A Phase Ib Study of LXH254-centric Combinations in NSCLC or Melanoma

Study Overview
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Brief Summary
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To characterize safety and tolerability and identify a recommended dose and regimen for the LXH254 in combination with LTT462 or trametinib or ribociclib.

Official Title
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A Phase Ib, Open-label, Multicenter Study of Oral LXH254-centric Combinations in Adult Patients With Advanced or Metastatic KRAS or BRAF Mutant Non-Small Cell Lung Cancer or NRAS Mutant Melanoma

Conditions
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Non-Small Cell Lung Cancer, 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: Patients must have advanced or metastatic NSCLC or cutaneous melanoma Presence of KRAS or BRAF mutation (NSCLC) or NRAS mutation (cutaneous melanoma) in tumor tissue All patients participating in this clinical trial must have progressed following standard therapy or, in the opinion of the Investigator, no effective standard therapy exists, is tolerated, appropriate or is considered equivalent to study treatment. ECOG (Eastern Cooperative Oncology Group) performance status ≤ 2 Exclusion Criteria: -Dose expansion - KRAS or NRAS mutant patients groups: Prior treatment with a RAFi (including any BRAFi and pan-RAFi), MEKi and/or ERKi. (Patients with KRAS mutant NSCLC with prior G12C inhibitor treatments are also excluded in the LXH254+trametinib expansion part). BRAF mutant patients group: Prior treatment with any EGFR, ALK, ROS1, KRAS, RAF (both BRAFV600 selective and pan-RAF), MEK1/2 and/or ERK1/2 inhibitors (for patients with BRAF V600 mutant NSCLC, prior treatments with BRAF and MEK1/2 inhibitors are allowed). Patients who have received more than 3 lines of anti-cancer therapy are excluded. History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO. 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. Patients receiving proton pump inhibitors (PPI) which cannot be discontinued 3 days prior to the start study treatment and for the duration of the study. Patients with Gilbert's syndrome or other heritable diseases of bile processing. Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Single Group 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: LXH254<br>* LXH254 will be supplied as tablet for oral use.<br>Drug: Trametinib<br>* Trametinib will be supplied as film-coated tablet for oral use<br>|
| Experimental: LXH254+Ribociclib<br> | Drug: LXH254<br>* LXH254 will be supplied as tablet for oral use.<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 |
| --- | --- | --- |
| Number of participants with Adverse Events (AEs) as a measure of safety and tolerability |  | up to 5 years | 
| Dose limiting toxicities (DLTs) (dose escalation only) |  | up to 3 years | 
| Tolerability measured by the number of subjects who have interruptions/reductions of study treatment and reason for interruptions/reductions |  | up to 5 years | 
| Tolerability measured by the dose intensity of study drug, Relative Dose intensity for subjects with non-zero duration of exposure is computed as the ratio of dose intensity and planned dose intentity |  | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) |  | Up to 5 years | 
| Duration of response (DOR) |  | Up to 5 years | 
| Disease Control Rate (DCR) |  | Up to 5 years | 
| Progression Free Survival (PFS) |  | Up to 5 years | 
| Overall Survival (OS) - (dose expansion part only) |  | Up to 5 years | 
| Derived PK parameter (Cmax) for LXH254 & LTT462: |  | Up to 5 years | 
| Derived PK parameter (AUC) for LXH254 & LTT462 |  | Up to 5 years | 
| Changes from baseline of pharmacodynamics (PD) marker DUSP6 in tumor samples |  | up to 5 years | 
| Derived PK parameter (Cmax) for LXH254 & trametinib |  | up to 5 years | 
| Derived PK parameter (AUC) for LXH254 & trametinib |  | Up to 5 years | 
| Derived PK parameter (Cmax) for LXH254 & ribociclib |  | Up to 5 years | 
| Derived PK parameter (AUC) for LXH254 & ribociclib |  | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSCLC, Non small cell lung cancer, Melanoma, NRAS, KRAS, BRAF, LXH254, LTT462, Trametinib, Ribocliclib, Non-small cell lung carcinoma (NSCLC), treatment of lung cancer after first metastasis, lung cancer, lung adenocarcinoma, Large-cell lung carcinoma, Non small cell lung carcinoma, Large cell lung carcinoma, Large cell lung cancer, squamous cell lung carcinoma