Ulixertinib + Cetuximab / Encorafenib for Colorectal Cancer

Overseen By Christine Parseghian, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: ERK1/2 inhibitors

Disqualifiers: Symptomatic brain metastasis, Cardiovascular diseases, Active infections, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 8-12 weeks

27 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial seeks to determine the optimal dose of ulixertinib (an experimental treatment) when combined with other treatments (cetuximab and/or encorafenib) for colorectal cancer that cannot be surgically removed or has metastasized. It targets individuals who have previously tried therapies such as EGFR or BRAF-targeted treatments and have colorectal cancer that is either KRAS, NRAS, EGFR, BRAF V600E wild-type or has a BRAF V600E mutation. Those with colorectal cancer that is difficult to treat or has progressed despite prior treatments may be suitable candidates. 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 this new treatment.

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

The trial protocol does not specify if you need to stop taking your current medications. However, there is a required 'washout period' (time without taking certain medications) of at least 21 days after your last chemotherapy dose and 7 days after radiotherapy before starting the study.

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

A previous study found the combination of ulixertinib with cetuximab to be safe, with no unexpected patient reactions. The treatment did not directly cause severe side effects; any serious issues stemmed from the cancer itself. This indicates that ulixertinib is generally well-tolerated.

Early research on the combination of ulixertinib, cetuximab, and encorafenib showed low rates of severe side effects. Only 8% of patients experienced significant skin problems, indicating good safety. The FDA has already approved encorafenib and cetuximab for certain colorectal cancers, supporting their safety.

Overall, studies have shown these treatments to be reasonably safe, with manageable side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Ulixertinib is unique because it targets the ERK pathway, which is often involved in cancer cell growth and survival, offering a different approach from the usual treatments like 5-FU-based chemotherapy and anti-EGFR therapies. Researchers are excited about combining ulixertinib with cetuximab and encorafenib for colorectal cancer because this combination could potentially overcome resistance mechanisms seen in standard treatments. This innovative strategy aims to enhance effectiveness against tumors with specific genetic mutations, offering hope for improved outcomes in patients who previously had limited options.

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

Research has shown that cetuximab, when combined with other treatments, can help fight colorectal cancer. For patients with a specific gene type (wild-type KRAS), cetuximab has been linked to longer survival. Additionally, combining encorafenib with cetuximab has significantly improved quality of life and reduced tumor size. This combination has received approval for treating colorectal cancer with a specific mutation (BRAF V600E). In this trial, one cohort will receive ulixertinib with cetuximab, while another cohort will receive ulixertinib with both cetuximab and encorafenib. These findings suggest that using ulixertinib with cetuximab and/or encorafenib may be promising for treating advanced colorectal cancer. ^{6 7 8 9 10}

Who Is on the Research Team?

Christine Parseghian

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults over 18 with unresectable/metastatic colorectal cancer who've had prior EGFR or BRAF therapy can join. They must have adequate organ function, be able to take oral meds, and use effective contraception if of childbearing potential. Exclusions include previous ERK1/2 inhibitor exposure, certain infections like hepatitis B/C, heart conditions, uncontrolled hypertension, recent major surgery, pregnancy/nursing status.

Inclusion Criteria

b. BRAF expansion Cohort: BRAF therapy (not including regorafenib) and anti-EGFR therapy (cetuximab or panitumumab)

Patients who received chemotherapy must have recovered (Common Terminology Criteria for Adverse Events [CTCAE] Grade ≤1) from the acute effects of chemotherapy except for residual alopecia or Grade 2 peripheral neuropathy prior to day 1 of study. A washout period of at least 21 days is required between last chemotherapy dose and day 1 of study (provided the patient did not receive radiotherapy).

Able to take oral medications.

Exclusion Criteria

Symptomatic chronic heart failure (i.e. NYHA class 3 or higher), history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality <6 months prior to screening except atrial fibrillation and paroxysmal supraventricular tachycardia,

Medical, psychiatric, cognitive or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study.

Previously exposed to ERK1/2 inhibitor

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ulixertinib in combination with cetuximab and/or encorafenib to determine the maximally tolerated dose and recommended phase 2 dose

8-12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of overall response rate and duration of response

4 weeks

Exploratory

Correlative studies performed using blood and tissue specimens to assess biomarkers and pharmacodynamic markers

What Are the Treatments Tested in This Trial?

Interventions

• Cetuximab
• Encorafenib
• Ulixertinib

Trial Overview The trial is testing the optimal dose of ulixertinib alone or combined with cetuximab and/or encorafenib in patients with advanced colorectal cancer previously treated with EGFR/BRAF therapies. It's an open-label study where everyone knows what treatment they're getting.

How Is the Trial Designed?

Group I: Cohort A Experimental Treatment 2 Interventions

1 of these 2 doses will be selected as the recommended dose of ulixertinib that can be given in combination with cetuximab alone.

Group II: BRAF Expansion Cohort Experimental Treatment 3 Interventions

1 of these 2 doses will be selected as the recommended dose of ulixertinib that can be given in combination with cetuximab and encorafenib.

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

Approved in United States as Erbitux for:

• Locally or regionally advanced squamous cell carcinoma of the head and neck
• Recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck
• K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer
• BRAF V600E mutation-positive metastatic colorectal cancer

Approved in European Union as Erbitux for:

• Squamous cell carcinoma of the head and neck
• K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

BioMed Valley Discoveries, Inc

Industry Sponsor

Trials

19

Recruited

650+

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

In a post-marketing surveillance study involving 2126 patients with metastatic colorectal cancer, cetuximab was found to be well tolerated, with a median treatment duration of 15.3 weeks and a high incidence of adverse reactions at 89.6%.

The most common adverse reactions included skin disorders (83.7%) and infusion reactions (5.7%), primarily occurring during the first administration, indicating that while side effects are common, they align with previous reports and suggest that cetuximab is clinically useful in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Japanese post-marketing surveillance of cetuximab (Erbitux®) in patients with metastatic colorectal cancer. Ishiguro, M., Watanabe, T., Yamaguchi, K., et al.[2022]

Cetuximab and panitumumab are effective treatments for patients with previously untreated RAS wild-type metastatic colorectal cancer, showing cost-effectiveness when combined with standard chemotherapy regimens (FOLFOX or FOLFIRI) compared to chemotherapy alone.

Both drugs meet the National Institute for Health and Care Excellence's end-of-life criteria and are recommended for use within the UK National Health Service, indicating their potential benefit for patients not eligible for liver resection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Economic Analysis of First-Line Treatment with Cetuximab or Panitumumab for RAS Wild-Type Metastatic Colorectal Cancer in England. Tikhonova, IA., Huxley, N., Snowsill, T., et al.[2021]

In a study involving approximately 550 Japanese patients with BRAF V600E-mutated metastatic colorectal cancer, the triplet and doublet regimens of encorafenib plus cetuximab showed a safety profile consistent with previous studies, with no deaths reported due to adverse drug reactions (ADRs).

The most common ADRs included nausea, retinal detachment, and decreased appetite, while serious ADRs were reported in 42 patients, with 20 out of 22 patients with serious eye disorders recovering during the study period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer: an early post-marketing phase vigilance study. Sakata, H., Murase, M., Kato, T., et al.[2023]

In a study of 8 patients with recurrent/advanced colorectal cancer, 6 patients showed a positive response to cetuximab, a targeted therapy that binds to epidermal growth factor receptors (EGFR), indicating its efficacy even in later lines of treatment.

Patients receiving cetuximab in combination with CPT-11 had significantly better progression-free survival (7.3 months) and time to treatment failure (9.3 months) compared to those on cetuximab monotherapy (3.0 months and 4.5 months, respectively), highlighting the potential benefits of combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The efficacy of cetuximab for metastatic colorectal cancer]. Katsumoto, Y., Aritake, N., Endoh, A.[2018]

In a study involving 65 patients with advanced colorectal cancer who had previously been treated with multiple therapies, the combination of cetuximab and irinotecan showed a response rate of 20% and a median overall survival of 10.4 months, confirming the efficacy of this treatment regimen.

The treatment was associated with low rates of severe toxicity, with only 8% experiencing grade 3 skin toxicity, indicating that cetuximab and irinotecan can be a safe option for heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab and irinotecan as third line therapy in patients with advanced colorectal cancer after failure of irinotecan, oxaliplatin and 5-fluorouracil. Pfeiffer, P., Nielsen, D., Yilmaz, M., et al.[2018]

In a retrospective study of 25 patients with BRAFV600E mutated metastatic colorectal cancer who had previously been treated with anti-EGFR agents, the combination of encorafenib and cetuximab showed a promising overall response rate of 40% and a disease control rate of 80%.

The median progression-free survival was 4.8 months and overall survival was 10.1 months, indicating that this combination therapy can be effective even in patients who had previously shown resistance to anti-EGFR treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Encorafenib plus cetuximab treatment in BRAF V600E-mutated metastatic colorectal cancer patients pre-treated with an anti-EGFR: An AGEO-GONO case series. Hafliger, E., Boccaccino, A., Lapeyre-Prost, A., et al.[2022]

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 and panitumumab are monoclonal antibodies that target the epidermal growth factor receptor (EGFR) and show promise as therapies for colorectal cancer, particularly in cases where chemotherapy has failed.

The review discusses their effectiveness in both advanced and initial treatment settings, as well as factors that may predict patient response or resistance to these therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical use of monoclonal antibodies to the epidermal growth factor receptor in colorectal cancer. Burtness, B.[2018]

In the BEACON CRC clinical trial, the combination of encorafenib and cetuximab significantly improved median overall survival and progression-free survival in adults with metastatic colorectal cancer harboring a BRAF V600E mutation, compared to standard therapies.

The treatment was found to have a manageable safety profile, making it a promising targeted option for patients who have already undergone previous systemic therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Encorafenib: A Review in Metastatic Colorectal Cancer with a BRAF V600E Mutation. Al-Salama, ZT.[2021]

Encorafenib in combination with cetuximab significantly improves overall survival (9.3 months) and progression-free survival (4.27 months) in adult patients with metastatic colorectal carcinoma (mCRC) with the BRAFV600E mutation compared to standard treatments, showing a hazard ratio of 0.61 for overall survival and 0.44 for progression-free survival.

The most common side effects reported with this treatment combination include fatigue, nausea, and skin-related issues, indicating that while the treatment is effective, it does come with a range of manageable adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The EMA assessment of encorafenib in combination with cetuximab for the treatment of adult patients with metastatic colorectal carcinoma harbouring the BRAFV600E mutation who have received prior therapy. Trullas, A., Delgado, J., Koenig, J., et al.[2021]

The combination of cytotoxic chemotherapy (FOLFOX or FOLFIRI) with the targeted therapy encorafenib + cetuximab (E+C) shows improved antitumor activity as a first-line treatment for BRAFV600E metastatic colorectal cancer (mCRC) compared to using either treatment alone.

Using FOLFOX with E+C as initial therapy, followed by E+C with or without 5-FU for maintenance, is the most effective strategy for long-term disease control, highlighting the importance of combining these treatment modalities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor Efficacy of Dual Blockade with Encorafenib + Cetuximab in Combination with Chemotherapy in Human BRAFV600E-Mutant Colorectal Cancer. Napolitano, S., Woods, M., Lee, HM., et al.[2023]

Cetuximab, a monoclonal antibody targeting the EGFR, has been approved for first-line treatment of KRAS mutation-negative metastatic colorectal cancer (mCRC) in combination with FOLFIRI, showing significant improvements in progression-free survival and overall survival.

The combination of cetuximab with FOLFIRI also resulted in higher objective response rates compared to FOLFIRI alone, making it a valuable treatment option for patients with EGFR-expressing, KRAS wild-type mCRC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab: a guide to its use in combination with FOLFIRI in the first-line treatment of metastatic colorectal cancer in the USA. Lyseng-Williamson, KA.[2021]

Citations

1. withpower.com withpower.com/trial/phase-1-colorectal-neoplasms-2024-85d46

Ulixertinib + Cetuximab / Encorafenib for Colorectal Cancer This suggests that Cetuximab can be effective in treating colorectal cancer, especially when combined with other treatments. Show more ...

2. facebook.com facebook.com/groups/208490666601307/posts/1928408284609528/

Ulixertinib and cetuximab for metastatic colorectal cancer ... cetuximab (Erbitux) resulted in equally effective outcomes for patients with metastatic colorectal cancer and wild-type KRAS.” Investigators ...

3. biomed-valley.com biomed-valley.com/wp-content/uploads/2024/01/2693.pdf

Combining ulixertinib (ERK1/2 inhibitor) with EGFR and ... The approved regimen of enco + cetux yielded 71% tumor volume (TV) change from baseline (BL) (p=0.001).

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7667584/

Up-and-Coming Experimental Drug Options for Metastatic ... The Phase II ANCHOR-CRC trial is underway examining cetuximab, encorafenib, and binimetinib in the first-line setting for mCRC to see if these ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7270202/

Chemotherapeutic Effectiveness of Combining Cetuximab for ... Combining cetuximab with chemotherapy, the PFS and OS of wild-type KRAS patients and the ORR of all patients were significantly improved.

6. aacrjournals.org aacrjournals.org/cancerres/article/83/7_Supplement/2693/719464/Abstract-2693-Combining-ulixertinib-ERK1-2

Combining ulixertinib (ERK1/2 Inhibitor) with EGFR and BRAF ... The efficacy of ulixertinib, in combination with EGFR inhibition (cetuximab), plus BRAF inhibition (encorafenib), was assessed in CRC cell line derived ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.e15101

Updated clinical outcomes from ULI-EAP-100, an ... Safety of ulixertinib in this program is consistent with previous experience and all grade 5 AEs were attributed to disease progression.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9282166/

Analysis from a Nonrandomized Trial of Ulixertinib for ... Ulixertinib is the first-in-class ERK1/2 kinase inhibitor with encouraging clinical activity in BRAF- and NRAS-mutant cancers.

9. asco.org asco.org/abstracts-presentations/ABSTRACT417518

A phase 2 basket trial of ulixertinib (BVD-523) in ... Primary study endpoints will include safety/toxicity as well as ORR by RECIST 1.1. ... cetuximab or panitumumab in metastatic BRAF-mutated colorectal cancer ...

10. clinicaltrials.gov clinicaltrials.gov/study/NCT04566393

NCT04566393 | Expanded Access to Ulixertinib (BVD-523) ... The objective of this expanded access program is to provide ulixertinib (BVD-523) for compassionate use in advanced cancer patients with MAPK ...