Nivolumab + Standard Treatment for Colorectal Cancer

Recruiting at 328 trial locations

Overseen By Deepak Vadehra

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: HIV antiretrovirals, BRAF inhibitors

Disqualifiers: HIV, Autoimmune diseases, Organ transplant, others

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

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

Compensation: Varies

Number of Visits: 1

Duration: Variable, based on disease progression

84 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial tests whether adding nivolumab to the usual treatment (encorafenib and cetuximab) works better than the usual treatment alone to shrink tumors in patients with colorectal cancer that has spread to other places in the body (metastatic) or that cannot be removed by surgery (unresectable) and whose tumor has a mutation in a gene called BRAF. Encorafenib is in a class of medications called kinase inhibitors. It is used in patients whose cancer has a certain mutation (change) in the BRAF gene. It works by blocking the action of mutated BRAF that signals cancer cells to multiply. This helps to stop or slow the spread of cancer cells. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of cancer cells. This may help keep cancer cells from growing. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving nivolumab in combination with encorafenib and cetuximab may be more effective than encorafenib and cetuximab alone at stopping tumor growth and spreading in patients with metastatic or unresectable BRAF-mutant colorectal cancer.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you are taking certain HIV medications or if you have conditions requiring high doses of corticosteroids. It's best to discuss your current medications with the trial team to see if they might interfere with the study.

What data supports the effectiveness of the drug combination Nivolumab and Cetuximab for colorectal cancer?

Cetuximab, when used with other drugs like FOLFIRI, has been shown to improve survival and response rates in patients with a specific type of colorectal cancer. This suggests that Cetuximab can be effective in treating colorectal cancer, especially when combined with other treatments. ^{1 2 3 4 5}

Is the combination of Nivolumab and Cetuximab safe for treating colorectal cancer?

Cetuximab, used in treating metastatic colorectal cancer, has been associated with side effects like acne-like rash and nail infections in patients. This suggests that while it can be effective, it may also cause some skin-related side effects. ^{1 2 3 4 6}

How is the drug Nivolumab + Standard Treatment for Colorectal Cancer different from other treatments?

This treatment combines nivolumab, an immune checkpoint inhibitor, with standard drugs like cetuximab and encorafenib, which target specific mutations in colorectal cancer cells. This combination is unique because it targets both the immune system and specific cancer cell mutations, potentially improving outcomes for patients with certain genetic profiles. ^{1 2 7 8 9}

Research Team

Van K Morris

Principal Investigator

SWOG Cancer Research Network

Eligibility Criteria

This trial is for adults with metastatic or unresectable colorectal cancer that has a BRAF mutation. They should have had one or two prior chemotherapy treatments, no severe heart conditions, and be able to swallow pills. Excluded are those with recent heart issues, uncontrolled hypertension, active infections like HIV, certain immune diseases, or who've had specific past treatments like anti-EGFR therapies.

Inclusion Criteria

I have chronic hepatitis B but it's under control with medication.

My scans show cancer that cannot be removed or has spread.

Participants must be informed of the investigational nature of the study and provide informed consent

Exclusion Criteria

Participants must not be pregnant or nursing and must agree to use effective contraception

I have not had any major heart problems recently.

Participants must not be receiving any other investigational agents

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive encorafenib and cetuximab, with or without nivolumab, in 28-day cycles until disease progression or unacceptable toxicity

Variable, based on disease progression

Visits on days 1 and 15 of each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Treatment Details

Interventions

• Cetuximab
• Encorafenib
• Nivolumab

Trial Overview The study tests if adding Nivolumab (an immunotherapy drug) to the standard treatment of Encorafenib and Cetuximab improves outcomes in patients. It's a phase II trial aiming to see if this combination better shrinks tumors compared to the usual treatment alone.

Participant Groups

Group I: Arm I (encorafenib, cetuximab, nivolumab) Experimental Treatment 3 Interventions

Patients receive encorafenib PO QD on days 1-28, cetuximab IV on days 1 and 15, and nivolumab IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: Arm II (encorafenib, cetuximab) Active Control 2 Interventions

Patients receive encorafenib PO QD on days 1-28 and cetuximab IV on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

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 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 is a monoclonal antibody that targets the epidermal growth factor receptor, which plays a crucial role in the growth of various cancers.

It received accelerated approval from the US FDA in February 2004 for treating metastatic colorectal cancer based on positive tumor response rates observed in Phase II clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab. Goldberg, RM.[2020]

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]

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]

Cetuximab, an EGFR-inhibiting antibody used for treating certain cancers, is generally considered safe and well-tolerated, but this case highlights the potential for severe complications following its use, particularly in complex surgical situations.

The patient experienced a rare and fatal combination of complications after surgery, raising concerns about the safety of cetuximab in the context of surgical procedures, and emphasizing the need for careful monitoring and documentation of adverse effects in clinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complications after oesophagectomy with possible contribution of neoadjuvant therapy including an EGFR-antibody to a fatal outcome. Knauer, M., Haid, A., Ammann, K., et al.[2021]

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]

References

1. New Zealand 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. [2021]

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

Economic Analysis of First-Line Treatment with Cetuximab or Panitumumab for RAS Wild-Type Metastatic Colorectal Cancer in England. [2021]

3. England pubmed.ncbi.nlm.nih.gov

A Japanese post-marketing surveillance of cetuximab (Erbitux®) in patients with metastatic colorectal cancer. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Cetuximab. [2020]

5. England pubmed.ncbi.nlm.nih.gov

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

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

[The efficacy of cetuximab for metastatic colorectal cancer]. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Complications after oesophagectomy with possible contribution of neoadjuvant therapy including an EGFR-antibody to a fatal outcome. [2021]

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

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

9. France pubmed.ncbi.nlm.nih.gov

[EGF receptors in colorectal cancers]. [2018]