Triple Drug Therapy for Non-Small Cell Lung Cancer

Overseen By Selina Laqui, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Jonathan Riess

Must not be taking: Strong CYP2C8 inhibitors

Disqualifiers: Pneumonitis, Seizures, Thromboembolism, others

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

Compensation: Varies

Number of Visits: 32

Duration: Up to 10 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a combination of three drugs—osimertinib, cetuximab, and tucatinib—to determine their safety and effectiveness in treating non-small cell lung cancer (NSCLC) with specific EGFR mutations. The goal is to identify the optimal dose that halts the growth and spread of cancer cells in individuals with advanced or recurrent cancer. Suitable candidates have stage IV NSCLC with specific EGFR mutations and have not responded to previous treatments like osimertinib. 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 protocol does not specify if you must stop taking your current medications. However, if you are on an EGFR-TKI other than osimertinib, it must be stopped at least 7 days before starting the study treatment.

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

In a previous study, researchers examined the safety of using osimertinib, cetuximab, and tucatinib together. The study is in its early stages, focusing primarily on the safety of these drugs and potential side effects in participants. This combination targets non-small cell lung cancer with specific genetic changes known as EGFR mutations.

Osimertinib has previously treated lung cancer, providing some confidence in its safety. Cetuximab targets certain cancer cells and has been used in other cancer treatments. Tucatinib is newer and remains under study to ensure its safety.

While the study continues, early reports highlight monitoring for dose-limiting toxicities, which are side effects that might restrict the safe dosage of the drug. As this is an early study, the primary goal is to determine the safest way to use these drugs together. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this triple drug therapy for non-small cell lung cancer because it brings together three targeted treatments: tucatinib, osimertinib, and cetuximab. Unlike traditional chemotherapy, which attacks all rapidly dividing cells, this combination specifically targets cancer cells, potentially reducing side effects. Tucatinib and osimertinib are both taken orally, providing a more convenient option compared to some existing intravenous treatments. Additionally, cetuximab specifically targets the EGFR protein, which plays a role in cancer cell growth. This targeted approach could offer a more effective and personalized treatment option for patients with this type of lung cancer.

What evidence suggests that this trial's treatments could be effective for non-small cell lung cancer?

This trial will evaluate the effectiveness of combining three drugs—osimertinib, cetuximab, and tucatinib—for treating non-small cell lung cancer (NSCLC) with specific EGFR mutations. Research has shown that osimertinib works well against tumors with these mutations. Adding cetuximab, which blocks a protein that aids cancer growth, has improved survival rates when used with other treatments. Tucatinib may further enhance treatment by blocking enzymes that help cancer cells grow. This combination aims to attack the cancer in different ways, potentially leading to better results for patients. ^{2 3 4 6 7}

Who Is on the Research Team?

Jonathan W. Riess

Principal Investigator

University of California, Davis

Are You a Good Fit for This Trial?

Adults (18+) with stage IV or recurrent non-small cell lung cancer and specific EGFR mutations, who've seen their disease progress on osimertinib. They should be in good physical condition (ECOG 0-1), have a life expectancy over 3 months, stable brain metastases if any, and meet certain blood/heart health criteria. Pregnant women and those with recent thrombosis, uncontrolled heart conditions, severe infections or allergies to trial drugs are excluded.

Inclusion Criteria

Ability to adhere to the study visit schedule and protocol requirements

Your blood and other body chemistry levels must be within certain limits.

Ability to swallow pills

Exclusion Criteria

Any condition that would prohibit the understanding or rendering of informed consent

Any condition that in the opinion of the investigator would interfere with the participant's safety or compliance while on trial

My doctor suspects or has confirmed I have cancer in the lining of my brain or spinal cord.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive tucatinib, osimertinib, and cetuximab in 28-day cycles

Up to 10 months

IV administration every 2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Follow-up at 30 days and every 12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cetuximab
• Osimertinib
• Tucatinib

Trial Overview The safety and optimal dosages of osimertinib, cetuximab, and tucatinib are being tested for treating advanced non-small cell lung cancer with EGFR mutations. This phase I trial aims to see if combining these drugs is more effective than current treatments by blocking tumor growth enzymes.

How Is the Trial Designed?

Group I: Treatment (tucatinib, osimertinib, cetuximab) Experimental Treatment 3 Interventions

Patients receive tucatinib 200mg orally BID, osimertinib 80mg orally daily, and cetuximab 250mg/m\^2 IV every 2 weeks of a 28-day cycle. Cycles repeat every 28 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?

Jonathan Riess

Lead Sponsor

Trials

2

Recruited

50+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

In a study of 57 patients with advanced non-small cell lung cancer (NSCLC), gefitinib and erlotinib showed significantly better progression-free survival (PFS) and overall survival (OS) compared to pemetrexed, with median PFS of 3.5 and 4.4 months versus 1.7 months for pemetrexed.

Both gefitinib and erlotinib had comparable efficacy and manageable safety profiles, indicating they may be more effective treatment options for certain patient subgroups, particularly those with non-squamous histology, males, and a smoking history.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed versus gefitinib versus erlotinib in previously treated patients with non-small cell lung cancer. Hong, J., Kyung, SY., Lee, SP., 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]

In a phase II study involving 53 patients with advanced non-small cell lung cancer, the combination of cetuximab, paclitaxel, and carboplatin resulted in a response rate of 57%, indicating significant clinical activity.

The treatment was well tolerated with manageable toxicities, including rash and neutropenia, and no grade 5 toxicities reported, suggesting a favorable safety profile for this regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of paclitaxel, carboplatin, and cetuximab as first line treatment, for patients with advanced non-small cell lung cancer (NSCLC): results of OPN-017. Borghaei, H., Langer, CJ., Millenson, M., et al.[2018]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8274319/

Progress in Treatment of Non-Small Cell Lung Cancer ... Early data suggested that although osimertinib was particularly effective against tumors with the EGFR T790M mutation, approximately 20% of EGFR ...

2. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2022-04431

Osimertinib, Cetuximab, and Tucatinib for the Treatment of ... Giving osimertinib, cetuximab, and tucatinib may work better in treating patients with non-small cell lung cancer. Eligibility Criteria. Inclusion Criteria.

3. withpower.com withpower.com/trial/phase-1-carcinoma-2024-71b3d

Triple Drug Therapy for Non-Small Cell Lung Cancer Research shows that adding cetuximab to chemotherapy significantly improves overall survival in patients with advanced non-small cell lung cancer compared to ...

4. researchgate.net researchgate.net/publication/361705977_High_dose_osimertinib_in_patients_with_advanced_stage_EGFR_exon_20_mutation-positive_NSCLC_Results_from_the_phase_2_multicenter_POSITION20_trial

High dose osimertinib in patients with advanced stage ... The combination of osimertinib and necitumumab, an EGFR monoclonal antibody, has shown preliminary efficacy in pre-treated EGFR ex20ins mutated ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12051098/

Strategies Beyond 3rd EGFR‐TKI Acquired Resistance NSCLC can transform into small cell lung cancer (SCLC)following third‐generation EGFR‐TKI treatment failure, as shown by extensive evidence [61, ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06067776?term=AREA%5BConditionSearch%5D(%22Lung%20Non-Small%20Cell%20Carcinoma%22)%20AND%20AREA%5BInterventionSearch%5D(%22Antineoplastic%20Agents,%20Immunological%22)&rank=8

Osimertinib, Cetuximab, and Tucatinib for the Treatment of ... An unfavorable change in the health of a participant, including abnormal laboratory findings, that happens during a clinical study or within a certain amount of ...

7. clin.larvol.com clin.larvol.com/trial/NCT06067776

Osimertinib, Cetuximab, and Tucatinib for the Treatment of ... The occurrence of a dose-limiting toxicity in participants receiving the combination of osimertinib, cetuximab, and tucatinib. First dose through cycle 1 (each ...