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

NCT02974725 | Terminated Phase 1 DMC FDA Drug

• 2 other identifiers: CLXH254X21022016-004293-18
• Study Type: interventional
• Target: 241
• Locations: 11 countries
• Sites: 32

Brief Summary

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

Conditions

Non-Small Cell Lung Cancer; Melanoma

Keywords

NSCLC; 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; Non small cell lung cancer; Large cell lung carcinoma; Large cell lung cancer; squamous cell lung carcinoma

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (12)

• 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

Study Arms (3)

LXH254+LTT462

EXPERIMENTAL

Drug: LXH254; Drug: LTT462

LXH254+Trametinib

EXPERIMENTAL

Drug: LXH254; Drug: Trametinib

LXH254+Ribociclib

EXPERIMENTAL

Drug: LXH254; Drug: Ribociclib

Interventions

LXH254 DRUG

LXH254 will be supplied as tablet for oral use.

LXH254+LTT462; LXH254+Ribociclib; LXH254+Trametinib

LTT462 DRUG

LTT462 will be supplied as hard gelatin capsule for oral use.

LXH254+LTT462

Trametinib DRUG

Trametinib will be supplied as film-coated tablet for oral use

LXH254+Trametinib

Ribociclib DRUG

Ribociclib will be supplied in tablets and hard gelatin capsules.

LXH254+Ribociclib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (32)

University of California San Diego .

San Diego, California, 92103, United States

Location

UCSF Medical Center

San Francisco, California, 94143, United States

Location

Massachusetts General Hospital SC

Boston, Massachusetts, 02114, United States

Location

Memorial Sloan Kettering Cancer Ctr .

New York, New York, 10065, United States

Location

Sarah Cannon Research Institute Tennessee Oncology

Nashville, Tennessee, 37203, United States

Location

Uni of TX MD Anderson Cancer Cntr

Houston, Texas, 77030, United States

Location

Novartis Investigative Site

Westmead, New South Wales, 2145, Australia

Location

Novartis Investigative Site

Melbourne, Victoria, 3000, Australia

Location

Novartis Investigative Site

Leuven, 3000, Belgium

Location

Novartis Investigative Site

Lyon, 69373, France

Location

Novartis Investigative Site

Paris, 75475, France

Location

Novartis Investigative Site

Villejuif, 94800, France

Location

Novartis Investigative Site

Cologne, 50937, Germany

Location

Novartis Investigative Site

Dresden, 01307, Germany

Location

Novartis Investigative Site

Essen, 45147, Germany

Location

Novartis Investigative Site

Frankfurt, 60590, Germany

Location

Novartis Investigative Site

Tel Aviv, 6423906, Israel

Location

Novartis Investigative Site

Milan, MI, 20133, Italy

Location

Novartis Investigative Site

Milan, MI, 20162, Italy

Location

Novartis Investigative Site

Rozzano, MI, 20089, Italy

Location

Novartis Investigative Site

Verona, VR, 37126, Italy

Location

Novartis Investigative Site

Napoli, 80131, Italy

Location

Novartis Investigative Site

Warsaw, 02 781, Poland

Location

Novartis Investigative Site

Seoul, 03080, South Korea

Location

Novartis Investigative Site

Seoul, 06351, South Korea

Location

Novartis Investigative Site

Seville, Andalusia, 41013, Spain

Location

Novartis Investigative Site

Barcelona, Catalonia, 08035, Spain

Location

Novartis Investigative Site

Barcelona, Catalonia, 08036, Spain

Location

Novartis Investigative Site

Pamplona, Navarre, 31008, Spain

Location

Novartis Investigative Site

Valencia, Valencia, 46010, Spain

Location

Novartis Investigative Site

Madrid, 28034, Spain

Location

Novartis Investigative Site

Stockholm, 171 76, Sweden

Location

Related Publications (2)

• Planchard D, Wolf J, Solomon B, Sebastian M, Wermke M, Heist RS, Sun JM, Min Kim T, Reguart N, Sanmamed MF, Felip E, Garrido P, Santoro A, Bootle D, Couillebault XM, Gaur A, Mueller C, Poggio T, Yang J, Moschetta M, Dooms C. A phase Ib study of the combination of naporafenib with rineterkib or trametinib in patients with advanced and metastatic KRAS- or BRAF-mutant non-small cell lung cancer. Lung Cancer. 2024 Nov;197:107964. doi: 10.1016/j.lungcan.2024.107964. Epub 2024 Sep 26.

  PMID: 39383771 DERIVED

• de Braud F, Dooms C, Heist RS, Lebbe C, Wermke M, Gazzah A, Schadendorf D, Rutkowski P, Wolf J, Ascierto PA, Gil-Bazo I, Kato S, Wolodarski M, McKean M, Munoz Couselo E, Sebastian M, Santoro A, Cooke V, Manganelli L, Wan K, Gaur A, Kim J, Caponigro G, Couillebault XM, Evans H, Campbell CD, Basu S, Moschetta M, Daud A. Initial Evidence for the Efficacy of Naporafenib in Combination With Trametinib in NRAS-Mutant Melanoma: Results From the Expansion Arm of a Phase Ib, Open-Label Study. J Clin Oncol. 2023 May 10;41(14):2651-2660. doi: 10.1200/JCO.22.02018. Epub 2023 Mar 22.

  PMID: 36947734 DERIVED

Related Links

• Study Results

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Melanoma; Lung Neoplasms; Adenocarcinoma of Lung

Interventions

naporafenib; trametinib; ribociclib

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Skin Diseases; Skin and Connective Tissue Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 23, 2016
• First Posted: November 28, 2016
• Study Start: February 24, 2017
• Primary Completion: April 24, 2024
• Study Completion: April 24, 2024
• Last Updated: April 13, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

KR (2); FR (3); ES (6); IT (5); SE (1); US (6); AU (2); BE (1); DE (4); IL (1); PL (1)