What side effects are associated with this type of intervention?

Common treatments for colorectal cancer include RAF/MEK inhibitors like VS-6766 and EGFR inhibitors like Cetuximab. The known side effects of Cetuximab include rash, febrile neutropenia, diarrhea, and infusion-related reactions. RAF/MEK inhibitors can cause side effects such as skin rash, diarrhea, fatigue, and elevated liver enzymes. Additionally, combining these treatments may increase the incidence of these side effects.

What prior FDA approvals exist?

Cetuximab, an EGFR inhibitor, has been FDA-approved for the treatment of metastatic colorectal cancer, especially in patients with KRAS wild-type tumors. Panitumumab, another EGFR inhibitor, is also approved for similar indications. While MEK inhibitors like selumetinib have been investigated, they have not demonstrated significant benefit in colorectal cancer, making EGFR inhibitors the primary FDA-approved treatments in this context.

What other types of research exist?

Promising novel alternatives for colorectal cancer treatment in 2024 include: 1) MEK inhibitors like AS703026 and AZD6244, especially for KRAS-mutated colorectal cancer resistant to EGFR monoclonal antibody therapy. 2) Combination therapies involving immune checkpoint inhibitors with other immune-modulating agents, although further studies are needed. 3) Targeted agents such as BTK inhibitors (e.g., ibrutinib, acalabrutinib) and venetoclax-based therapies, particularly for patients with specific genetic profiles. These alternatives are based on recent clinical trials and ongoing research.

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Monoclonal Antibodies

VS-6766 + Cetuximab for Colorectal Cancer

Q: What is the mechanism of action of this treatment?

RAF/MEK inhibitors, such as VS-6766, target the RAF/MEK/ERK signaling pathway, which is often overactive in colorectal cancer cells, leading to uncontrolled growth. By inhibiting this pathway, these drugs can reduce tumor proliferation. Cetuximab, an EGFR inhibitor, binds to the epidermal growth factor receptor on cancer cells, blocking signals that promote cell division and survival. This can slow or stop cancer growth. These targeted therapies are important for colorectal cancer patients as they offer more precise treatment options, potentially improving outcomes and reducing side effects compared to traditional chemotherapy.

Phase 1 & 2

Recruiting

Led By Ardaman S. Shergill, MD

Research Sponsored by University of Chicago

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Participants should not be receiving any other study agents concurrently with the study drugs.

For participants with a history of chronic hepatitis B virus infection, the hepatitis B virus (HBV) viral load must be undetectable on suppressive therapy, if indicated.

Must not have

- Patient must not have presence of neurosensory retinal detachment, or neovascular macular degeneration on screening ophthalmologic exam.

Participants with uncontrolled intercurrent illness including, but not limited to: ongoing or active infection requiring systemic treatment, symptomatic congestive heart failure, cardiac arrhythmia, psychiatric illness/social situations that would limit compliance with study requirements, hypertension, defined as systolic blood pressure > 160 mmHg despite medical management, myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting < 12 months prior to screening.

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 2 years

Awards & highlights

All Individual Drugs Already Approved

No Placebo-Only Group

Summary

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.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

Potential side effects may include allergic reactions similar to those from compounds like cetuximab (e.g., skin reactions), heart issues such as uncontrolled arrhythmias or cardiac insufficiency if predisposed, high blood pressure management problems, and gastrointestinal disturbances.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am not taking any other experimental drugs.

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My hepatitis B virus load is undetectable with treatment.

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I am 18 years old or older.

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My colorectal cancer has spread, cannot be cured, and has a KRAS mutation.

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I had hepatitis C but am cured, or I'm being treated with no detectable virus.

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I am fully active or can carry out light work.

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My colorectal cancer has spread and has a KRAS mutation, with no curable treatment options.

Select...

I haven't had treatments targeting specific cancer growth factors.

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I haven't had chemotherapy, radiotherapy, or major surgery in the last 2 weeks.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

Select...

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

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

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I do not have eye conditions that could lead to retinal vein occlusion.

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I do not have serious heart issues or very high blood pressure.

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I have a muscle disorder that increases my CPK levels.

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I do not have serious eye diseases that could risk my vision during the trial.

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I do not have glaucoma, retinal vein occlusion, uncontrolled high blood pressure, or uncontrolled diabetes.

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I do not have active gastrointestinal issues like ulcers or uncontrolled vomiting.

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I do not have severe nerve damage.

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I will not consume grapefruit, St. John's Wort, or certain medications and supplements while on VS-6766.

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I have had rhabdomyolysis in the last 3 months.

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I do not have a history of retinal degenerative disease.

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I have a history of heart rhythm issues related to QT interval.

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I do not have a history of serious eye surface conditions.

Select...

I am not taking strong CYP3A4 inhibitors, or can stop them for 14 days before the study.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 2 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~2 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and 2 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Phase 2 Primary Objective: Objective Response Rate of Participants Who Take Phase I /MTD Dose of VS-6766 combined with Cetuximab

Phase I Primary Objective: Maximum Tolerated Dose (MTD) of VS-6766 combined with Cetuximab

Secondary study objectives

Phase 1 Objective: Frequency/ Type of Dose-Limiting Toxicities (Serious Side Effects) Reported Among Participants Taking VS-6766 and Cetuximab

Phase 1 Objective: The Number of Dose-Limiting Toxicities (Serious Side Effects) Reported Among Participants Taking VS-6766 and Cetuximab

Phase 2 Objective: Duration of Response

+6 more

Side effects data

From 2012 Phase 3 trial • 73 Patients • NCT01177956

43%

Leucopenia

43%

Weight Decreased

40%

Nausea

35%

Rash

34%

Hypomagnesaemia

32%

Hypokalemia

31%

Constipation

28%

Vomiting

28%

Neutropenia

26%

Decreased Appetite

22%

Pyrexia

19%

Hyponatremia

19%

Acne

19%

Hemoglobin Decreased

18%

Stomatitis

18%

Diarrhea

15%

Pruritus

15%

Fatigue

13%

Mucosal Inflammation

13%

Neutrophil Count Decreased

12%

Mouth Ulceration

10%

Insomnia

10%

Thrombocytopenia

10%

Asthenia

Dizziness

Cough

White Blood Cell Count Decreased

Hypocalcaemia

Dermatitis Acneiform

Hypochloremia

Abdominal Pain Upper

Paronychia

Aspartate Aminotransferase Increased

Weight Increased

Dyspnoea

Neck pain

Oral Pain

Headache

Anaphylactic reaction

Mouth hemorrhage

Staphylococcal skin infection

Tumor hemorrhage

Electrolyte imbalance

Microcytic anemia

Myocardial infarction

Pneumonitis

Pneumonia

Pulmonary embolism

Respiratory alkalosis

Toxic encephalopathy

Venous thrombosis

100%

80%

60%

40%

20%

Study treatment Arm

Cetuximab + Cisplatin + 5-FU : Treatment Emergent Phase

Cetuximab + Cisplatin + 5-FU : Late Phase

Awards & Highlights

All Individual Drugs Already Approved

Therapies where all constituent drugs have already been approved are likely to have better-understood side effect profiles.

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

5Treatment groups

Experimental Treatment

Group I: Phase 2 (Efficacy Arm/ Expansion Cohort)Experimental Treatment3 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 2Experimental Treatment2 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 1Experimental Treatment2 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 Treatment2 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 Treatment2 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.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Cetuximab

FDA approved

0 / 24Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

RAF/MEK inhibitors, such as VS-6766, target the RAF/MEK/ERK signaling pathway, which is often overactive in colorectal cancer cells, leading to uncontrolled growth. By inhibiting this pathway, these drugs can reduce tumor proliferation. Cetuximab, an EGFR inhibitor, binds to the epidermal growth factor receptor on cancer cells, blocking signals that promote cell division and survival. This can slow or stop cancer growth. These targeted therapies are important for colorectal cancer patients as they offer more precise treatment options, potentially improving outcomes and reducing side effects compared to traditional chemotherapy.