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

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

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

Conditions
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NSCLC, Ovarian Cancer, Melanoma, Other Solid Tumors

Intervention / Treatment
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* Drug: LXH254
* Drug: PDR001


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LXH254, CRAF, MAPK, solid tumor, PDR001