Trastuzumab + Pertuzumab vs. Cetuximab + Irinotecan for Colorectal Cancer

Recruiting at 798 trial locations

Overseen By Christy Klepetko

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Southwest Oncology Group

Must not be taking: Cetuximab, Panitumumab, EGFR inhibitors

Disqualifiers: Diabetes, Hypertension, Heart failure, 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: 22

Duration: Up to 3 years

240 Participants Needed

Trial Summary

What is the purpose of this trial?

This randomized phase II trial studies how well trastuzumab and pertuzumab work compared to cetuximab and irinotecan hydrochloride in treating patients with HER2/neu amplified colorectal cancer that has spread from where it started to other places in the body and cannot be removed by surgery. Monoclonal antibodies, such as trastuzumab and pertuzumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as cetuximab and 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 trastuzumab and pertuzumab may work better compared to cetuximab and irinotecan hydrochloride in treating patients with colorectal cancer.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, you must not be planning treatment with other systemic anti-cancer agents that are not part of the study.

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

Research shows that the combination of Cetuximab and Irinotecan is effective in treating patients with advanced colorectal cancer, especially those who have not responded to previous treatments. Studies have demonstrated improved progression-free survival and overall survival rates when Cetuximab is added to Irinotecan, particularly in patients with specific genetic markers. ^{1 2 3 4 5}

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

The combination of Cetuximab and Irinotecan has been studied for safety in patients with advanced colorectal cancer. Common side effects include skin reactions, diarrhea, nausea, vomiting, and fatigue, but severe side effects are rare. Safety has been confirmed in various studies, including post-marketing surveillance and community practice settings. ^{1 6 7 8 9}

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

This drug combination is unique because it combines targeted therapies (Trastuzumab and Pertuzumab) typically used for breast cancer with Cetuximab and Irinotecan, which are used for colorectal cancer, potentially offering a novel approach for patients who have not responded to standard treatments. ^{1 4 9 10 11}

Research Team

Kanwal Raghav

Principal Investigator

SWOG Cancer Research Network

Eligibility Criteria

This trial is for adults with HER2/neu amplified colorectal cancer that's spread and can't be surgically removed. They must have had one prior chemotherapy, no severe reactions to the study drugs or similar treatments, no other cancers within two years (except certain skin cancers), and not be pregnant. Participants need a good performance status, adequate organ function, controlled brain metastases if present, and use effective contraception.

Inclusion Criteria

LVEF >= 50% or >= within normal limits for the institution

This is not actually a screening criterion, but a step in the clinical trial process where participants are randomly assigned to different treatment groups.

I've had a full physical exam and shared my medical history within the last 28 days.

Exclusion Criteria

I have received HER-2 targeted therapy for colorectal cancer.

You have had past or current conditions that make you more likely to have an allergic reaction.

My cancer has a specific mutation in the KRAS/NRAS or BRAF gene.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive either trastuzumab and pertuzumab or cetuximab and irinotecan hydrochloride. Courses repeat every 21 or 14 days respectively, in the absence of disease progression or unacceptable toxicity.

Up to 3 years

Every 14 or 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Every 8 weeks after treatment until progression

Crossover (optional)

Patients with documented disease progression may optionally crossover to receive trastuzumab and pertuzumab

Treatment Details

Interventions

• Cetuximab
• Irinotecan Hydrochloride
• Pertuzumab
• Trastuzumab

Trial Overview The trial compares two treatments: trastuzumab plus pertuzumab versus cetuximab with irinotecan hydrochloride in patients with advanced colorectal cancer. It aims to see which combination is more effective at stopping tumor growth by either killing cancer cells or preventing them from dividing and spreading.

Participant Groups

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

Patients receive cetuximab IV over 60-120 minutes and irinotecan hydrochloride IV over 90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients with documented disease progression may optionally crossover to Arm I.

Group II: Arm I (pertuzumab, trastuzumab) Experimental Treatment 4 Interventions

Patients receive pertuzumab IV over 30-60 minutes and trastuzumab IV over 30-120 minutes on day 1. Courses repeat every 21 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?

Southwest Oncology Group

Lead Sponsor

Trials

389

Recruited

260,000+

SWOG Cancer Research Network

Lead Sponsor

Trials

403

Recruited

267,000+

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 multicenter phase II study involving 79 Latin American patients with metastatic colorectal cancer (mCRC) who had previously failed irinotecan treatment, the combination of cetuximab and irinotecan showed an overall response rate of 27% and a disease control rate of 56%.

The treatment was found to be tolerable, with a median overall survival of 9.2 months and a safety profile consistent with previous studies, although 57% of patients experienced grade 3/4 adverse events, primarily skin-related issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab Plus irinotecan in pretreated metastatic colorectal cancer progressing on irinotecan: the LABEL study. Buzaid, AC., Mathias, Cde C., Perazzo, F., et al.[2018]

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]

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]

In a study of 1147 patients with metastatic colorectal cancer, using a combination of antihistamines and corticosteroids as premedication significantly reduced the incidence of infusion-related reactions (IRRs) from 25.6% to 9.6%.

Despite the reduction in IRRs with combined premedication, there was no significant difference in progression-free survival (PFS) or overall survival (OS) between patients receiving antihistamines with or without corticosteroids, indicating that while safety may improve, efficacy remains similar.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced incidence of infusion-related reactions in metastatic colorectal cancer during treatment with cetuximab plus irinotecan with combined corticosteroid and antihistamine premedication. Siena, S., Glynne-Jones, R., Adenis, A., et al.[2018]

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]

In a study of 56 colorectal cancer patients treated with cetuximab, smokers experienced fewer skin reactions compared to non-smokers, suggesting that smoking may alter the drug's effectiveness.

However, smokers also reported higher rates of anorexia, indicating that while smoking might reduce certain side effects, it could negatively impact overall treatment outcomes, highlighting the importance of quitting smoking during cetuximab therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab-induced skin reactions are suppressed by cigarette smoking in patients with advanced colorectal cancer. Kajizono, M., Saito, M., Maeda, M., et al.[2021]

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]

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

Cetuximab Plus irinotecan in pretreated metastatic colorectal cancer progressing on irinotecan: the LABEL study. [2018]

3. 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]

4. France pubmed.ncbi.nlm.nih.gov

Cetuximab: new drug. Metastatic colorectal cancer: an inappropriate evaluation. [2018]

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

Recent data with anti-epidermal growth factor receptor antibodies and irinotecan in colon cancer. [2019]

6. England pubmed.ncbi.nlm.nih.gov

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

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

Reduced incidence of infusion-related reactions in metastatic colorectal cancer during treatment with cetuximab plus irinotecan with combined corticosteroid and antihistamine premedication. [2018]

8. Japan pubmed.ncbi.nlm.nih.gov

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

9. Japan pubmed.ncbi.nlm.nih.gov

Cetuximab-induced skin reactions are suppressed by cigarette smoking in patients with advanced colorectal cancer. [2021]

10. Czech Republic pubmed.ncbi.nlm.nih.gov

[Cetuximab and irinotecan for the treatment of metastatic colorectal cancer--pilot results from Masaryk Memorial Cancer Institute]. [2018]

11. England pubmed.ncbi.nlm.nih.gov

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