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

• ClinicalTrials.gov Identifier: NCT02607813
• Recruitment Status: Terminated
• First Posted: November 18, 2015
• Last Update Posted: December 21, 2022
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
NSCLC; Ovarian Cancer; Melanoma; Other Solid Tumors	Drug: LXH254; Drug: PDR001	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 142 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I Dose Finding Study of Oral LXH254 in Adult Patients With Advanced Solid Tumors Harboring MAPK Pathway Alterations
• Actual Study Start Date: January 18, 2016
• Actual Primary Completion Date: February 18, 2022
• Actual Study Completion Date: February 19, 2022

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Safety and tolerability as assessed by incidence and severity of adverse events (AEs), dose interruptions, reductions, and dose intensity. [ Time Frame: 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) ]
   cycle = 28 days
2. Incidence and nature of dose limiting toxicities (DLTs) (dose escalation and LXH254 single agent only) [ Time Frame: 28 days ]
   cycle = 28 days
3. Incidence and nature of dose limiting toxicities (DLTs) (dose escalation and LXH254 in combination with PDR001 only) [ Time Frame: 56 days ]
   cycle =28 days

Secondary Outcome Measures :

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

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, Massachusetts

Massachusetts General Hospital MGH Cancer Center

Boston, Massachusetts, United States, 02114

United States, New York

Memorial Sloan Kettering Cancer Center SC - LXH254X2101

New York, New York, United States, 10065

United States, Texas

UT M.D Anderson Cancer Center SC - LXH254X2101

Houston, Texas, United States, 77030

Canada, Ontario

Novartis Investigative Site

Toronto, Ontario, Canada, M5G 2C1

France

Novartis Investigative Site

Paris Cedex 10, France, 75475

Novartis Investigative Site

Toulouse, France, 31059

Germany

Novartis Investigative Site

Heidelberg, Germany, 69120

Italy

Novartis Investigative Site

Milano, MI, Italy, 20133

Novartis Investigative Site

Modena, MO, Italy, 41124

Novartis Investigative Site

Napoli, Italy, 80131

Japan

Novartis Investigative Site

Chuo ku, Tokyo, Japan, 104 0045

Korea, Republic of

Novartis Investigative Site

Seoul, Korea, Republic of, 03080

Netherlands

Novartis Investigative Site

Groningen, Netherlands, 9713 GZ

Medical Oncology, Erasmus MC

Rotterdam, Netherlands, 3075 CE

Spain

Novartis Investigative Site

Barcelona, Catalunya, Spain, 08035

Novartis Investigative Site

Madrid, Spain, 28009

Novartis Investigative Site

Madrid, Spain, 28046

Switzerland

Novartis Investigative Site

Zuerich, Switzerland, 8091

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

Additional Information:

Study Results 

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02607813
• Other Study ID Numbers: CLXH254X2101; 2015-003421-33 ( EudraCT Number )
• First Posted: November 18, 2015
• Last Update Posted: December 21, 2022
• Last Verified: March 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

LXH254, CRAF, MAPK, solid tumor, PDR001

Additional relevant MeSH terms:

Spartalizumab; Naporafenib; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Immunological; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors