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

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

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

Study Overview

• Status: Active, not recruiting
• Conditions: Melanoma
• Intervention / Treatment: Drug: LXH254; Drug: LTT462; Drug: Trametinib; Drug: Ribociclib

• Study Type: Interventional
• Enrollment (Actual): 134
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1426ANZ
      • Novartis Investigative Site
• Australia
  • New South Wales
    • North Sydney, New South Wales, Australia, 2060
      • Novartis Investigative Site
  • Queensland
    • Wooloongabba, Queensland, Australia, 4102
      • Novartis Investigative Site
  • Western Australia
    • Subiaco, Western Australia, Australia, 6008
      • Novartis Investigative Site
• Belgium
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
  • Wilrijk, Belgium, 2610
    • Novartis Investigative Site
• France
  • Lille Cedex, France, 59037
    • Novartis Investigative Site
  • Marseille Cedex 05, France, 13885
    • Novartis Investigative Site
  • Paris 10, France, 75475
    • Novartis Investigative Site
  • Pierre Benite, France, 69495
    • Novartis Investigative Site
  • Toulouse, France, 31059
    • Novartis Investigative Site
  • Villejuif, France, 94800
    • Novartis Investigative Site
• Germany
  • Dresden, Germany, 01307
    • Novartis Investigative Site
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
  • Tuebingen, Germany, 72076
    • Novartis Investigative Site
• Israel
  • Ramat Gan, Israel, 52621
    • Novartis Investigative Site
• Italy
  • Napoli, Italy, 80131
    • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20133
      • Novartis Investigative Site
• Netherlands
  • Maastricht, Netherlands, 6229 HX
    • Novartis Investigative Site
• Norway
  • Oslo, Norway, 0379
    • Novartis Investigative Site
• Switzerland
  • Lausanne, Switzerland, 1011
    • Novartis Investigative Site
  • Zuerich, Switzerland, 8091
    • Novartis Investigative Site
• United Kingdom
  • Manchester, United Kingdom, M20 2BX
    • Novartis Investigative Site
• United States
  • California
    • Los Angeles, California, United States, 90025
      • The Angeles Clinic and Research Institute .
    • San Francisco, California, United States, 94143
      • UCSF Medical Center .
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Florida Cancer Specialists Sarasota Office
    • Tampa, Florida, United States, 33612
      • H Lee Moffitt Cancer Center and Research Institute Moffitt McKinley Outpatient Ct
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute Dept.of DFCI
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Mayo Rochester
  • New York
    • New York, New York, United States, 10016
      • NYU Laura and Isaac Perlmutter Cancer Center
    • New York, New York, United States, 10017
      • Memorial Sloan Kettering Dept. of MSKCC
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • University of TX MD Anderson Cancer Center .

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 120 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel 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: Trametinib; Trametinib will be supplied as film-coated tablet for oral use
Experimental: LXH254 + ribociclib	Drug: Ribociclib; Ribociclib will be supplied in tablets and hard gelatin capsules.

What is the study measuring?

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
Overall Survival (OS)		4 years
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
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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Moschos SJ. War against NRAS-Mutant Melanoma Using Targeted Therapies Remains Challenging. Clin Cancer Res. 2022 Jul 15;28(14):2977-2979. doi: 10.1158/1078-0432.CCR-22-1256.

Study record dates

Study Major Dates

• Study Start (Actual): October 30, 2020
• Primary Completion (Estimated): April 26, 2024
• Study Completion (Estimated): April 26, 2024

Study Registration Dates

• First Submitted: June 3, 2020
• First Submitted That Met QC Criteria: June 3, 2020
• First Posted (Actual): June 4, 2020

Study Record Updates

• Last Update Posted (Actual): October 23, 2023
• Last Update Submitted That Met QC Criteria: October 19, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Melanoma; Trametinib; LXH254; BRAF; NRAS; LTT462; Ribocliclib
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Trametinib; Naporafenib
• Other Study ID Numbers: CLXH254C12201; 2020-000873-26 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

Drug and device information, study documents

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