Targeted Therapy for Colorectal Cancer

Recruiting at3 trial locations

Overseen by Aparna Parikh, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Massachusetts General Hospital

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Metastatic disease, Uncontrolled illness, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This research study is comparing two standard of care treatment options based on blood test results for participants who have metastatic colon cancer. The names of the potential treatments involved in this study are: * Active surveillance * FOLFIRI treatment * Nivolumab treatment * Encorafenib/Binimetinib/Cetuximab treatment * Trastuzumab + Pertuzumab

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.

What data supports the effectiveness of the drug combination Encorafenib/Binimetinib/Cetuximab for colorectal cancer?

Research shows that the combination of encorafenib and cetuximab, with or without binimetinib, improves survival and response rates in patients with a specific type of colorectal cancer (BRAF V600E-mutated) compared to standard treatments. This combination has been shown to extend the time patients live without the cancer getting worse and increase overall survival. ^{1 2 3 4 5}

What safety data exists for the treatment involving encorafenib, binimetinib, and cetuximab in colorectal cancer?

The treatment with encorafenib and cetuximab, with or without binimetinib, has been studied in patients with a specific type of colorectal cancer. Common side effects reported include tiredness, nausea, diarrhea, skin rash, and joint pain. These studies help ensure the treatment is safe for use in humans. ^{1 4 5 6 7}

What makes the Encorafenib/Binimetinib/Cetuximab drug unique for colorectal cancer?

This drug combination is unique because it specifically targets the BRAF V600E mutation in metastatic colorectal cancer, which is not addressed by standard chemotherapy. It has shown improved survival rates and response rates compared to traditional treatments, making it a significant option for patients with this specific genetic mutation. ^{1 2 3 4 6}

Research Team

Aparna Parikh, MD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

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

I am 18 years old or older.

My cancer has been surgically removed.

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

Exclusion Criteria

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

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

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

Trial Timeline

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

Treatment Details

Interventions

• ACTIVE SURVEILLANCE (Other)
• Encorafenib/Binimetinib/Cetuximab Protocol (Targeted Therapy)
• FOLFIRI Protocol (Chemotherapy)
• Nivolumab Protocol (Checkpoint Inhibitor)

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.

Participant Groups

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 Canada for the following indications:

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+

Dr. William Curry

Massachusetts General Hospital

Chief Medical Officer

MD from Harvard Medical School

Dr. Anne Klibanski

Massachusetts General Hospital

Chief Executive Officer since 2019

MD from Harvard Medical School

Stand Up To Cancer

Collaborator

Trials

53

Recruited

40,100+

Findings from Research

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]

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 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]

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]

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]

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 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]

References

1. England 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. [2022]

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

Antitumor Efficacy of Dual Blockade with Encorafenib + Cetuximab in Combination with Chemotherapy in Human BRAFV600E-Mutant Colorectal Cancer. [2023]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Encorafenib: A Review in Metastatic Colorectal Cancer with a BRAF V600E Mutation. [2021]

4. United States 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. [2022]

5. England 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. [2021]

6. 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]

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

Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer: an early post-marketing phase vigilance study. [2023]