Drug Combination for Advanced Colorectal Cancer

Overseen By Christine Parseghian, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: ERK1/2, MEK, BRAF inhibitors

Disqualifiers: Symptomatic brain metastasis, Cardiovascular diseases, Active infections, 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: Unknown

33 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a combination of three drugs—avutometinib, cetuximab, and defactinib—can control advanced colorectal cancer that cannot be surgically removed and has stopped responding to standard treatment. The trial aims to test the safety and optimal dose of this new combination. It seeks participants with advanced colorectal cancer that has spread and who have previously tried anti-EGFR therapy, such as cetuximab, without success. Those who have undergone prior treatment for this type of cancer and meet these criteria may be suitable candidates. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people, offering a chance to contribute to significant advancements in cancer therapy.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) of at least 21 days after the last chemotherapy dose and 7 days after the end of radiotherapy before starting the study. The protocol does not specify if you need to stop other medications, so it's best to discuss with the trial team.

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

Research has shown that the combination of the drugs avutometinib, cetuximab, and defactinib has been tested for safety in other studies. Avutometinib and cetuximab have been used together in patients with colorectal cancer to assess their safety and tolerability. Reports indicate that this combination is manageable, though it can have side effects like all treatments.

The FDA has already approved cetuximab for treating certain cancers, including colorectal cancer. Its safety profile is well-known, and it is generally well-tolerated, although some people may experience side effects.

Defactinib has been studied in various contexts, and research suggests it is well-tolerated at different doses. Studies have found that participants generally handle the treatment well without serious side effects.

In this trial, researchers are studying how these three drugs work together to determine the best dose of avutometinib when used with cetuximab and defactinib. The trial is in a phase where safety is a primary focus, so researchers are closely monitoring for any serious side effects to ensure participant safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Avutometinib, Cetuximab, and Defactinib for advanced colorectal cancer because it targets the cancer cells in a unique way. Most standard treatments, like chemotherapy, broadly attack rapidly dividing cells, but this combination specifically inhibits pathways that cancer cells rely on for growth and survival. Avutometinib, in particular, blocks the MAPK pathway, which is often overactive in colorectal cancer, potentially leading to more effective tumor control with fewer side effects. By targeting cancer at this molecular level, the treatment may offer new hope for patients who do not respond well to existing therapies.

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

Research shows that using the drugs avutometinib and defactinib together may help treat certain cancers. One study found that this combination caused tumors to shrink in 86% of patients. In this trial, participants may receive avutometinib with cetuximab to see if it can help those with advanced colorectal cancer. Cetuximab alone has been shown to help patients with metastatic colorectal cancer live longer. Meanwhile, when defactinib is combined with avutometinib, it demonstrated a 42.3% response rate and prevented some solid tumors from growing for about 20 months. These results suggest that these drugs together might help manage advanced colorectal cancer. ^{3 4 6 7 8}

Who Is on the Research Team?

Christine Parseghian

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with advanced colorectal cancer that can't be surgically removed and hasn't responded to anti-EGFR therapy. Participants should meet specific health criteria not detailed here.

Inclusion Criteria

Negative serum pregnancy test required for female participants of childbearing potential within 7 days prior to enrollment

Provision of signed Informed Consent prior to any screening procedures being performed

Willing and able to participate in the trial and comply with all trial requirements

Exclusion Criteria

Any other condition contraindicating participation in the clinical study

I haven't had cancer in the last 3 years, except for certain types.

I have had rhabdomyolysis in the past.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Run In

Participants receive varying doses of avutometinib to determine the recommended dose in combination with cetuximab and defactinib

8-12 weeks

Expansion

Participants receive the recommended dose of avutometinib in combination with cetuximab and defactinib

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Avutometinib
• Cetuximab
• Defactinib

Trial Overview The study tests avutometinib combined with defactinib and cetuximab to see if they can manage advanced colorectal cancer that's resistant to previous treatments.

How Is the Trial Designed?

Group I: Safety Run In Experimental Treatment 3 Interventions

If you are enrolled in the Safety Run In group, the dose of avutometinib you receive will depend on when you join this study. Up to 3 dose levels of avutometinib will be tested, and between 3-6 participants will be enrolled at each dose level. The first group of participants will receive the planned starting dose level of avutometinib. Then, if no intolerable side effects are seen, a second group of participants will be enrolled to receive a higher dose. If intolerable side effects are seen, the second group will receive a lower dose. One of these 3 doses will be selected as the recommended dose of avutometinib in combination with cetuximab and defactinib.

Group II: Expansion Experimental Treatment 3 Interventions

If you are enrolled in the Expansion, you will receive avutometinib at the recommended dose that was found in Safety Run In.

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

Cetuximab and panitumumab are effective treatments for patients with previously untreated RAS wild-type metastatic colorectal cancer, showing cost-effectiveness when combined with standard chemotherapy regimens (FOLFOX or FOLFIRI) compared to chemotherapy alone.

Both drugs meet the National Institute for Health and Care Excellence's end-of-life criteria and are recommended for use within the UK National Health Service, indicating their potential benefit for patients not eligible for liver resection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Economic Analysis of First-Line Treatment with Cetuximab or Panitumumab for RAS Wild-Type Metastatic Colorectal Cancer in England. Tikhonova, IA., Huxley, N., Snowsill, T., et al.[2021]

In a phase II trial involving 82 patients with advanced colorectal cancer, the combination of cetuximab and FOLFOX6 showed an overall response rate of 44.8%, indicating its efficacy as a first-line treatment.

Patients who developed skin toxicity while on the treatment had significantly longer median survival times (21.7 months) compared to those who did not experience this side effect, suggesting a potential correlation between skin reactions and treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II trial of FOLFOX6 and cetuximab in the first-line treatment of patients with metastatic colorectal cancer. Boccia, RV., Cosgriff, TM., Headley, DL., et al.[2016]

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]

Cetuximab, an EGFR-inhibiting antibody used for treating certain cancers, is generally considered safe and well-tolerated, but this case highlights the potential for severe complications following its use, particularly in complex surgical situations.

The patient experienced a rare and fatal combination of complications after surgery, raising concerns about the safety of cetuximab in the context of surgical procedures, and emphasizing the need for careful monitoring and documentation of adverse effects in clinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complications after oesophagectomy with possible contribution of neoadjuvant therapy including an EGFR-antibody to a fatal outcome. Knauer, M., Haid, A., Ammann, K., et al.[2021]

In the phase III CRYSTAL study, adding cetuximab to the FOLFIRI regimen significantly improved overall survival and progression-free survival in patients with KRAS exon 2 wild-type metastatic colorectal cancer, highlighting its efficacy in this specific patient group.

However, patients with other RAS mutations did not experience any benefit from cetuximab, indicating the importance of comprehensive RAS mutation testing to tailor treatment and maximize effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. Van Cutsem, E., Lenz, HJ., Köhne, CH., et al.[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]

Citations

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2. clinicaltrials.gov clinicaltrials.gov/study/NCT05200442

A Study of VS-6766 and Cetuximab in Patients With ... This study will instead combine cetuximab and VS-6766 to find out if the two medications can help people living with advanced colorectal cancers.

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mutated metastatic colorectal cancer: Results of phase 1 ... Avutometinib plus cetuximab after chemotherapy in patients with KRAS-mutated metastatic colorectal cancer: Results of phase 1 dose escalation.

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Avutometinib/Defactinib Combo Generates Early Efficacy ... The tumor shrinkage [rate], the number of patients whose cancer stopped growing and began to shrink, was 86%. It took time [for patients] to ...

5. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-03302

Avutometinib, Defactinib and Cetuximab for the Treatment ... This phase II trial tests how well avutometinib, defactinib and cetuximab works for the treatment of patients with colorectal cancer that cannot be removed ...

6. aacrjournals.org aacrjournals.org/cancerres/article/83/7_Supplement/530/720345/Abstract-530-Preclinical-evaluation-of

Preclinical evaluation of avutometinib (VS-6766; RAF/MEK ... Avutometinib (avuto, VS-6766) is a unique RAF/MEK clamp that inhibits MEK kinase activity and induces dominant negative RAF/MEK complexes.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12393057/

Efficacy and Safety of Avutometinib ± Defactinib in Recurrent ... ORR was 44% in KRAS-mutant and 17% in KRAS wild-type cohorts. The median progression-free survival was 12.9 months (95% CI, 10.9 to 20.2) ...

8. investor.verastem.com investor.verastem.com/news-releases/news-release-details/verastem-oncology-announces-nature-medicine-publication-results

Press Release - Verastem, Inc. The first-in-human study to evaluate the safety, tolerability, and efficacy of avutometinib in combination with defactinib in patients with low-grade serous ...