NSCLC, Ovarian Cancer, Melanoma, Other Solid Tumors
Conditions
Keywords
LXH254, CRAF, MAPK, solid tumor, PDR001
Brief summary
A Phase I Study of LXH254 in Patients With Advanced Solid Tumors That Harbor MAPK Pathway Alterations.
Interventions
DRUGLXH254
pan-RAF inhibitor
DRUGPDR001
Biological: PDR001 anti-PD1 antibody
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| Incidence and nature of dose limiting toxicities (DLTs) (dose escalation and LXH254 single agent only) | 28 days | cycle = 28 days |
| Incidence and nature of dose limiting toxicities (DLTs) (dose escalation and LXH254 in combination with PDR001 only) | 56 days | cycle =28 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival (PFS) | Every 2 cycles after starting study treatment until disease progression; 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 |
| 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 |
| 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 |
| Overall response rate (ORR) | Every 2 cycles after starting study treatment until end of treatment; expected duration approximately 12 months | 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 |
| 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 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: 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 |
| 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 |
| 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 |
| Disease control rate (DCR) | 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 |
Countries
Canada, France, Germany, Italy, Japan, Netherlands, South Korea, Spain, Switzerland, United States
Outcome results
None listed