VS-6766 + Cetuximab for Colorectal Cancer

Overseen By Ardaman S. Shergill, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Chicago

Must not be taking: Lonsurf, Regorafenib, MEK inhibitors, others

Disqualifiers: Uncontrolled hypertension, Cardiac arrhythmia, others

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

Compensation: Varies

Number of Visits: Unknown

53 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug combination (VS-6766 and cetuximab) for patients with advanced colorectal cancer who have not responded to other treatments. The combination aims to stop cancer cells from growing and make it easier for the body to fight the cancer. Cetuximab has been used in various combinations for treating advanced colorectal cancer.

Do I need to stop taking my current medications to join the trial?

The trial protocol does not specify if you must stop all current medications, but you cannot take strong CYP3A4 inhibitors or inducers. If you are on these, you must stop them 14 days before starting the trial. Also, avoid grapefruit, grapefruit juice, and St. John's Wort during the trial.

What data supports the idea that VS-6766 + Cetuximab for Colorectal Cancer is an effective drug?

The available research shows that Cetuximab, when combined with other drugs like irinotecan, has been effective in treating advanced colorectal cancer. For example, in one study, patients who had already tried other treatments showed a 20% response rate and lived longer after receiving Cetuximab with irinotecan. Another study found that adding Cetuximab to a treatment plan improved survival and response rates compared to using other drugs alone. Although these studies don't specifically mention VS-6766, they suggest that Cetuximab can be an effective part of a treatment plan for colorectal cancer. ^{1 2 3 4 5}

What safety data is available for the treatment of VS-6766 and Cetuximab in colorectal cancer?

The safety data for Cetuximab (Erbitux) in colorectal cancer includes findings from various studies. A Japanese post-marketing surveillance study confirmed the safety of Cetuximab in practical use for metastatic colorectal cancer. Common side effects reported include acneiform rash and paronychia. In a study evaluating Cetuximab and irinotecan as third-line therapy, skin toxicity, diarrhea, nausea, vomiting, and fatigue were observed, with grade 3 toxicity being rare. The severity of skin toxicity was correlated with response and survival rates. Overall, Cetuximab has been shown to be effective with manageable toxicity in heavily pretreated patients. ^{1 2 3 6 7}

Is the drug Cetuximab a promising treatment for colorectal cancer?

Yes, Cetuximab is a promising drug for treating colorectal cancer. It has been shown to improve survival rates and response in patients with certain types of colorectal cancer, especially when combined with other treatments. It works by targeting specific cancer cell receptors, helping the immune system attack the cancer more effectively. ^{2 3 4 8 9}

Research Team

Ardaman Shergill, MD

Principal Investigator

University of Chicago Comprehensive Cancer Center

Eligibility Criteria

Adults with advanced colorectal cancer that has worsened after standard treatments or those who can't tolerate them. Participants must have specific KRAS mutations, not be pregnant or breastfeeding, agree to use contraception, and have no recent major surgeries or other cancer treatments. They should also not be on conflicting medications and must meet health criteria including organ function tests.

Inclusion Criteria

You must have a detectable tumor that can be measured using specific medical criteria.

I am not taking any other experimental drugs.

I am 18 years old or older.

Exclusion Criteria

I don't have specific eye conditions like retinal detachment or macular degeneration.

You have had allergic reactions to drugs or biological substances similar to cetuximab, or have a history of red meat allergy or tick bites.

I do not have any severe illnesses that are not under control.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Dose-Finding

Participants receive VS-6766 and cetuximab in 28-day cycles to determine the maximum tolerated dose

12 cycles (approximately 12 months)

Bi-weekly visits for cetuximab administration

Phase 2 Efficacy

Participants receive the best tolerated dose of VS-6766 and cetuximab to assess efficacy

Up to 12 months

Regular visits for monitoring and pill diary checks

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Treatment Details

Interventions

• Cetuximab
• VS-6766

Trial Overview The trial is testing the safety of combining VS-6766, a new drug, with cetuximab in patients with advanced colorectal cancer. It aims to see how well these drugs work together for up to 24 months of participation. Patients will keep a pill diary as part of the study.

Participant Groups

Group I: Phase 2 (Efficacy Arm/ Expansion Cohort) Experimental Treatment 3 Interventions

Participants in this arm will help test the efficacy of the VS-6766 and cetuximab dose established in phase 1 of the study. Participants will take the same two drugs ( VS-6766 and cetuximab) at the best tolerated dose that was found during the first phase of the study. Participants in this group will also keep a pill diary. This helps you keep track of when you take your pills. The study team at your doctor's office will show you how to use this diary. Each time you visit the clinic, you must bring the pill diary, any remaining pills, and the pill bottle.

Group II: Phase 1(Dose-Finding Arm): Group 4 - Lower Dose Level 2 Experimental Treatment 2 Interventions

Participants in this group will received the second lowest dose of the VS6766 and cetuximab regimen. Inclusion in this group is optional and based on whether the participant reports serious side effects in response to a higher dose of the regimen. If participants are included in this group, they will receive: * VS-6766 (2.4mg) orally twice a week * cetuximab (300mg) via intravenous (IV) needle in vein every 2 weeks

Group III: Phase 1(Dose-Finding Arm): Group 3 - Lower Dose Level 1 Experimental Treatment 2 Interventions

Participants in this group will received a lower dose of the VS6766 and cetuximab regimen. Inclusion in this group is optional and based on whether the participant reports serious side effects in response to a higher dose of the regimen. If participants are included in this group, they will receive: * VS-6766 (2.4mg) orally twice a week * cetuximab (400mg) via intravenous (IV) needle in vein every 2 weeks

Group IV: Phase 1(Dose-Finding Arm): Group 2- Dose Level 2 (Second Highest Dose) Experimental Treatment 2 Interventions

This study will use two dose levels (a starting dose at level 1 and a second dose highest dose at level 2) of the VS-6766 and cetuximab regimen. If participants in group 1 don't experience severe negative side effects to the starting dose of the regimen, then more participants will be assigned to group 2 at a higher dose until the safest/ most tolerable dose is found. If participants show toxic side effects to the first pre-determined dose, the dose will be decreased to the next lower dose level. Participants in group 2 will receive the second highest dose of study drugs (below): * VS-6766 (3.4mg) orally twice a week * cetuximab (500mg) via intravenous (IV) needle in vein every 2 weeks During phase 1, VS-6766 and cetuximab will be given in 28-day "cycles" (a period of time when participants receive study drugs). Participants in this portion of the study will receive 12 cycles of VS-6766 and cetuximab.

Group V: Phase 1(Dose-Finding Arm): Group 1 - Dose Level 1 (Starting Dose) Experimental Treatment 2 Interventions

This study will use two dose levels (a starting dose at level 1 and a second dose highest dose at level 2) of the VS-6766 and cetuximab regimen. If participants in group 1 don't experience severe negative side effects to the starting dose of the regimen, then more participants will be assigned to group 2 at a higher dose until the safest/ most tolerable dose is found. If participants show toxic side effects to the first pre-determined dose, the dose will be decreased to the next lower dose level. Group 1/ Dose Level 1: Participants in group 0 will receive the starting dose of study drugs (below): * VS-6766 (2.4mg) orally twice a week * cetuximab (500mg) via intravenous (IV) needle in vein every 2 weeks During phase 1, VS-6766 and cetuximab will be given in 28-day "cycles" (a period of time when participants receive study drugs). Participants in this portion of the study will receive 12 cycles of VS-6766 and cetuximab.

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?

University of Chicago

Lead Sponsor

Trials

1,086

Recruited

844,000+

Verastem, Inc.

Industry Sponsor

Trials

42

Recruited

2,800+

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]

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]

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, 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 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 has demonstrated significant efficacy in treating metastatic colorectal cancer, achieving a partial response in 10.8% of patients receiving it alone and 22.9% when combined with irinotecan, based on a Phase III trial involving 329 patients.

The drug is generally well tolerated, with common side effects like acnelike rash and hypersensitivity reactions, but the lack of reliable predictive markers for patient selection remains a challenge for its clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer. Wong, SF.[2022]

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]

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. England pubmed.ncbi.nlm.nih.gov

Cetuximab, irinotecan and fluorouracile in fiRst-line treatment of immunologically-selected advanced colorectal cancer patients: the CIFRA study protocol. [2020]

4. 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]

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

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

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

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Cetuximab. [2020]

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

Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer. [2022]

9. Germany pubmed.ncbi.nlm.nih.gov

Cetuximab: appraisal of a novel drug against colorectal cancer. [2019]