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

33 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of vemurafenib when given together with cetuximab and irinotecan hydrochloride in treating patients with solid tumors that have spread to other parts of the body or cannot be removed by surgery. Vemurafenib and irinotecan hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as cetuximab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving vemurafenib with cetuximab and irinotecan hydrochloride may be a better treatment for solid tumors.

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.

What data supports the effectiveness of the drug combination used in the Triple Therapy for Advanced Solid Cancers?

Research shows that cetuximab combined with irinotecan is effective in treating advanced colorectal cancer, improving survival and response rates. Additionally, cetuximab has been shown to enhance survival when added to chemotherapy in advanced non-small-cell lung cancer. ^{1 2 3 4 5}

What safety data exists for the combination of Cetuximab and Irinotecan in humans?

The combination of Cetuximab and Irinotecan has been studied in patients with advanced colorectal cancer, showing that severe side effects like skin reactions, diarrhea, nausea, vomiting, and fatigue were rare. A Japanese post-marketing surveillance also aimed to verify the safety of Cetuximab in practical use. ^{2 3 6 7 8}

What makes the drug combination of Cetuximab, Irinotecan Hydrochloride, and Vemurafenib unique for treating advanced solid cancers?

This drug combination is unique because it combines Cetuximab, which targets the epidermal growth factor receptor (EGFR), with Irinotecan, a chemotherapy drug, and Vemurafenib, which targets specific mutations in cancer cells. This multi-targeted approach may offer a novel way to treat advanced solid cancers by attacking the cancer cells through different mechanisms. ^{1 3 4 9 10}

Research Team

David Hong, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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 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]

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]

References

1. 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]

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 and irinotecan as third line therapy in patients with advanced colorectal cancer after failure of irinotecan, oxaliplatin and 5-fluorouracil. [2018]

4. England pubmed.ncbi.nlm.nih.gov

EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. [2022]

5. 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]

6. Japan pubmed.ncbi.nlm.nih.gov

Cetuximab-induced skin reactions are suppressed by cigarette smoking in patients with advanced colorectal cancer. [2021]

7. Japan pubmed.ncbi.nlm.nih.gov

Retrospective analysis of cetuximab monotherapy for patients with irinotecan-intolerant metastatic colorectal cancer. [2021]

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

Cetuximab. [2020]

9. England pubmed.ncbi.nlm.nih.gov

Cetuximab plus FOLFIRINOX (ERBIRINOX) as first-line treatment for unresectable metastatic colorectal cancer: a phase II trial. [2022]

10. Czech Republic pubmed.ncbi.nlm.nih.gov

[Cetuximab and irinotecan for the treatment of metastatic colorectal cancer--pilot results from Masaryk Memorial Cancer Institute]. [2018]