Clinical trial NCT02607813: Phase I Study of LXH254 in Patients With Advanced Solid Tumors Haboring MAPK Pathway Alterations
Official title: A Phase I Dose Finding Study of Oral LXH254 in Adult Patients With Advanced Solid Tumors Harboring MAPK Pathway Alterations
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: NSCLC
Ovarian Cancer
Melanoma
Other Solid Tumors
Keywords: LXH254, CRAF, MAPK, solid tumor, PDR001
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2015-11-18
Enrollment: 142
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


Eligibility 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.

Primary outcomes:
measure: Safety and tolerability as assessed by incidence and severity of adverse events (AEs), dose interruptions, reductions, and dose intensity.
timeFrame: 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)
measure: Incidence and nature of dose limiting toxicities (DLTs) (dose escalation and LXH254 single agent only)
timeFrame: 28 days
measure: Incidence and nature of dose limiting toxicities (DLTs) (dose escalation and LXH254 in combination with PDR001 only)
timeFrame: 56 days
Secondary outcomes:
measure: Overall response rate (ORR)
timeFrame: Every 2 cycles after starting study treatment until end of treatment; expected duration approximately 12 months
measure: Disease control rate (DCR)
timeFrame: Every 2 cycles after starting study treatment until end of treatment; expected duration approximately 12 months
measure: Duration of response (DoR)
timeFrame: Every 2 cycles after starting study treatment until end of treatment; expected duration approximately 12 months
measure: Progression-free survival (PFS)
timeFrame: Every 2 cycles after starting study treatment until disease progression; expected duration approximately 12 months
measure: Overall survival (OS) - only for dose expansion
timeFrame: From time of start treatment until the date of death; expected duration approximately 12 months
measure: Plasma concentrations of LXH254
timeFrame: Cycle 1 days 1, 2, 3, 8, 15, and 16; Cycle 2 days 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1
measure: Derived PK parameters of LXH254: Area Under the Curve (AUC)
timeFrame: Cycle 1 days 1, 2, 3, 8, 15, and 16; Cycle 2 days 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1
measure: Derived PK parameters of LXH254: Peak Plasma Concentration (Cmax)
timeFrame: Cycle 1 days 1, 2, 3, 8, 15, and 16; Cycle 2 days 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1
measure: Derived PK parameters of LXH254: Time to Peak Plasma Concentration (Tmax)
timeFrame: Cycle 1 days 1, 2, 3, 8, 15, and 16; Cycle 2 days 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1
measure: Derived PK parameters of LXH254: half-life (T1/2)
timeFrame: Cycle 1 days 1, 2, 3, 8, 15, and 16; Cycle 2 days 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1
measure: Changes from baseline of pharmacodynamics (PD) marker DUSP6 in tumor tissue and in blood
timeFrame: Cycle 1 day 1, 2, 3, 15, and 16; upon disease progression (expected duration approximately 12 months)
measure: Plasma concentrations of PDR001
timeFrame: 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
measure: Derived PK parameters of PDR001: Area Under the Curve (AUC)
timeFrame: 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
measure: Derived PK parameters of PDR001: Peak Plasma Concentration (Cmax)
timeFrame: 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
measure: Derived PK parameters of PDR001: Time to Peak Plasma Concentration (Tmax)
timeFrame: 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
measure: Derived PK parameters of PDR001: half-life (T1/2)
timeFrame: 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
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital MGH Cancer Center
state: Massachusetts
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center SC - LXH254X2101
state: New York
city: Houston
country: United States
facility: UT M.D Anderson Cancer Center SC - LXH254X2101
state: Texas
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Paris Cedex 10
country: France
facility: Novartis Investigative Site
city: Toulouse
country: France
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Modena
country: Italy
facility: Novartis Investigative Site
state: MO
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Chuo ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Groningen
country: Netherlands
facility: Novartis Investigative Site
city: Rotterdam
country: Netherlands
facility: Medical Oncology, Erasmus MC
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Zuerich
country: Switzerland
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: