Utomilumab + Cetuximab + Irinotecan for Colorectal Cancer

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CYP3A4 inhibitors/inducers

Disqualifiers: Symptomatic brain metastases, Autoimmune disorders, Active infections, Unstable medical conditions, others

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

Compensation: Varies

Number of Visits: 1

Duration: Up to 4 years

42 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the best dose and side effects of irinotecan hydrochloride when given with utomilumab and cetuximab in treating patients with colorectal cancer that has spread to other places in the body (metastatic). Monoclonal antibodies, such as utomilumab and cetuximab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving utomilumab, cetuximab, and irinotecan hydrochloride may work better in treating patients with 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, but it does exclude those taking strong inhibitors or inducers of CYP3A4. It's best to discuss your specific medications with the trial team.

Is the combination of Utomilumab, Cetuximab, and Irinotecan generally safe for humans?

The combination of Cetuximab and Irinotecan has been studied in patients with advanced colorectal cancer, showing some side effects like skin reactions, diarrhea, and fatigue, but severe side effects were rare. No allergic reactions were reported, and the treatment was generally well-tolerated in heavily pretreated patients. ^{1 2 3 4 5}

What makes the drug combination of Utomilumab, Cetuximab, and Irinotecan unique for colorectal cancer?

The combination of Utomilumab, Cetuximab, and Irinotecan is unique because it includes Utomilumab, an immune-boosting drug, alongside Cetuximab and Irinotecan, which are already known to be effective in treating advanced colorectal cancer. This combination aims to enhance the body's immune response while targeting cancer cells, potentially offering a novel approach for patients who have not responded to other treatments. ^{1 6 7 8 9}

Research Team

David Hong, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with metastatic colorectal cancer who've had at least one line of chemotherapy. They must have known RAS tumor status, be willing to use two contraception methods if applicable, and not be pregnant or breastfeeding. Exclusions include brain metastases requiring steroids, recent major surgery or radiation therapy, autoimmune disorders affecting the immune system, serious infections like hepatitis B/C or HIV/AIDS, unstable medical conditions in the past 6 months.

Inclusion Criteria

Absolute neutrophil count (ANC) >= 1.0 x 10^9/L (1,000/uL)

Platelet count >= 75 x 10^9/L (75000/L)

Hemoglobin >= 8.0 g/dL (>= 5.0 mmol/L)

Exclusion Criteria

You have certain autoimmune disorders or conditions that weaken your immune system, except if you have mild psoriasis that is under control or mild autoimmune thyroiditis that is managed with medication.

Patients with known symptomatic brain metastases requiring steroids. Patients with previously diagnosed brain metastases are eligible if they are asymptomatic or have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to the start of study medication, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable

Patient has had any treatment specific for tumor control within 3 weeks of dosing, or for investigational drugs and cytotoxic agents, within 5 half-lives or 3 weeks, whichever is shorter

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive irinotecan hydrochloride IV over 90 minutes and cetuximab IV over 1-2 hours on days 1 and 15, and utomilumab IV over 1 hour on day 2. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Up to 4 years

Visits on days 1, 2, and 15 of each 28-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 3 months

Treatment Details

Interventions

• Cetuximab
• Irinotecan Hydrochloride
• Utomilumab

Trial Overview The trial tests how well patients respond to a combination of utomilumab and cetuximab with irinotecan hydrochloride chemotherapy. It aims to find the best dose while assessing side effects. Utomilumab and cetuximab are monoclonal antibodies that may prevent cancer growth; irinotecan hydrochloride is a chemo drug that kills or stops cancer cells from dividing.

Participant Groups

Group I: Treatment (irinotecan hydrochloride, cetuximab, utomilumab) Experimental Treatment 4 Interventions

Patients receive irinotecan hydrochloride IV over 90 minutes and cetuximab IV over 1-2 hours on days 1 and 15, and utomilumab IV over 1 hour on day 2. 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?

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

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 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, 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]

Irinotecan has shown significant activity against advanced colorectal cancer when combined with traditional chemotherapy agents like fluorouracil, leading to clinical responses including complete remissions in patients.

The combination therapies have acceptable toxicity profiles, with neutropenia and delayed diarrhea being the most common side effects, indicating that irinotecan could be a safe option for treatment, although further large-scale phase III studies are needed to confirm its benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

European experience with irinotecan plus fluorouracil/folinic acid or mitomycin. Khayat, D., Gil-Delgado, M., Antoine, EC., et al.[2018]

The combination of fluorouracil (5-FU)/leucovorin and irinotecan (CPT-11) has significantly improved response rates and survival times for patients with metastatic colorectal cancer, making it a recommended first-line treatment.

Ongoing randomized phase III trials in Europe are investigating the efficacy of this combination as adjuvant chemotherapy for patients with stage II or III colorectal cancer, aiming to enhance cure rates in those with resected, locally advanced, nonmetastatic disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on European adjuvant trials with irinotecan for colorectal cancer. Douillard, JY., Barbarot, V., Bennouna, J.[2018]

Capecitabine, an oral chemotherapy drug, is at least as effective as traditional 5-FU plus leucovorin regimens for metastatic colorectal cancer (mCRC) and has a favorable safety profile.

Combining cetuximab with chemotherapy (like FOLFIRI) has been shown to improve progression-free survival and response rates in mCRC patients, with a recent phase III trial confirming these benefits over chemotherapy alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab plus XELIRI or XELOX for first-line therapy of metastatic colorectal cancer. Moosmann, N., Heinemann, V.[2018]

References

1. England 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. [2018]

2. England pubmed.ncbi.nlm.nih.gov

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

3. France pubmed.ncbi.nlm.nih.gov

Cetuximab efficacy in patients treated routinely in university hospitals. [2020]

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

Cetuximab and irinotecan as third-line therapy in advanced colorectal cancer patients: a single centre phase II trial. [2022]

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

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

6. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Cetuximab/irinotecan-chemotherapy in KRAS wild-type pretreated metastatic colorectal cancer: a pooled analysis and review of literature. [2019]

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

European experience with irinotecan plus fluorouracil/folinic acid or mitomycin. [2018]

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

Update on European adjuvant trials with irinotecan for colorectal cancer. [2018]

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

Cetuximab plus XELIRI or XELOX for first-line therapy of metastatic colorectal cancer. [2018]