Phase I Study of LXH254 in Patients With Advanced Solid Tumors Haboring MAPK Pathway Alterations
Phase 1
Terminated
- Conditions
- MelanomaOther Solid TumorsNSCLCOvarian Cancer
- Interventions
- Registration Number
- NCT02607813
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
A Phase I Study of LXH254 in Patients With Advanced Solid Tumors That Harbor MAPK Pathway Alterations.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 142
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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Dose expansion LXH254: Group 1 LXH254 - Dose expansion LXH254: Group 3 LXH254 - Dose escalation LXH254 LXH254 - Dose expansion LXH254: Group 2 LXH254 - Dose escalation LXH254 + PDR001 PDR001 - Dose expansion: LXH254 + PDR001 LXH254 - Dose expansion: LXH254 + PDR001 PDR001 - Dose escalation LXH254 + PDR001 LXH254 -
- Primary Outcome Measures
Name Time Method Incidence and nature of dose limiting toxicities (DLTs) (dose escalation and LXH254 in combination with PDR001 only) 56 days cycle =28 days
Incidence and nature of dose limiting toxicities (DLTs) (dose escalation and LXH254 single agent only) 28 days cycle = 28 days
Safety and tolerability as assessed by incidence and severity of adverse events (AEs), dose interruptions, reductions, and dose intensity. 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
- Secondary Outcome Measures
Name Time Method Derived PK parameters of LXH254: half-life (T1/2) 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
Progression-free survival (PFS) Every 2 cycles after starting study treatment until disease progression; expected duration approximately 12 months cycle = 28 days
Plasma concentrations of PDR001 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
Derived PK parameters of LXH254: Peak Plasma Concentration (Cmax) 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
Changes from baseline of pharmacodynamics (PD) marker DUSP6 in tumor tissue and in blood Cycle 1 day 1, 2, 3, 15, and 16; upon disease progression (expected duration approximately 12 months) cycle = 28 days
Derived PK parameters of PDR001: Time to Peak Plasma Concentration (Tmax) 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
Disease control rate (DCR) Every 2 cycles after starting study treatment until end of treatment; expected duration approximately 12 months cycle = 28 days
Overall survival (OS) - only for dose expansion From time of start treatment until the date of death; expected duration approximately 12 months cycle = 28 days
Plasma concentrations of LXH254 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
Derived PK parameters of LXH254: Area Under the Curve (AUC) 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
Overall response rate (ORR) Every 2 cycles after starting study treatment until end of treatment; expected duration approximately 12 months cycle = 28 days
Duration of response (DoR) Every 2 cycles after starting study treatment until end of treatment; expected duration approximately 12 months cycle = 28 days
Derived PK parameters of LXH254: Time to Peak Plasma Concentration (Tmax) 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
Derived PK parameters of PDR001: Area Under the Curve (AUC) 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
Derived PK parameters of PDR001: Peak Plasma Concentration (Cmax) 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
Derived PK parameters of PDR001: half-life (T1/2) 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
Trial Locations
- Locations (5)
Massachusetts General Hospital MGH Cancer Center
🇺🇸Boston, Massachusetts, United States
Novartis Investigative Site
🇨🇭Zuerich, Switzerland
Medical Oncology, Erasmus MC
🇳🇱Rotterdam, Netherlands
UT M.D Anderson Cancer Center SC - LXH254X2101
🇺🇸Houston, Texas, United States
Memorial Sloan Kettering Cancer Center SC - LXH254X2101
🇺🇸New York, New York, United States