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

46 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug combination LY3214996 + Cetuximab / Abemaciclib for colorectal cancer?

Research shows that cetuximab, a component of the treatment, has been effective in improving survival and response rates in patients with metastatic colorectal cancer, especially when combined with chemotherapy. This suggests that cetuximab can be a valuable part of treatment strategies for colorectal cancer. ^{1 2 3 4 5}

What safety information is available for the treatment LY3214996 + Cetuximab / Abemaciclib for colorectal cancer?

Cetuximab, one of the drugs in the treatment, is generally well tolerated but can cause side effects like skin issues, infusion reactions, and low magnesium levels. It's important to manage these side effects promptly to continue treatment safely. ^{4 6 7 8 9}

What makes the drug LY3214996 + Cetuximab / Abemaciclib unique for colorectal cancer?

This treatment combines LY3214996, a novel drug, with Cetuximab and Abemaciclib, which are known for targeting specific cancer pathways. Cetuximab is a monoclonal antibody that blocks the epidermal growth factor receptor (EGFR), while Abemaciclib inhibits proteins involved in cell division, potentially offering a new approach for patients who have not responded to other treatments. ^{10 11 12 13 14}

What is the purpose of this trial?

This phase Ib/II trial investigates the side effects and best dose of LY3214996 when given together with cetuximab alone or in combination with abemaciclib and to see how well they work in treating patients with colorectal cancer that cannot be removed by surgery (unresectable) and/or has spread to other places in the body (metastatic). Cetuximab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. LY3214996 and abemaciclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving LY3214996 and cetuximab alone or in combination with abemaciclib may help treat patients with colorectal cancer.

Research Team

Christine M Parseghian, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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, 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]

References

1. England pubmed.ncbi.nlm.nih.gov

Synergy between cetuximab and chemotherapy in tumors of the gastrointestinal tract. [2022]

2. Greece pubmed.ncbi.nlm.nih.gov

Association KRAS G13D tumor mutated outcome in patients with chemotherapy refractory metastatic colorectal cancer treated with cetuximab. [2016]

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

Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. [2022]

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

Phase Ib/II Study of Cetuximab plus Pembrolizumab in Patients with Advanced RAS Wild-Type Colorectal Cancer. [2023]

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

Cetuximab plus irinotecan in heavily pretreated metastatic colorectal cancer progressing on irinotecan: MABEL Study. [2022]

6. Japan pubmed.ncbi.nlm.nih.gov

[Anti-epidermal growth factor receptor monoclonal antibodies induced adverse events]. [2018]

7. Japan pubmed.ncbi.nlm.nih.gov

Retrospective analysis of cetuximab monotherapy for patients with irinotecan-intolerant metastatic colorectal cancer. [2021]

8. United States 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. [2023]

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

An Update of Efficacy and Safety of Cetuximab in Metastatic Colorectal Cancer: A Narrative Review. [2019]

10. Germany pubmed.ncbi.nlm.nih.gov

Cetuximab: appraisal of a novel drug against colorectal cancer. [2019]

11. England pubmed.ncbi.nlm.nih.gov

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

12. England pubmed.ncbi.nlm.nih.gov

Multicenter Phase II study of cetuximab plus irinotecan in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin and fluoropyrimidines. [2018]

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

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

14. Cyprus pubmed.ncbi.nlm.nih.gov

Cetuximab in third-line therapy of patients with metastatic colorectal cancer: A single institution experience. [2016]