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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose and understand the side effects of a new treatment combination for metastatic colorectal cancer. The treatment includes two monoclonal antibodies, Utomilumab and Cetuximab, and the chemotherapy drug Irinotecan Hydrochloride. Together, they work to stop cancer cells from growing and spreading. This trial is for patients whose colorectal cancer did not respond to at least one round of standard chemotherapy. For those with metastatic colorectal cancer and unsuccessful previous treatments, this trial may be suitable. As a Phase 1 trial, researchers focus on understanding how the treatment works in people, offering participants the chance to be among the first to receive this new treatment.

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

Research has shown that cetuximab and irinotecan, two treatments in this study, are generally well tolerated. In a study with 2,126 patients who had advanced colorectal cancer, cetuximab was well tolerated. Additionally, using cetuximab every two weeks with irinotecan is considered both effective and safe.

Utomilumab is another treatment in the study, but less information exists about its safety when combined with these other drugs. As this is an early phase trial, the main goal is to determine the best dose and monitor side effects. Therefore, the safety of using utomilumab with cetuximab and irinotecan remains under investigation.

This trial is crucial for understanding how well this combination is tolerated and what side effects might occur. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of utomilumab, cetuximab, and irinotecan hydrochloride for colorectal cancer because it targets the disease in a novel way. Unlike standard treatments that often focus solely on chemotherapy, this combination includes utomilumab, an immune-enhancing agent that can potentially boost the body's own defense systems to fight cancer more effectively. Furthermore, cetuximab is an antibody that specifically targets cancer cell growth signals, adding a precision element to the treatment. This multi-faceted approach could offer a more comprehensive attack on cancer cells, potentially improving outcomes compared to traditional therapies alone.

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

Studies have shown that using cetuximab and irinotecan together can extend the lives of patients with advanced colorectal cancer by 1.7 to 2.0 years, demonstrating the effectiveness of these drugs in controlling the disease. The treatment stopped cancer growth in 60% of patients. On average, cancer began to grow again after about 3.4 months, and patients lived for about 8 months overall. In this trial, participants will receive a combination of irinotecan, cetuximab, and utomilumab. Utomilumab, a drug that aids the immune system in fighting cancer, may enhance these outcomes. Combining these treatments could offer a more robust approach to managing advanced colorectal cancer. ^{1 3 4 6 7}

Who Is on the Research Team?

David Hong, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

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]

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]

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 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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03290937

Utomilumab, Cetuximab, and Irinotecan Hydrochloride in ... Giving utomilumab, cetuximab, and irinotecan hydrochloride may work better in treating patients with colorectal cancer. SECONDARY OBJECTIVES: I.

2. withpower.com withpower.com/trial/utomilumab-cetuximab-irinotecan-for-colorectal-cancer-edbf8

Utomilumab + Cetuximab + Irinotecan for Colorectal Cancer 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 ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2527794/

Biweekly cetuximab and irinotecan in advanced colorectal ... The disease control rate was 60%. The time to progression was 3.4 months and the overall survival was 8 months. The toxicity compared very ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03290937?term=Irinotecan&viewType=Table&rank=10

Utomilumab, Cetuximab, and Irinotecan Hydrochloride in ... An unfavorable change in the health of a participant, including abnormal laboratory findings, that happens during a clinical study or within a certain amount of ...

5. frontiersin.org frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1356708/full

The effective combination therapies with irinotecan for ... The FOLFOXIRI regimen showed promising outcomes with a PFS of 13.37 ± 9 months, an overall response rate of 79.4%, a significant decrease in the risk of early ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/20407241/

Cetuximab given every 2 weeks plus irinotecan is an active ... The progression-free rates confirm that cetuximab q2w in combination with irinotecan is an option, and is as active and safe as the standard weekly regimen.

7. esmoopen.com esmoopen.com/article/S2059-7029(21)00116-2/pdf

Strategies to tackle RAS-mutated metastatic colorectal cancer In this review, we discuss different therapeutic strategies tackling RAS mutations specifically in mCRC, focusing on those approaches which have ...