthenia (56.0%), with notable survival benefits observed in patients experiencing these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events Associated with Encorafenib Plus Cetuximab in Patients with BRAFV600E-mutant Metastatic Colorectal Cancer: An in-depth Analysis of the BEACON CRC Study. Taieb, J., Lonardi, S., Desai, J., et al.[2023]

Cetuximab, when combined with irinotecan, can provide patients with metastatic colorectal cancer an additional 1.7 to 2.0 years of life, indicating its efficacy as a treatment option.

However, the cost-effectiveness analysis revealed that the treatment is quite expensive, with costs per life year gained ranging from 205,536 to 323,040 Euros, highlighting the financial considerations of using cetuximab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab in the treatment of metastatic colorectal cancer: a model-based cost-effectiveness analysis. Norum, J.[2019]

Cetuximab has demonstrated significant efficacy in treating metastatic colorectal cancer, achieving a partial response in 10.8% of patients receiving it alone and 22.9% when combined with irinotecan, based on a Phase III trial involving 329 patients.

The drug is generally well tolerated, with common side effects like acnelike rash and hypersensitivity reactions, but the lack of reliable predictive markers for patient selection remains a challenge for its clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer. Wong, SF.[2022]

Cetuximab is a chimeric monoclonal antibody that targets the epidermal growth-factor receptor (EGFR) and has been clinically approved in Europe for treating metastatic colorectal cancer and locally advanced head and neck cancer since 2004 and 2006, respectively.

The review discusses cetuximab's established role in colorectal cancer treatment, ongoing studies, and future challenges, highlighting its significance as the leading anti-EGFR monoclonal antibody in clinical evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab: appraisal of a novel drug against colorectal cancer. Hildebrandt, B., le Coutre, P., Nicolaou, A., et al.[2019]

Cetuximab is an effective monoclonal antibody that targets the epidermal growth factor receptor, showing significant clinical efficacy in treating colorectal cancer (CRC) either alone or in combination with chemotherapy.

The combination of cetuximab with chemotherapy is well tolerated, with minimal overlapping toxicities, making it a crucial treatment option for patients with metastatic CRC who do not respond to traditional chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergy between cetuximab and chemotherapy in tumors of the gastrointestinal tract. Mahtani, RL., Macdonald, JS.[2022]

In the phase III CRYSTAL study, adding cetuximab to the FOLFIRI regimen significantly improved overall survival and progression-free survival in patients with KRAS exon 2 wild-type metastatic colorectal cancer, highlighting its efficacy in this specific patient group.

However, patients with other RAS mutations did not experience any benefit from cetuximab, indicating the importance of comprehensive RAS mutation testing to tailor treatment and maximize effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. Van Cutsem, E., Lenz, HJ., Köhne, CH., et al.[2022]

In a study involving 1,147 patients with metastatic colorectal cancer (mCRC), the combination of cetuximab and irinotecan achieved a 12-week progression-free survival (PFS) rate of 61% and a median overall survival of 9.2 months, confirming its efficacy in a community practice setting.

The treatment was generally well tolerated, with the most common severe side effects being diarrhea (19%) and neutropenia (10%), while the incidence of severe infusion-related reactions was notably low at 1% when patients received premedication with antihistamines and corticosteroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab plus irinotecan in heavily pretreated metastatic colorectal cancer progressing on irinotecan: MABEL Study. Wilke, H., Glynne-Jones, R., Thaler, J., et al.[2022]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.3534

Open-label phase Ib/II study of cetuximab (CET) plus ... Results: Of 44 pts treated on trial, 2 did not meet inclusion criteria; 39 were evaluable for activity, and 34 for efficacy. The RP2D was 200 mg ...

2. researchgate.net researchgate.net/publication/392303341_Open-label_phase_IbII_study_of_cetuximab_CET_plus_LY3214996_with_or_without_abemaciclib_in_patients_pts_with_anti-EGFR-refractory_metastatic_colorectal_cancer_mCRC

Open-label phase Ib/II study of cetuximab (CET) plus ... Results: Of 44 pts treated on trial, 2 did not meet inclusion criteria; 39 were evaluable for activity, and 34 for efficacy. The RP2D was 200 mg LY3214996 p.o. ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10136970/

The Therapeutic Landscape for KRAS-Mutated Colorectal ... Adagrasib was found to be sufficiently tolerated and induced a roughly 50% partial response in NSCLC (8/15) and colorectal cancer (1/2) patients ...

4. delta.larvol.com delta.larvol.com/Products/?ProductId=e64cfd4d-8116-4b85-9480-b4653d7ef1e0

temuterkib (LY3214996) / Eli Lilly Open-label phase Ib/II study of cetuximab (CET) plus LY3214996 ... Enrollment change • Trial primary completion date • Trial termination • Colorectal Cancer ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT02484833

Erbitux MEtastatic Colorectal Cancer Strategy Study With the availability of an effective treatment such as cetuximab in monotherapy4 without major side effects on blood counts and liver and kidney function, the ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02857270

NCT02857270 | A Study of LY3214996 Administered ... The purpose of this study is to determine the safety of an extracellular signal regulated kinase (ERK1/2) inhibitor LY3214996 administered alone or in ...

7. erbitux.lilly.com erbitux.lilly.com/hcp/mcrc

Metastatic Colorectal Cancer | mCRC | HCP - Erbitux - Eli Lilly ERBITUX provides approximately 22% higher exposure compared to the cetuximab product used in CRYSTAL; however, the safety data from CRYSTAL is consistent in ...

8. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2019/125084s273lbl.pdf

ERBITUX (cetuximab) - accessdata.fda.gov The data described below reflect exposure to ERBITUX in 242 patients with K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer (mCRC) [see Warnings ...

9. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT02857270/

Clinical Trial: NCT02857270 The purpose of this study is to determine the safety of an extracellular signal regulated kinase (ERK1/2) inhibitor LY3214996 administered alone ...