LXH254 Combinations for Melanoma

Recruiting at 59 trial locations

Overseen By Novartis Pharmaceuticals

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Novartis Pharmaceuticals

Must be taking: Checkpoint inhibitors

Must not be taking: Radiation, Small molecules

Disqualifiers: CNS tumors, Retinal vein occlusion, 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

Duration: 35 months

134 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new medication called LXH254, used in combination with other treatments, for people with a type of skin cancer that can't be removed by surgery and has spread. These patients have already tried other treatments. LXH254 works by blocking signals in the cancer cells to slow or stop their growth.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it does require a waiting period after certain treatments before starting the study. For example, you need to wait 2 to 6 weeks after your last cancer treatment, depending on the type, before joining the trial.

What evidence supports the effectiveness of the drug combination LXH254, Ribociclib, Kisqali, Trametinib, and Mekinist for treating melanoma?

Research shows that combining drugs targeting BRAF/MEK pathways, like Trametinib and Mekinist, with immune therapies can lead to better control of melanoma, as seen in studies with similar drug combinations. These combinations have shown promise in improving survival and controlling tumor growth in advanced melanoma. ^{1 2 3 4 5}

What safety data exists for LXH254, Ribociclib, Kisqali, Trametinib, and Mekinist in humans?

Trametinib, often used in combination with other drugs like dabrafenib, has been shown to cause various side effects, including skin, eye, heart, digestive, muscle, and kidney issues. These side effects can vary in frequency and intensity, and proper management is important to minimize their impact on quality of life. The combination therapies have been effective but come with significant toxicity, requiring careful monitoring and management. ^{1 2 6 7 8}

How does the drug LXH254 differ from other melanoma treatments?

LXH254 is unique because it targets specific pathways involved in melanoma progression, potentially offering a novel approach compared to existing treatments. While other treatments may focus on different mechanisms, LXH254's specific action could provide an alternative for patients with certain types of melanoma. ^{9 10 11 12 13}

Eligibility Criteria

This trial is for adults and adolescents (12+) with a body weight over 40kg who have unresectable or metastatic melanoma. Participants must have tried certain therapies before, like checkpoint inhibitors or targeted therapy, depending on their mutation type (NRAS or BRAFV600). They should not have received recent cancer treatments that could interfere with the study.

Inclusion Criteria

I am 12 years old or older.

My melanoma cannot be removed with surgery and has spread.

I have NRAS mutation melanoma and have had up to 2 treatments with specific immune therapies.

Exclusion Criteria

Any medical condition that would, in the investigator's judgment, prevent the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures.

I do not have unstable brain tumors or symptoms from brain metastases.

Participants participating in additional parallel investigational drug or medical device studies.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive LXH254 combinations for previously treated unresectable or metastatic melanoma

35 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 years

Treatment Details

Interventions

• LXH254
• Ribociclib
• Trametinib

Trial Overview The study tests combinations of LXH254 with other drugs (LTT462, Trametinib, Ribociclib) in patients who've had previous treatments for advanced melanoma. It aims to find out how effective these drug combos are in treating this condition.

Participant Groups

Group I: LXH254 + trametinib Experimental Treatment 1 Intervention

Group II: LXH254 + ribociclib Experimental Treatment 1 Intervention

Group III: LXH254 + LTT462 Experimental Treatment 2 Interventions

Who Is Running the Clinical Trial?

Novartis Pharmaceuticals

Lead 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

Findings from Research

The FDA approved two groundbreaking drugs for malignant melanoma in 2011, marking a significant advancement in treatment after a 13-year gap, specifically ipilimumab for immune checkpoint modulation and targeted therapies like vemurafenib and dabrafenib for BRAF(V600) mutations.

These new therapies have changed the landscape of melanoma treatment, but they also raise important questions about how to best combine and sequence these agents for patients with BRAF mutant melanoma to enhance efficacy and manage resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab, vemurafenib, dabrafenib, and trametinib: synergistic competitors in the clinical management of BRAF mutant malignant melanoma. Luke, JJ., Hodi, FS.[2021]

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]

Recent advances in treating metastatic melanoma have been achieved through targeted therapies using BRAF and MEK inhibitors for patients with the BRAF V600 mutation, with combinations like vemurafenib+cobimetinib and dabrafenib+trametinib showing significant efficacy in clinical trials.

Combination therapies have different toxicity profiles compared to single-agent treatments, necessitating new strategies for prevention, detection, and management of adverse events, as outlined in the tolerance data from pivotal trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Management of toxicities of BRAF inhibitors and MEK inhibitors in advanced melanoma]. Sibaud, V., Baric, L., Cantagrel, A., et al.[2021]

References

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

Short-term treatment with multi-drug regimens combining BRAF/MEK-targeted therapy and immunotherapy results in durable responses in Braf-mutated melanoma. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Ipilimumab, vemurafenib, dabrafenib, and trametinib: synergistic competitors in the clinical management of BRAF mutant malignant melanoma. [2021]

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

Developing melanoma therapeutics: overview and update. [2018]

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

Combinatorial Approaches to the Treatment of Advanced Melanoma. [2022]

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

Combination therapies for the treatment of advanced melanoma: a review of current evidence. [2021]

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

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

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

Dabrafenib-trametinib combination in 'field-practice': an Italian experience. [2019]

8. France pubmed.ncbi.nlm.nih.gov

[Management of toxicities of BRAF inhibitors and MEK inhibitors in advanced melanoma]. [2021]

9. Poland pubmed.ncbi.nlm.nih.gov

MDA-19 Suppresses Progression of Melanoma Via Inhibiting the PI3K/Akt Pathway. [2022]

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

Discovery of Clinically Used Octenidine as NRAS Repressor That Effectively Inhibits NRAS-Mutant Melanoma. [2023]

11. China pubmed.ncbi.nlm.nih.gov

[Expression of protein 4.1 family in melanoma cell lines and its effect on cell proliferation]. [2019]

12. England pubmed.ncbi.nlm.nih.gov

Integrative molecular and clinical profiling of acral melanoma links focal amplification of 22q11.21 to metastasis. [2023]

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

Deltex-3-like (DTX3L) stimulates metastasis of melanoma through FAK/PI3K/AKT but not MEK/ERK pathway. [2018]