Immunotherapy + Cetuximab for Colon Cancer

Overseen By Maria Morelli

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Antibiotics, Immunosuppressants, Vaccines, others

Disqualifiers: Autoimmune disease, Transplantation, HIV, others

Stay on Your Current Meds You can continue your current medications while participating

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment that combines immunotherapy with the drug cetuximab to target residual cancer cells in individuals with colon cancer. Researchers aim to evaluate the treatment's effectiveness in patients who have cancer DNA in their bloodstream after completing standard treatments, despite showing no visible signs of cancer. It suits those with high-risk stage II or III colorectal cancer or treated stage IV cancer who meet specific criteria. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on certain treatments like systemic immunosuppressive medications, you may need to stop them at least 2 weeks before starting the study treatment. It's best to discuss your specific medications with the study team.

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

Previous studies have used cetuximab to treat colorectal cancer, and patients generally tolerate it well. Common side effects include mild skin rash and low magnesium levels, while serious side effects are rare but possible.

For the immunotherapy treatment CB-NK-TGF-βR2-/NR3C1, limited safety information is available. This trial is a Phase 1 study, focusing on understanding the treatment's safety and determining the right dose.

Cyclophosphamide and fludarabine phosphate are also part of this trial. These drugs, often used in cancer treatments, can cause side effects like low blood cell counts and nausea, which are generally manageable.

The safety of the combination treatment is still under study. Researchers will closely monitor participants to ensure their well-being throughout the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for colon cancer, which often involve chemotherapy and targeted therapies like bevacizumab and oxaliplatin, the combination of immunotherapy and cetuximab in this trial presents a novel approach. Researchers are excited about this treatment because it leverages the immune system by using CB-NK-TGF-βR2-/NR3C1, which is engineered to boost natural killer cell activity against cancer cells. Additionally, cetuximab, an existing targeted therapy, is combined with this innovative immunotherapy to potentially enhance its effectiveness. This combination could offer a more powerful and precise method of attacking cancer cells, potentially improving outcomes for patients with high-risk colorectal cancer.

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

Research shows that cetuximab, a treatment in this trial, can extend the lives of people with advanced colorectal cancer when combined with chemotherapy. Studies have found that cetuximab treatments significantly improve survival and effectively shrink tumors, with about 57% of patients experiencing a noticeable reduction in tumor size compared to those on other treatments. Meanwhile, the trial also studies CB-NK treatments, which involve a type of immune cell. Evidence suggests these cells can be engineered to target specific cancer traits and improve survival in colorectal cancer cases. In summary, both cetuximab and CB-NK cells, as separate treatment options in this trial, show promise in treating colon cancer by reducing tumor size and potentially increasing survival rates. ^{6 7 8 9 10}

Who Is on the Research Team?

Maria Morelli

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults with high-risk stage II or III colorectal cancer who've finished standard treatment and show no relapse but have ctDNA in their blood, or those with resected stage IV treated with curative intent. Participants must be healthy enough for the trial, not pregnant, without severe allergies to certain antibodies or components of the therapy, free from other cancers within 5 years, and not recently treated with similar drugs.

Inclusion Criteria

Has signed the Informed Consent Form

I had surgery for stage IV colorectal cancer, finished all treatments, have no visible cancer left, but still have cancer DNA in my blood.

I am fully active or can carry out light work.

Exclusion Criteria

Is pregnant or breastfeeding, or intends to become pregnant during the study

I have not taken any antibiotics by mouth or IV in the last 2 weeks.

Received treatment with an investigational therapy within 28 days prior to initiation of study treatment

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive CB-NK cell infusion in combination with cetuximab

6 weeks

Follow-up

Participants are monitored for ctDNA clearance and safety after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• CB-NK-TGF-βR2-/NR3C1
• Cetuximab
• Cyclophosphamide
• Fludarabine phosphate

Trial Overview The study tests a combination of immunotherapy using CB-NK cells pre-activated and expanded ex vivo along with cetuximab against minimal residual disease in colon cancer patients. It aims to see if this can target remaining cancer indicated by circulating tumor DNA (ctDNA) after primary treatment.

How Is the Trial Designed?

Group I: Cetuximab Experimental Treatment 4 Interventions

given to patients with high-risk colorectal cancer

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

In a review of clinical trials for colorectal cancer, 76.9% of studies on cetuximab reported dermatologic adverse drug reactions (dADRs), with 50% showing a positive correlation between these reactions and patient survival, indicating that dADRs may be relevant for treatment outcomes.

In contrast, only 42.9% of studies on panitumumab reported dADRs, highlighting significant variability in reporting practices, which limits the ability to assess patient risk and compare the safety profiles of these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Completeness in the reporting of dermatologic adverse drug reactions associated with monoclonal antibody epidermal growth factor receptor inhibitors in phase II and III colorectal cancer clinical trials. Bauer, KA., Hammerman, S., Rapoport, B., et al.[2018]

In a study of 57 patients with KRAS wild-type metastatic colorectal cancer, those with the EGFR CA repeat genotype of 36 or more showed a trend towards longer overall survival when treated with cetuximab and FOLFIRI, suggesting a potential genetic influence on treatment outcomes.

The presence of specific FcγR haplotypes (131H and 158V alleles) was linked to a lower response rate to cetuximab, indicating that genetic variations may affect the efficacy of this treatment in mCRC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FcγR and EGFR polymorphisms as predictive markers of cetuximab efficacy in metastatic colorectal cancer. Inoue, Y., Hazama, S., Iwamoto, S., et al.[2021]

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 is a chimeric monoclonal antibody that targets the epidermal growth-factor receptor (EGFR) and has been clinically approved in Europe for treating metastatic colorectal cancer and locally advanced head and neck cancer since 2004 and 2006, respectively.

The review discusses cetuximab's established role in colorectal cancer treatment, ongoing studies, and future challenges, highlighting its significance as the leading anti-EGFR monoclonal antibody in clinical evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab: appraisal of a novel drug against colorectal cancer. Hildebrandt, B., le Coutre, P., Nicolaou, A., et al.[2019]

Cetuximab, a monoclonal antibody targeting EGFR, showed a tumor growth control rate of 38% and a mean overall survival of 49.4 weeks in 24 patients with chemotherapy-refractory metastatic colorectal cancer, indicating its efficacy as a salvage therapy.

The treatment was associated with manageable side effects, the most common being skin reactions (67% reported acne), and other adverse effects included hypocalcemia (50%) and stomatitis (20%), suggesting that while cetuximab is effective, monitoring for these side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab as salvage monotherapy in chemotherapy-refractory metastatic colorectal cancer: A single-center report. Mekata, E., Endo, Y., Sonoda, H., et al.[2021]

Cetuximab is an effective monoclonal antibody that targets the epidermal growth factor receptor, which is linked to poor outcomes in solid tumors, by blocking its activation and associated oncogenic processes.

While cetuximab can cause infusion reactions and skin-related side effects, its overall safety profile is favorable compared to traditional chemotherapy, and these side effects are generally manageable with appropriate treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab: adverse event profile and recommendations for toxicity management. Thomas, M.[2020]

Cetuximab is an effective monoclonal antibody that targets the epidermal growth factor receptor, showing significant clinical efficacy in treating colorectal cancer (CRC) either alone or in combination with chemotherapy.

The combination of cetuximab with chemotherapy is well tolerated, with minimal overlapping toxicities, making it a crucial treatment option for patients with metastatic CRC who do not respond to traditional chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergy between cetuximab and chemotherapy in tumors of the gastrointestinal tract. Mahtani, RL., Macdonald, JS.[2022]

The combination of anti-EGFR antibody Erbitux (cetuximab) and anti-VEGFR2 antibody DC101 demonstrated significant antitumor synergy in preclinical models of pancreatic and colon cancer, with a combination index indicating strong interaction (CI = 0.1, P < 0.01).

This synergistic effect is likely due to overlapping impacts on tumor cell proliferation and vascularization, with VEGF production and hypoxia-inducible factor 1alpha serving as potential molecular links between the two pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergistic antitumor effects of combined epidermal growth factor receptor and vascular endothelial growth factor receptor-2 targeted therapy. Tonra, JR., Deevi, DS., Corcoran, E., et al.[2018]

The CIFRA study is investigating the effectiveness of cetuximab combined with irinotecan and fluorouracil in patients with metastatic colorectal cancer who have a specific genetic profile (FcγRIIIa V/V), which may enhance the drug's action through a mechanism called Antibody-Dependent Cell-mediated Cytotoxicity (ADCC).

This phase II trial aims to determine if patients with the FcγRIIIa V/V genotype have a higher response rate to cetuximab, potentially improving treatment outcomes, while also assessing safety and survival metrics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab, irinotecan and fluorouracile in fiRst-line treatment of immunologically-selected advanced colorectal cancer patients: the CIFRA study protocol. Ottaiano, A., Scala, S., Normanno, N., et al.[2020]

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]

Citations

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Regulation of transforming growth factor-β signaling as a ... Several recent studies have reported that activation of TGF-β signaling is related to drug resistance in CRC. Because the mechanisms of drug resistance are ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04991870

NCT04991870 | Phase I CB-NK-TGF-ßR2-/NR3C1- in rGBM This phase I trial is to find out the best dose, possible benefits and/or side effects of engineered natural killer (NK) cells containing deleted TGF-betaR2 ...

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Regulation of transforming growth factor-β signaling as a ... While TGF-β-induced extracellular matrix production promotes tumor development, the inhibitory response to TGF suppresses tumor formation. Thus, ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9323201/

NK Cell-Based Immunotherapy in Colorectal Cancer - PMC Based on these clinical data correlating NK cell infiltration with better survival in CRC patients, it is conceivable that novel immune-mediated therapies aimed ...

5. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2021-00598

Engineered NK Cells Containing Deleted TGF-BetaR2 and ... This phase I trial is to find out the best dose, possible benefits and/or side effects of engineered natural killer (NK) cells containing deleted TGF-betaR2 ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2019/125084s273lbl.pdf

ERBITUX (cetuximab) - accessdata.fda.gov The data described below reflect exposure to ERBITUX in 242 patients with K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer (mCRC) [see Warnings ...

7. erbitux.lilly.com erbitux.lilly.com/hcp/mcrc

Metastatic Colorectal Cancer | mCRC | HCP - Erbitux - Eli Lilly ERBITUX provides approximately 22% higher exposure compared to the cetuximab product used in CRYSTAL; however, the safety data from CRYSTAL is consistent in ...

8. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK459293/

Cetuximab - StatPearls - NCBI Bookshelf - NIH Cetuximab is an epidermal growth factor receptor (EGFR) inhibitor with the following FDA-approved indications: colorectal cancer, metastatic, KRAS wild-type ( ...

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Cetuximab for the Treatment of Colorectal Cancer The collective data suggest that cetuximab can benefit patients with advanced colorectal cancer, whether their disease is resistant or sensitive to chemotherapy ...

10. medsafe.govt.nz medsafe.govt.nz/profs/datasheet/e/Erbituxinf.pdf

Erbitux Data Sheet Version: A017-0124 Page 1 of 22 ... Colorectal Cancer Patients with RAS Mutated Tumours. Cetuximab should not be used in the treatment of colorectal cancer patients whose tumours have RAS ...