Targeted Therapy for Colorectal Cancer

Recruiting at 3 trial locations

Overseen By Aparna Parikh, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Massachusetts General Hospital

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Metastatic disease, Uncontrolled illness, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 4

Duration: 24-48 weeks

400 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores different treatment options for individuals with metastatic colon cancer. Researchers will use blood test results to compare standard care treatments, including chemotherapy, targeted therapies, and immunotherapy. Participants may receive one of several treatments, such as active monitoring (also known as active surveillance), FOLFIRI chemotherapy, or specific targeted drugs like Encorafenib, Binimetinib, and Cetuximab. This trial suits those whose colon cancer has spread after surgery and chemotherapy and who wish to explore options based on specific tumor markers. As a Phase 3 trial, it represents the final step before FDA approval, offering participants access to potentially effective treatments.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that patients should not be on other investigational therapies or certain medications that might interfere with the study drugs. It's best to discuss your current medications with the study team to ensure they don't conflict with the trial requirements.

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

A previous study found that the combination of trastuzumab and pertuzumab was well-tolerated in patients with HER2-positive metastatic colorectal cancer. Most patients did not experience serious side effects, though some had mild to moderate reactions during treatment, similar to mild allergic reactions.

Research has shown that treatment with encorafenib, binimetinib, and cetuximab for BRAF mutant metastatic colorectal cancer is generally safe. However, there is a risk of developing new skin cancers with this treatment, so regular skin checks are recommended.

The FOLFIRI regimen, which includes folinic acid, fluorouracil, and irinotecan, is another option. It is usually well-tolerated, but some patients may need to delay or reduce their dose due to side effects like nausea or low blood counts.

Nivolumab, an immunotherapy for certain types of colorectal cancer, is FDA-approved and has a manageable safety profile. Some patients may experience serious side effects like diarrhea or lung problems, but these are not common.

Overall, these treatments have been studied extensively and are considered safe with manageable side effects for many patients with metastatic colorectal cancer. Discussing potential risks and benefits with a healthcare provider can help you make an informed decision about joining a trial. ^{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 offer targeted and personalized approaches that differ from traditional chemotherapy. The Encorafenib/Binimetinib/Cetuximab protocol is distinct because it specifically targets the BRAF mutation, a genetic alteration found in some colorectal cancers, using a combination of a BRAF inhibitor, MEK inhibitor, and anti-EGFR antibody. The Nivolumab protocol, on the other hand, uses an immune checkpoint inhibitor to enhance the body's own immune response against cancer cells, particularly effective in cases with high microsatellite instability (MSI-H). Finally, the FOLFIRI protocol, while also a chemotherapy regimen, is being studied in combination with ctDNA monitoring to potentially optimize its use by better tracking treatment response. These innovations could lead to more effective and personalized treatment strategies for patients with colorectal cancer.

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

Research has shown that using trastuzumab and pertuzumab together, one of the treatment arms in this trial, benefits nearly half of patients with HER2-positive metastatic colorectal cancer. This combination helps patients live longer and is usually well-tolerated.

Another treatment arm involves the combination of encorafenib, binimetinib, and cetuximab. Studies have found this to be effective for patients with BRAF V600E-mutant metastatic colorectal cancer, reducing the risk of death by about 48%.

The FOLFIRI protocol, another option in this trial, is a chemotherapy mix often used for colorectal cancer. It can extend patients' lives but may cause more side effects than single-drug treatments.

Nivolumab, also under study in this trial, is an immunotherapy drug that has shown lasting benefits for patients with certain genetic markers, like MSI-H (microsatellite instability-high). It enhances the immune system's ability to fight cancer. ^{1 5 6 7 8}

Who Is on the Research Team?

Aparna Parikh, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

This trial is for adults over 18 with Stage III colon cancer that's been surgically removed. They must have finished standard chemo, not received neoadjuvant chemo, and be in good health with a life expectancy over 3 months. Women should test negative for pregnancy and all participants must agree to use contraception.

Inclusion Criteria

My cancer has been surgically removed.

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

My cancer has a known mismatch repair deficiency.

Exclusion Criteria

I have another cancer that is getting worse or needs treatment.

Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial

I have had more than 3-6 months of standard follow-up cancer treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive treatment based on ctDNA status, including FOLFIRI, Nivolumab, Encorafenib/Binimetinib/Cetuximab, or Trastuzumab and Pertuzumab

24-48 weeks

Bi-weekly to monthly visits for infusions

Active Surveillance

Observation and monitoring with imaging, tumor markers, and ctDNA collections

3 years

Every 3 months for the first 3 years, then every 6 months

Follow-up

Participants are monitored for disease-free survival and overall survival

5 years

What Are the Treatments Tested in This Trial?

Interventions

• ACTIVE SURVEILLANCE
• Encorafenib/Binimetinib/Cetuximab Protocol
• FOLFIRI Protocol
• Nivolumab Protocol

Trial Overview

The study compares two standard treatments based on blood tests for metastatic colorectal cancer: active surveillance or one of the FOLFIRI, Nivolumab, or Encorafenib/Binimetinib/Cetuximab protocols. The choice depends on specific genetic markers in the tumor DNA.

How Is the Trial Designed?

Group I: ctDNA-POSITIVE: FOLFIRI Protocol Experimental Treatment 1 Intervention

Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests. If these tests show that the participant is eligible to participate in the research study . The participant will be randomized into 1 of 3 groups : ctDNA-Positive: Folfiri or ctDNA-Positive: Active Surveillance or ctDNA Negative: Active Surveillance \- ctDNA-POSITIVE: FOLFIRI Protocol * FOLFIRI chemotherapy via intravenous infusion on days 1-3 of each cycle. Cycle is 14 days long. This will occur for up to 12 cycles (24 weeks). * infusions will consist of the drugs * 5-Fluorouracil * Irinotecan * Leucovorin

Group II: ctDNA-POSITIVE MSI-H: NIVOLUMAB Experimental Treatment 1 Intervention

Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests. If these tests show that the participant is eligible to participate in the research study and is ctDNA positive and MSI-H, the participant will not be randomized and will be placed into the group: ctDNA positive, MSI-H: Nivolumab -ctDNA-Positive, MSI-H: Nivolumab Protocol * Nivolumab treatment via intravenous infusion on day 1 of each cycle. Cycle is 28 days long. This will occur for up to 12 cycles (48 weeks). * infusions will consist of the drug Nivolumab

Group III: ctDNA-POSITIVE BRAF Mutant: ENCORAFENIB/BINIMETINIB/CETUXIMAB Experimental Treatment 1 Intervention

Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests. If these tests show that the participant is eligible to participate in the research study and is ctDNA positive and has a BRAF mutation, the participant will not be randomized and will be placed into the group: ctDNA positive, BRAF mutant: Encorafenib/Binimetinib/Cetuximab -ctDNA-Positive, MSI-H: Encorafenib/Binimetinib/Cetuximab Protocol * Encorafenib/Binimetinib treatment is received orally every day and Cetuximab via intravenous infusion on day 1 of each cycle. Cycle is 14 days long. This will occur for up to 12 cycles (24 weeks). * infusions will consist of the drug Cetuximab

Group IV: 6 Months Additional Trastuzumab and Pertuzumab Experimental Treatment 1 Intervention

Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests. Participants that are eligible to receive Trastuzumab and Pertuzumab will be placed in this HER2 cohort: ctDNA-positive \& HER2 amplification and MSS Trastuzumab and Pertuzumab. Trastuzumab is received via intravenous administration, and Pertuzumab treatment is received intravenously by infusion. Cycle is 21 days. This will occur for up to 8 cycles.

Group V: ctDNA-POSITIVE: ACTIVE SURVEILLANCE Active Control 1 Intervention

Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests. If these tests show that the participant is eligible to participate in the research study . The participant will be randomized into 1 of 3 groups : ctDNA-Positive: Folfiri or ctDNA-Positive: Active Surveillance or ctDNA Negative: Active Surveillance \-- Active surveillance. * Observation and monitoring with imaging (every 3 months), tumor markers, and ctDNA draws every 1 month for the initial 6 months. * After 6 months, followed with ctDNA, tumor markers, and scans every 3 months for the first 3 years and every 6 months thereafter. Additional scans and tumor markers will be at the discretion of the clinician. .

Group VI: ctDNA-NEGATIVE: ACTIVE SURVEILLANCE Active Control 1 Intervention

Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests. If these tests show that the participant is eligible to participate in the research study . The participant will be randomized into 1 of 3 groups : ctDNA-Positive: Folfiri or ctDNA-Positive: Active Surveillance or ctDNA Negative: Active Surveillance \- Observation and monitoring with imaging, tumor markers, and ctDNA collections every 3 months for the first 3 years and every 6 months thereafter. Additional scans and tumor markers will be at the discretion of the clinician

ACTIVE SURVEILLANCE is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Active Surveillance for:

• Prostate cancer
• Colon cancer
• Other cancers where watchful waiting is appropriate

Approved in United States as Active Surveillance for:

• Prostate cancer
• Colon cancer
• Other cancers where watchful waiting is appropriate

Approved in Canada as Active Surveillance for:

• Prostate cancer
• Colon cancer
• Other cancers where watchful waiting is appropriate

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Stand Up To Cancer

Collaborator

Trials

53

Recruited

40,100+

Published Research Related to This Trial

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]

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 133 patients with BRAF V600E-mutated metastatic colorectal cancer, the combination of encorafenib and cetuximab showed a 23% overall response rate and a 69% disease control rate, with slightly better outcomes in patients receiving the triplet therapy with binimetinib (31% ORR).

The treatment was generally safe, with common side effects including asthenia and skin rash, and the study confirmed that patients in better health and with fewer prior treatments are more likely to benefit from this targeted therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Encorafenib plus cetuximab with or without binimetinib in patients with BRAF V600E-mutated metastatic colorectal cancer: real-life data from an Italian multicenter experience. Boccaccino, A., Borelli, B., Intini, R., 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]

In the BEACON CRC study involving 665 patients with BRAF V600E-mutant metastatic colorectal cancer, the combination of encorafenib and cetuximab significantly improved overall survival (OS) to 9.3 months compared to 5.9 months for standard chemotherapy, indicating its efficacy as a treatment option.

The triplet regimen of encorafenib, binimetinib, and cetuximab achieved a confirmed objective response rate (ORR) of 26.8%, demonstrating a substantial improvement over the control group's ORR of only 1.8%, while maintaining a manageable safety profile with similar rates of grade ≥ 3 adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated BRAF V600E-Mutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses from the BEACON Study. Tabernero, J., Grothey, A., Van Cutsem, E., et al.[2022]

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]

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