Phase I Study of LXH254 in Patients With Advanced Solid Tumors Haboring MAPK Pathway Alterations

A Phase I Dose Finding Study of Oral LXH254 in Adult Patients With Advanced Solid Tumors Harboring MAPK Pathway Alterations

A Phase I Study of LXH254 in Patients With Advanced Solid Tumors That Harbor MAPK Pathway Alterations.

Study Overview

• Status: Terminated
• Conditions: Melanoma; Ovarian Cancer; NSCLC; Other Solid Tumors
• Intervention / Treatment: Drug: LXH254; Drug: PDR001

• Study Type: Interventional
• Enrollment (Actual): 142
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2C1
      • Novartis Investigative Site
• France
  • Paris Cedex 10, France, 75475
    • Novartis Investigative Site
  • Toulouse, France, 31059
    • Novartis Investigative Site
• Germany
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
• Italy
  • Napoli, Italy, 80131
    • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20133
      • Novartis Investigative Site
  • MO
    • Modena, MO, Italy, 41124
      • Novartis Investigative Site
• Japan
  • Tokyo
    • Chuo ku, Tokyo, Japan, 104 0045
      • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • Novartis Investigative Site
  • Rotterdam, Netherlands, 3075 CE
    • Medical Oncology, Erasmus MC
• Spain
  • Madrid, Spain, 28046
    • Novartis Investigative Site
  • Madrid, Spain, 28009
    • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
• Switzerland
  • Zuerich, Switzerland, 8091
    • Novartis Investigative Site
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital MGH Cancer Center
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center SC - LXH254X2101
  • Texas
    • Houston, Texas, United States, 77030
      • UT M.D Anderson Cancer Center SC - LXH254X2101

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• All patients participating in this clinical trial must have progressed following standard therapy, or for whom, in the opinion of the Investigator, no effective standard therapy exists, is tolerated or appropriate.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
• Presence of at least one measurable lesion according to RECIST v1.1.
• Documented MAPK alteration

Additional inclusion criteria for the Dose Expansion part: LXH254 in combination with PDR001:

• Patients with confirmed KRAS-mutated NSCLC
• Patients with confirmed NRAS-mutated melanoma (cutaneous melanoma only)

Exclusion Criteria:

- Prior treatment with a BRAFi, MEKi and/or pan-RAF inihibitors for patients to be enrolled in the dose expansion part.

Exceptions may be made after documented agreement between Novartis and Investigator.

• 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 which cannot be discontinued 3 days prior to the start study treatment and for the duration of the study.
• Pregnant or nursing (lactating) women

Additional exclusion criteria for LXH254 in combination with PDR001

• History of severe hypersensitivity reactions, which in the opinion of the investigator may cause in increased risk of serious infusion reaction.
• Known human immunodeficiency virus (HIV).
• Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection.
• Active, known or suspected autoimmune disease.
• Active infection requiring systemic antibiotic therapy
• Patients requiring systemic steroid therapy or any immunosuppressive therapy (≥10mg/day prednisone or equivalent) which cannot be discontinued at least 7 days prior to first dose of study treatment.
• Use of any live vaccines against infectious diseases within 4 weeks of initiation of study treatment.

Other inclusion/exclusion criteria as per protocol may apply.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose escalation LXH254	Drug: LXH254; pan-RAF inhibitor
Experimental: Dose expansion LXH254: Group 1	Drug: LXH254; pan-RAF inhibitor
Experimental: Dose expansion LXH254: Group 2	Drug: LXH254; pan-RAF inhibitor
Experimental: Dose expansion LXH254: Group 3	Drug: LXH254; pan-RAF inhibitor
Experimental: Dose expansion: LXH254 + PDR001	Drug: LXH254; pan-RAF inhibitor; Drug: PDR001; Biological: PDR001 anti-PD1 antibody
Experimental: Dose escalation LXH254 + PDR001	Drug: LXH254; pan-RAF inhibitor; Drug: PDR001; Biological: PDR001 anti-PD1 antibody

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability as assessed by incidence and severity of adverse events (AEs), dose interruptions, reductions, and dose intensity.	cycle = 28 days	From Cycle 1 Day 1 until 30 days for LXH254 single agent and 150 days for LXH254 in combination with PDR001 post study treatment (expected duration approximately 12 months)
Incidence and nature of dose limiting toxicities (DLTs) (dose escalation and LXH254 single agent only)	cycle = 28 days	28 days
Incidence and nature of dose limiting toxicities (DLTs) (dose escalation and LXH254 in combination with PDR001 only)	cycle =28 days	56 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR)	cycle = 28 days	Every 2 cycles after starting study treatment until end of treatment; expected duration approximately 12 months
Disease control rate (DCR)	cycle = 28 days	Every 2 cycles after starting study treatment until end of treatment; expected duration approximately 12 months
Duration of response (DoR)	cycle = 28 days	Every 2 cycles after starting study treatment until end of treatment; expected duration approximately 12 months
Progression-free survival (PFS)	cycle = 28 days	Every 2 cycles after starting study treatment until disease progression; expected duration approximately 12 months
Overall survival (OS) - only for dose expansion	cycle = 28 days	From time of start treatment until the date of death; expected duration approximately 12 months
Plasma concentrations of LXH254	cycle = 28 days	Cycle 1 days 1, 2, 3, 8, 15, and 16; Cycle 2 days 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1
Derived PK parameters of LXH254: Area Under the Curve (AUC)	cycle = 28 days	Cycle 1 days 1, 2, 3, 8, 15, and 16; Cycle 2 days 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1
Derived PK parameters of LXH254: Peak Plasma Concentration (Cmax)	cycle = 28 days	Cycle 1 days 1, 2, 3, 8, 15, and 16; Cycle 2 days 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1
Derived PK parameters of LXH254: Time to Peak Plasma Concentration (Tmax)	cycle = 28 days	Cycle 1 days 1, 2, 3, 8, 15, and 16; Cycle 2 days 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1
Derived PK parameters of LXH254: half-life (T1/2)	cycle = 28 days	Cycle 1 days 1, 2, 3, 8, 15, and 16; Cycle 2 days 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1
Changes from baseline of pharmacodynamics (PD) marker DUSP6 in tumor tissue and in blood	cycle = 28 days	Cycle 1 day 1, 2, 3, 15, and 16; upon disease progression (expected duration approximately 12 months)
Plasma concentrations of PDR001	cycle = 28 days	Cycle 1 days 1, 2, 8, and 15; Cycle 2 days 1; Cycle 3 Day 1, 2 and 8; Cycle 4 Day 1; Cycle 5 Day 1; Cycle 6 Day 1
Derived PK parameters of PDR001: Area Under the Curve (AUC)	cycle = 28 days	Cycle 1 days 1, 2, 8, and 15; Cycle 2 days 1; Cycle 3 Day 1, 2 and 8; Cycle 4 Day 1; Cycle 5 Day 1; Cycle 6 Day 1
Derived PK parameters of PDR001: Peak Plasma Concentration (Cmax)	cycle = 28 days	Cycle 1 days 1, 2, 8, and 15; Cycle 2 days 1; Cycle 3 Day 1, 2 and 8; Cycle 4 Day 1; Cycle 5 Day 1; Cycle 6 Day 1
Derived PK parameters of PDR001: Time to Peak Plasma Concentration (Tmax)	cycle = 28 days	Cycle 1 days 1, 2, 8, and 15; Cycle 2 days 1; Cycle 3 Day 1, 2 and 8; Cycle 4 Day 1; Cycle 5 Day 1; Cycle 6 Day 1
Derived PK parameters of PDR001: half-life (T1/2)	cycle = 28 days	Cycle 1 days 1, 2, 8, and 15; Cycle 2 days 1; Cycle 3 Day 1, 2 and 8; Cycle 4 Day 1; Cycle 5 Day 1; Cycle 6 Day 1

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• Study Results

Study record dates

Study Major Dates

• Study Start (Actual): January 18, 2016
• Primary Completion (Actual): February 18, 2022
• Study Completion (Actual): February 19, 2022

Study Registration Dates

• First Submitted: November 5, 2015
• First Submitted That Met QC Criteria: November 17, 2015
• First Posted (Estimate): November 18, 2015

Study Record Updates

• Last Update Posted (Actual): December 21, 2022
• Last Update Submitted That Met QC Criteria: December 20, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: LXH254, CRAF, MAPK, solid tumor, PDR001
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immune Checkpoint Inhibitors; Spartalizumab
• Other Study ID Numbers: CLXH254X2101; 2015-003421-33 (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