Triple Therapy for Advanced Solid Cancers

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Chemotherapy, CYP3A4 inhibitors

Disqualifiers: Heart failure, Angina, K-RAS mutant, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 14 days per course

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of three treatments to determine if they work better together in stopping the growth of advanced solid tumors that have spread or cannot be removed by surgery. The treatments include vemurafenib and irinotecan hydrochloride, which may block enzymes that help tumors grow, and cetuximab, an immunotherapy that may help the immune system attack the cancer. People with metastatic cancer that has a specific BRAF mutation and no mutations in their K-RAS gene might be suitable candidates. 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 combination therapy.

Will I have to stop taking my current medications?

The trial requires that you do not take any concurrent chemotherapy or medications that strongly affect certain liver enzymes (CYP3A4). If you are on such medications, you may need to stop them before joining the trial.

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

Research has shown that the combination of vemurafenib, cetuximab, and irinotecan is generally well tolerated by patients with hard-to-treat cancers. In earlier studies, this drug mix was tested on patients with a specific type of advanced colorectal cancer, and the results were promising regarding safety. Patients did not experience severe side effects, suggesting the treatment is manageable for most. Although it is still early for this particular combination, the evidence so far indicates it could be a safe option for those considering joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of vemurafenib, cetuximab, and irinotecan hydrochloride for advanced solid cancers because it targets cancer cells in a unique way. Vemurafenib specifically inhibits the BRAF V600E mutation, a common driver in certain cancers, offering a more tailored approach compared to broad-spectrum chemotherapies. Cetuximab adds another layer by blocking the epidermal growth factor receptor (EGFR), which is often overexpressed in tumors, while irinotecan hydrochloride disrupts cancer cell division. This triple therapy could potentially offer a more comprehensive attack on cancer cells, possibly leading to better outcomes for patients with advanced cancers.

What evidence suggests that this trial's treatments could be effective for advanced solid cancers?

Research has shown that vemurafenib can help control tumors in some advanced cancers, particularly in patients with certain gene mutations. When combined with chemotherapy, cetuximab has improved survival rates for people with advanced colorectal cancer by aiding the immune system in fighting cancer cells. Irinotecan hydrochloride plays a crucial role in treating metastatic cancers and can extend survival when used with other treatments. In this trial, participants will receive a combination of vemurafenib, cetuximab, and irinotecan hydrochloride, which together have shown promise in combating advanced cancers. ^{6 7 8 9 10}

Who Is on the Research Team?

David Hong, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with solid tumors that have spread or can't be surgically removed, and who have a specific BRAF V600 mutation. They should not have received recent tumor treatment, must be able to swallow pills, and agree to use contraception. Those with severe medical conditions or certain heart issues are excluded.

Inclusion Criteria

Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria

Hemoglobin (Hb) >= 9 mg/dl (within 14 days)

Life expectancy of greater than 3 months

Exclusion Criteria

Known anaphylactic or severe hypersensitivity to the study drugs or their analogs

I have not had a heart attack or severe heart symptoms in the last 6 months.

I have fluid buildup in my chest or heart area that hasn't been treated.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive vemurafenib orally twice daily on days 1-14, cetuximab intravenously over 90 minutes, and irinotecan hydrochloride intravenously over 90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

14 days per course

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cetuximab
• Irinotecan Hydrochloride
• Vemurafenib

Trial Overview The trial tests the combination of vemurafenib, cetuximab, and irinotecan hydrochloride on patients with advanced solid tumors. It aims to find the safest dose while assessing how these drugs affect tumor growth by blocking enzymes and boosting the immune system's response.

How Is the Trial Designed?

Group I: Treatment (vemurafenib, cetuximab, irinotecan hydrochloride) Experimental Treatment 5 Interventions

Patients receive vemurafenib PO BID on days 1-14, cetuximab IV over 90 minutes, and irinotecan hydrochloride IV over 90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Published Research Related to This Trial

In a study of 56 colorectal cancer patients treated with cetuximab, smokers experienced fewer skin reactions compared to non-smokers, suggesting that smoking may alter the drug's effectiveness.

However, smokers also reported higher rates of anorexia, indicating that while smoking might reduce certain side effects, it could negatively impact overall treatment outcomes, highlighting the importance of quitting smoking during cetuximab therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab-induced skin reactions are suppressed by cigarette smoking in patients with advanced colorectal cancer. Kajizono, M., Saito, M., Maeda, M., et al.[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]

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 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]

Cetuximab monotherapy is a feasible treatment option for patients with metastatic colorectal cancer (MCRC) who are intolerant to irinotecan, with no severe adverse events reported in the study of 22 patients.

The efficacy of cetuximab was modest, with a response rate of only 9.1% and median overall survival of 3.5 months, indicating a need for more effective therapies for this patient group, especially since most had wild-type KRAS tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective analysis of cetuximab monotherapy for patients with irinotecan-intolerant metastatic colorectal cancer. Mizota, A., Shitara, K., Kondo, C., et al.[2021]

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, 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7270202/

Chemotherapeutic Effectiveness of Combining Cetuximab for ... Our results showed that the chemotherapy alone group has shorter OS, PFS, and ORR than the chemotherapy plus cetuximab group, with significant differences.

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa071834

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 ...

3. tandfonline.com tandfonline.com/doi/full/10.1080/1758194X.2024.2390822

Investigation on the cost–effectiveness of Cetuximab in ... We found that some studies supported the idea that Cetuximab is cost-effective, meaning it provides good value for the money spent.

4. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/cetuximab?pn=1

Clinical Trials Using Cetuximab - NCI A Study to Investigate the Safety and Efficacy of KQB365 as Monotherapy and in Combination in Participants With Advanced Solid Malignancies. Status: Active.

5. activehealth.com activehealth.com/content/2022/07/Erbitux-AHM-1.pdf

Erbitux - Cetuximab AHM There are no data to support the use of cetuximab or panitunumab (Vectibix) after failure of the other drug. Colorectal cancer guidelines from the National ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/27729313/

Phase IB Study of Vemurafenib in Combination with Irinotecan ... Vemurafenib, in combination with irinotecan and cetuximab, was well tolerated in patients with refractory, BRAF-mutated metastatic colorectal cancer.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5562357/

Phase 1B study of vemurafenib in combination with ... The safety and efficacy of vemurafenib, irinotecan, and cetuximab in BRAF-mutated malignancies are not defined. In this 3+3 phase I study, patients with BRAF ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT01787500

Vemurafenib, Cetuximab, and Irinotecan Hydrochloride in ... This phase I trial studies the side effects and best dose of vemurafenib when given together with cetuximab and irinotecan hydrochloride in treating ...

9. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.4_suppl.TPS316

Cetuximab and vemurafenib plus liposomal irinotecan (II), ... To further validate the efficacy and safety of this regimen, we designed a randomized controlled trial. Methods: IMPROVEMENT2 (NCT06603376) is a ...

10. aacrjournals.org aacrjournals.org/cancerdiscovery/article-abstract/6/12/1352/5463

Phase IB Study of Vemurafenib in Combination with Irinotecan ... Vemurafenib plus irinotecan and cetuximab was generally well tolerated and achieved a 35% response rate in patients with BRAFV600E metastatic colorectal.