LXH254 Combinations for Melanoma

Not currently recruiting at 65 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of different combinations of the experimental drug LXH254 in treating melanoma that cannot be surgically removed or has metastasized. The researchers aim to determine if combining LXH254 with other drugs, such as LTT462, trametinib (a MEK inhibitor), or ribociclib (Kisqali, a CDK4/6 inhibitor), can effectively manage the disease in patients who have already received treatment. Ideal participants have melanoma that has returned or progressed despite previous treatments and possess either the NRAS or BRAFV600 gene mutation. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research has shown that LXH254 combinations for melanoma are generally well-tolerated by patients. Studies found that these treatments had safety profiles that patients could handle, with the most common side effects related to the skin, which many patients managed well.

For the LXH254 + LTT462 combination, earlier studies found that most side effects were manageable. The combination did not cause serious harm, though some patients experienced mild to moderate skin issues.

Research suggests that the LXH254 + trametinib combination is also promising, with most side effects similar to those seen with other combinations, mainly affecting the skin.

In the case of LXH254 + ribociclib, previous research focused on finding the best dose and schedule. Like the other combinations, side effects were generally mild and manageable.

Overall, these treatments are in an advanced stage of study, indicating they have already demonstrated a basic level of safety in earlier research phases. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for melanoma, such as immunotherapy and targeted therapy, LXH254 combinations present a novel approach by targeting specific pathways in cancer cells. LXH254 is unique because it inhibits the CRAF and BRAF proteins, which play a critical role in melanoma cell growth and survival. When combined with other agents like LTT462, trametinib, or ribociclib, these treatments aim to overcome resistance often seen with current therapies. Researchers are excited about these combinations because they offer a potential new mechanism to tackle melanoma more effectively, possibly leading to better outcomes for patients.

What evidence suggests that this trial's treatments could be effective for melanoma?

Research has shown that combining LXH254 with other drugs may help treat certain types of melanoma. In this trial, participants will receive different combinations of LXH254 with other treatments. Studies have found that LXH254 with either LTT462 or trametinib works well for NRAS-mutant melanoma, a type that often doesn't respond to other treatments. Specifically, in some patients, LXH254 with trametinib led to tumor shrinkage in nearly half of the cases. Additionally, LXH254 with ribociclib helped control the disease in 61% of patients, meaning their condition either stayed the same or improved. These early results suggest that these drug combinations might be effective for managing melanoma, especially when other treatments haven't worked. ^{1 2 3 5 6}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04417621

NCT04417621 | Study of Efficacy and Safety of LXH254 ... The primary purpose of this study is to evaluate the efficacy of LXH254 combinations in previously treated unresectable or metastatic melanoma.

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0169500224004987

A phase Ib study of the combination of naporafenib with ... Patients with NSCLC may benefit from treatment with the pan-RAF inhibitor naporafenib (LXH254) plus the ERK1/2 inhibitor rineterkib (LTT462) or MEK1/2 inhibitor ...

3. annalsofoncology.org annalsofoncology.org/article/S0923-7534(22)03916-3/fulltext

LBA40 Phase II study of multiple LXH254 drug ... LXH254 in combination with LTT462 or trametinib shows promising efficacy in NRAS-mutant, immuno-resistant melanoma. Clinical trial identification.

4. clinicaltrial.be clinicaltrial.be/en/details/3526?per_page=20&only_recruiting=0&only_eligible=0&only_active=0

Study of Efficacy and Safety of LXH254 Combinations in Pa... A Randomized, Open-label, Multi-arm, Two-part, Phase II Study to Assess Efficacy and Safety of Multiple LXH254 Combinations in Patients With ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10296143/

New Approaches to Targeted Therapy in Melanoma - PMC Here we review the persisting efforts to identify and exploit molecular targets to optimize clinical outcomes for patients with melanoma.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39383771/

or BRAF-mutant non-small cell lung cancer Patients with NSCLC may benefit from treatment with the pan-RAF inhibitor naporafenib (LXH254) plus the ERK1/2 inhibitor rineterkib (LTT462) or MEK1/2 inhibitor ...