Study of Efficacy and Safety of LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma

Study Overview
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Brief Summary
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The primary purpose of this study is to evaluate the efficacy of LXH254 combinations in previously treated unresectable or metastatic melanoma

Official Title
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A Randomized, Open-label, Multi-arm, Two-part, Phase II Study to Assess Efficacy and Safety of Multiple LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic BRAFV600 or NRAS Mutant Melanoma

Conditions
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Melanoma

Intervention / Treatment
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* Drug: LXH254
* Drug: LTT462
* Drug: Trametinib
* Drug: Ribociclib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female must be ≥ 12 years For adolescents only (12-17 years): body weight > 40kg Histologically confirmed unresectable or metastatic cutaneous melanoma Previously treated for unresectable or metastatic melanoma: Participants with NRAS mutation: Participants must have received prior systemic therapy for unresectable or metastatic melanoma with checkpoint inhibitors (CPI), either an anti-PD-1/PD-L1 as a single agent or in combination with anti-CTLA-4, investigational agents, chemotherapy or locally directed anti-neoplastic agents. A maximum of two prior lines of systemic CPI-containing immunotherapy for unresectable or metastatic melanoma are allowed. Additional agents administered with CPI are permitted. To rule out pseudo-progression, participants must have documented confirmed progressive disease as per RECIST v1.1 while on/after treatment with checkpoint inhibitor therapy. Confirmation is not required for patients who remained on treatment for >6 months. Participants with BRAFV600 mutant disease: Participants must have received prior systemic therapy for unresectable or metastatic melanoma with checkpoint inhibitors (CPI), either an anti-PD-1/PD-L1 as a single agent or in combination with anti-CTLA-4, investigational agents, chemotherapy or locally directed anti-neoplastic agents. Additionally, participants must have received targeted therapy with a RAFi as a single agent or in combination with a MEKi (+/- CPI allowed) as the last prior therapy. A maximum of two prior lines of systemic CPI-containing immunotherapy for unresectable or metastatic melanoma are allowed. Additional agents with CPI are permitted. A maximum of one line of targeted therapy is allowed, and it must be the most recent line of therapy. Participants must have documented progressive disease as per RECIST v1.1 while on/after treatment with targeted therapy. Other protocol-defined inclusion criteria may apply. Exclusion Criteria: Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment within the stated timeframes: ≤ 4 weeks for radiation therapy or ≤ 2 weeks for limited field radiation for palliation prior to the first dose of study treatment. ≤ 2 weeks for small molecule therapeutics. ≤ 4 weeks for any immunotherapy treatment including immune checkpoint inhibitors. ≤ 4 weeks for chemotherapy agents, locally directed anti-neoplastic agents, or other investigational agents. ≤ 6 weeks for cytotoxic agents with major delayed toxicities, such as nitrosourea and mitomycin c. Participants participating in additional parallel investigational drug or medical device studies. All primary central nervous system (CNS) tumors or symptomatic CNS metastases that are neurologically unstable History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes). 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. Other protocol-defined exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LXH254 + LTT462<br> | Drug: LXH254<br>* LXH254 will be supplied as tablet for oral use.<br>Drug: LTT462<br>* LTT462 will be supplied as hard gelatin capsule for oral use.<br>|
| Experimental: LXH254 + trametinib<br> | Drug: Trametinib<br>* Trametinib will be supplied as film-coated tablet for oral use<br>|
| Experimental: LXH254 + ribociclib<br> | Drug: Ribociclib<br>* Ribociclib will be supplied in tablets and hard gelatin capsules.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Confirmed ORR using RECIST v1.1, per local assessment | 35 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Reposnse (DOR) | Local and central assessment | 4 years | 
| Progression Free Survival (PFS) |  | 4 years | 
| Disease Control Rate (DCR) | Using RECIST v1.1, per local and central assessment | 3 years | 
| Overall Survival (OS) |  | 4 years | 
| Derived PK parameter (Cmax) for LXH254 & LTT462 |  | Up to 5 months | 
| Derived PK parameter (Cmax) for LXH254 & trametinib |  | Up to 5 months | 
| Derived PK parameter (Cmax) for LXH254 & ribociclib |  | Up to 5 months | 
| Derived PK parameter (AUC) for LXH254 & LTT462 |  | Up to 5 months | 
| Derived PK parameter (AUC) for LXH254 & trametinib |  | Up to 5 months | 
| Derived PK parameter (AUC) for LXH254 & ribociclib |  | Up to 5 months | 
| Incidence of adverse events (AEs) and serious adverse events (SAEs) | Number of participants with Adverse Events (AEs) and SAEs as a measure of safety and tolerability | 35 months | 
| Dose Interruptions | Tolerability measured by the number of subjects who have interruptions of study treatment and reason for interruptions | 35 months | 
| Dose reductions | Tolerability measured by the number of subjects who have reductions of study treatment and reason for reductions | 35 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LXH254, Melanoma, NRAS, BRAF, LTT462, Trametinib, Ribocliclib