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

Trial Summary

What is the purpose of this trial?

To learn if avutometinib in combination with defactinib and cetuximab can help to control unresectable, anti-EGFR-refractory, advanced colorectal cancer.

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.

What data supports the effectiveness of the drug combination for advanced colorectal cancer?

Research shows that adding cetuximab to standard chemotherapy significantly improves survival and response rates in patients with certain types of metastatic colorectal cancer, particularly those without specific genetic mutations (KRAS wild-type). ^{1 2 3 4 5}

Is the drug combination generally safe for humans?

Cetuximab, one of the drugs in the combination, is generally considered safe and well-tolerated, with common side effects being mild skin reactions. However, there is some risk of severe adverse events, so it's important to discuss potential risks with your doctor. ^{2 6 7 8 9}

What makes the drug combination of Avutometinib, Cetuximab, and Defactinib unique for advanced colorectal cancer?

This drug combination is unique because it includes Avutometinib and Defactinib, which are not standard components in existing colorectal cancer treatments. Cetuximab, a part of this combination, is known for targeting the epidermal growth factor receptor (EGFR) and is effective in patients with KRAS wild-type tumors, but the addition of Avutometinib and Defactinib may offer a novel approach by potentially targeting different pathways or mechanisms in cancer cells. ^{2 3 9 10 11}

Research Team

Christine Parseghian

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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 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]

References

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

Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. [2022]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Economic Analysis of First-Line Treatment with Cetuximab or Panitumumab for RAS Wild-Type Metastatic Colorectal Cancer in England. [2021]

3. Italy pubmed.ncbi.nlm.nih.gov

Progress in metastatic colorectal cancer: growing role of cetuximab to optimize clinical outcome. [2022]

4. Germany pubmed.ncbi.nlm.nih.gov

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

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

Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. [2020]

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

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

7. England pubmed.ncbi.nlm.nih.gov

Complications after oesophagectomy with possible contribution of neoadjuvant therapy including an EGFR-antibody to a fatal outcome. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Treatment related severe and fatal adverse events with cetuximab in colorectal cancer patients: a meta-analysis. [2022]

9. 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]

10. Japan pubmed.ncbi.nlm.nih.gov

[Cetuximab for patients with metastatic colorectal cancer-from the result of recent clinical trials]. [2016]

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

A phase II trial of FOLFOX6 and cetuximab in the first-line treatment of patients with metastatic colorectal cancer. [2016]