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

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

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

Study Overview

• Status: Terminated
• Conditions: Melanoma; Non-Small Cell Lung Cancer
• Intervention / Treatment: Drug: LXH254; Drug: LTT462; Drug: Trametinib; Drug: Ribociclib

• Study Type: Interventional
• Enrollment (Actual): 241
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Novartis Investigative Site
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Novartis Investigative Site
• Belgium
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
• France
  • Lyon, France, 69373
    • Novartis Investigative Site
  • Paris 10, France, 75475
    • Novartis Investigative Site
  • Villejuif, France, 94800
    • Novartis Investigative Site
• Germany
  • Dresden, Germany, 01307
    • Novartis Investigative Site
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Frankfurt, Germany, 60590
    • Novartis Investigative Site
  • Koeln, Germany, 50937
    • Novartis Investigative Site
• Israel
  • Tel Aviv, Israel, 6423906
    • Novartis Investigative Site
• Italy
  • Napoli, Italy, 80131
    • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20162
      • Novartis Investigative Site
    • Milano, MI, Italy, 20133
      • Novartis Investigative Site
    • Rozzano, MI, Italy, 20089
      • Novartis Investigative Site
  • VR
    • Verona, VR, Italy, 37126
      • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 06351
    • Novartis Investigative Site
• Poland
  • Warszawa, Poland, 02 781
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28034
    • Novartis Investigative Site
  • Andalucia
    • Sevilla, Andalucia, Spain, 41013
      • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
    • Barcelona, Catalunya, Spain, 08036
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46010
      • Novartis Investigative Site
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Novartis Investigative Site
• Sweden
  • Stockholm, Sweden, 171 76
    • Novartis Investigative Site
• United States
  • California
    • San Diego, California, United States, 92103
      • University of California San Diego .
    • San Francisco, California, United States, 94143
      • UCSF Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital SC
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Ctr .
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute Tennessee Oncology
  • Texas
    • Houston, Texas, United States, 77030
      • Uni Of TX MD Anderson Cancer Cntr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	Time Frame
Disease Control Rate (DCR)	Up to 5 years
Overall Response Rate (ORR)	Up to 5 years
Duration of response (DOR)	Up to 5 years
Progression Free Survival (PFS)	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
Overall Survival (OS) - (dose expansion part only)	Up to 5 years

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• Study Results

Study record dates

Study Major Dates

• Study Start (Actual): February 24, 2017
• Primary Completion (Actual): April 24, 2024
• Study Completion (Actual): April 24, 2024

Study Registration Dates

• First Submitted: November 23, 2016
• First Submitted That Met QC Criteria: November 23, 2016
• First Posted (Estimated): November 28, 2016

Study Record Updates

• Last Update Posted (Actual): April 13, 2025
• Last Update Submitted That Met QC Criteria: April 9, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: NSCLC; lung cancer; Melanoma; Trametinib; LXH254; lung adenocarcinoma; Non small cell lung cancer; KRAS; Non-small cell lung carcinoma (NSCLC); treatment of lung cancer after first metastasis; Non small cell lung carcinoma; BRAF; NRAS; LTT462; Ribocliclib; Large-cell lung carcinoma; Large cell lung carcinoma; Large cell lung cancer; squamous cell lung carcinoma
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Neoplasms by Histologic Type; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Carcinoma, Bronchogenic; Bronchial Neoplasms; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Melanoma; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Naporafenib; Trametinib
• Other Study ID Numbers: CLXH254X2102; 2016-004293-18 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No