Trametinib + Ceritinib for Melanoma

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: QT prolonging, CYP3A4/5, Warfarin, Corticosteroids

Disqualifiers: Brain metastases, Heart disease, Diabetes, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 3

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, trametinib and ceritinib, to evaluate their joint effectiveness for people with advanced melanoma (a type of skin cancer) that has not responded well to previous treatments. The goal is to determine if this combination is safe and effective in slowing cancer growth. Suitable participants have melanoma that cannot be surgically removed and have already tried other cancer treatments without success. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering a chance to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

You may need to stop taking certain medications before joining the trial. Specifically, you must stop medications that affect the heart's rhythm, certain enzyme-affecting drugs, warfarin, unstable doses of corticosteroids, and some anticonvulsants at least one week before starting the trial.

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

In a previous study, researchers found that using ceritinib and trametinib together did not cause any unexpected side effects. This means the side effects aligned with what doctors anticipated based on past use of these drugs. Studies have shown that patients generally tolerated this combination well, and doctors identified a manageable dose. No new safety issues emerged, which is a positive sign. Overall, the combination appears safe based on the available information. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Trametinib and Ceritinib for treating melanoma because it offers a unique approach by targeting multiple pathways involved in cancer growth. Unlike standard treatments like immunotherapy or chemotherapy, Trametinib works by inhibiting MEK, a protein that contributes to cell division, while Ceritinib targets ALK and ROS1, which are involved in cancer cell survival and proliferation. By combining these two drugs, the treatment has the potential to more effectively halt the progression of melanoma, especially in cases where other treatments might not be as effective. This dual-target strategy could improve patient outcomes by addressing resistance mechanisms that often limit the success of current therapies.

What evidence suggests that this treatment might be an effective treatment for melanoma?

Research suggests that combining trametinib and ceritinib might be promising for treating melanoma, a type of skin cancer. In this trial, participants will receive both trametinib and ceritinib. Studies have shown that ceritinib can enhance the effectiveness of trametinib in certain melanoma cells. This combination has demonstrated potential benefits for patients who have already tried anti-PD-1 therapies, with some evidence indicating longer survival times. Observations indicate that using ceritinib with trametinib is more effective than using either drug alone. While more research is needed, early findings support the potential benefit of this combination for melanoma patients who have not responded to other treatments. ^{1 2 6 7 8}

Who Is on the Research Team?

Zeynep Eroglu, M.D.

Principal Investigator

H. Lee Moffitt Cancer Center and Research Institute

Are You a Good Fit for This Trial?

This trial is for adults with advanced melanoma that can't be surgically removed and who have already tried certain therapies without success. They must be in relatively good health, able to use birth control, and have tumors measurable by standard criteria. People with severe allergies to the drugs' ingredients, uncontrolled brain metastases, recent heart issues, or those on conflicting medications are excluded.

Inclusion Criteria

My last cancer treatment did not include BRAF/MEK inhibitors.

I agree to use effective birth control during and for 90 days after the study.

I have had radiation treatment before.

Exclusion Criteria

I have stable brain metastases not needing steroids, or no brain metastases.

I have had cancer before, but it's under control and I'm not currently on cancer treatment.

I am on medication that cannot be stopped for the study, including those affecting heart rhythm or requiring careful monitoring.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive trametinib and ceritinib in 4-week cycles

12 months

Monthly visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Every 3 months for the first year, then every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Ceritinib
• Trametinib

Trial Overview

The study tests a combination of two drugs: Trametinib and Ceritinib. It aims to see if this combo is effective for patients whose melanoma has worsened despite previous treatments including PD1/PD-L1 inhibitors (and BRAF/MEK inhibitors if they have a specific mutation).

How Is the Trial Designed?

Group I: Trametinib + Ceritinib Treatment Experimental Treatment 2 Interventions

Study treatment will be given in cycles. Each cycle will be 4 weeks (28 days). Post-Treatment (follow-up) Period: Participants will return to the study site between 30-40 days after the last dose of trametinib + ceritinib for an end-of-treatment assessment. Additional follow-up will occur for related Adverse Events (AEs) that are not resolved by this time and related Serious Adverse Events (SAEs) that occur after the time of this visit. Participants will be followed for survival every 3 months for the first year following end of treatment, and then every 6 months for up to 5 years after end of treatment.

Ceritinib is already approved in United States for the following indications:

Approved in United States as Danyelza for:

• High-risk neuroblastoma in the bone or bone marrow

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

Novartis Pharmaceuticals

Industry Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Published Research Related to This Trial

The study found that the combination of encorafenib and trametinib showed the highest anti-tumor activity, effectively suppressing cell proliferation and inducing apoptosis in both BRAF and NRAS mutant melanoma cells.

Encouragingly, this combination also delayed the development of resistance more effectively than currently approved treatments, suggesting it could lead to better outcomes for patients with melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Head-to-Head Comparison of BRAF/MEK Inhibitor Combinations Proposes Superiority of Encorafenib Plus Trametinib in Melanoma. Schulz, A., Raetz, J., Karitzky, PC., et al.[2022]

In a study of 66 patients with metastatic BRAF-mutated melanoma treated with dabrafenib and trametinib, 15 patients achieved a complete response (CR), indicating a significant survival benefit from this treatment.

The likelihood of achieving a complete response was higher in patients with smaller lesions (39.3% CR rate) compared to those with larger lesions (10.5% CR rate), suggesting that lesion size and the number of metastatic sites are important factors in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BRAFi/MEKi in patients with metastatic melanoma: predictive factors of complete response. Ribero, S., Malavenda, O., Fava, P., et al.[2019]

Combination therapy with dabrafenib and trametinib for BRAF-mutated metastatic melanoma showed a high overall response rate, with 64.6% of patients achieving a partial response and 6.2% achieving a complete response, indicating its efficacy in treating this condition.

The treatment was found to be relatively safe, with only 8.3% of patients experiencing severe adverse events, and 62.5% of patients remained on treatment, suggesting good tolerability in a real-life clinical setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined therapy with dabrafenib and trametinib in BRAF-mutated metastatic melanoma in a real-life setting: the INT Milan experience. Cavalieri, S., Di Guardo, L., Cimminiello, C., et al.[2017]

Targeted therapies using BRAF and MEK inhibitors have become the standard treatment for advanced-stage BRAF V600-mutant melanoma, significantly improving patient outcomes.

Effective management of drug-related adverse events (AEs) is crucial for maximizing treatment benefits, as understanding the specific toxicity profiles of these inhibitors allows for timely adjustments in therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of Treatment-Related Adverse Events with Agents Targeting the MAPK Pathway in Patients with Metastatic Melanoma. Daud, A., Tsai, K.[2019]

Dabrafenib plus trametinib has been approved for treating non-small cell lung cancer (NSCLC) with the BRAF V600E mutation, showing a response rate of approximately 65% and a median progression-free survival of 10-11 months based on clinical trials.

While the combination therapy has a manageable safety profile, it presents unique toxicities such as pyrexia, fatigue, and nausea, which may be unfamiliar to oncologists treating lung cancer, but can be effectively managed using strategies developed from experience in melanoma treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Event Management in Patients with BRAF V600E-Mutant Non-Small Cell Lung Cancer Treated with Dabrafenib plus Trametinib. Chalmers, A., Cannon, L., Akerley, W.[2020]

In a study of 77 East Asian patients with advanced BRAF V600-mutant cutaneous melanoma, the combination of dabrafenib and trametinib showed a high objective response rate of 61%, indicating significant efficacy in treating this patient population.

The treatment was generally well-tolerated, with the most common adverse event being pyrexia (fever) occurring in 56% of patients, and serious adverse events were reported in 38%, suggesting that while effective, monitoring for side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-label, phase IIa study of dabrafenib plus trametinib in East Asian patients with advanced BRAF V600-mutant cutaneous melanoma. Si, L., Zhang, X., Shin, SJ., et al.[2020]

In a phase III study involving patients with BRAF V600 mutation-positive melanoma, trametinib significantly improved quality of life (QOL) compared to chemotherapy, with patients reporting better global health status and less functional impairment.

Patients treated with trametinib experienced improvements in symptoms like pain and insomnia, while chemotherapy led to worsening symptoms and a decline in overall health, highlighting trametinib's potential as a more tolerable treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Functional and symptom impact of trametinib versus chemotherapy in BRAF V600E advanced or metastatic melanoma: quality-of-life analyses of the METRIC study. Schadendorf, D., Amonkar, MM., Milhem, M., et al.[2023]

Citations

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NCT03501368 | Study of Trametinib + Ceritinib in Patients ...

The main purpose of this study is to determine the risks and benefits of ceritinib (ZYKADIA) given in combination with trametinib ( MEKINIST ) in patients who ...

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Ceritinib Enhances the Efficacy of Trametinib in BRAF/NRAS-Wild-Type Melanoma Cell Lines ... Validation studies suggested that ceritinib could suppress ...

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aacrjournals.org

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Abstract CT057: Phase 1/2 trial of trametinib + ceritinib in ...

Overall, patients with immediate prior line of anti-PD-1 before trial treatment had a trend toward improved OS (10.2 months vs 5.1 months; p= ...

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Dr Eroglu on Ceritinib With or Without Trametinib in ...

Zeynep Eroglu, MD, discusses the efficacy and safety of ceritinib as monotherapy and in combination with trametinib in pretreated advanced ...

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Targeted therapy given after anti-PD-1 leads to prolonged ...

In the present study, we demonstrated that the sequence of anti-PD1 followed by ceritinib-trametinib (IT->TT) was more effective than either treatment alone in ...

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onclive.com

onclive.com/view/dr-eroglu-on-the-safety-profile-of-ceritinib-plus-trametinib-in-advanced-melanoma

Dr Eroglu on the Safety Profile of Ceritinib Plus Trametinib ...

The open-label study was designed to determine the risks and benefits of administering ceritinib plus trametinib in patients with melanoma who ...

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pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC5752595/

Ceritinib enhances the efficacy of trametinib in BRAF/ ...

Co-administration of ceritinib and trametinib led to robust inhibition of tumor growth in an in vivo xenograft BRAF/NRAS-WT melanoma model; this ...

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pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC9761844/

Phase 1 Study of Ceritinib Combined With Trametinib in ...

Data from this trial indicate that the combination of ceritinib and trametinib had no unexpected toxicities and that a tolerable dose could be identified.