The LOGIC 2 Trial A Phase II, Multi-center, Open-label Study of Sequential LGX818/MEK162 Combination Followed by a Rational Combination With Targeted Agents After Progression, to Overcome Resistance in Adult Patients With Locally Advanced or Metastatic BRAF V600 Melanoma.

简要总结

详细描述

主要结局

次要结局

• Number of Participants With Worst Post-baseline Hematology Results Based on Common Terminology Criteria for Adverse Events (CTCAE) v4.03 Grade: Part I(Baseline up to last dose (maximum treatment exposure for Part I was 403.7 weeks))
• Number of Participants With Worst Post-baseline Hematology Results Based on CTCAE v4.03 Grade: Part II(Baseline up to last dose (maximum treatment exposure for Part II was 97.0 weeks))
• Number of Participants With Worst Post-baseline Serum Chemistry Results Based on CTCAE v4.03 Grade: Part II(Baseline up to last dose (maximum treatment exposure for Part II was 97.0 weeks))
• Number of Participants With At Least One Dose Reduction: Part II(During study treatment (maximum treatment exposure for Part II was 97.0 weeks))
• Actual Dose Intensity: Part I(During study treatment (maximum treatment exposure for Part I was 403.7 weeks))
• Last Measurable Plasma Concentration at Steady State (Clast, ss) of Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Infigratinib, Infigratinib Metabolites, Capmatinib, and Buparlisib: Part II(C1 D15: 0.5 hour ± 10 min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2 hour)
• Measured Concentration at the End of a Dosing Interval at Steady State (Ctrough, ss) of Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Infigratinib, Infigratinib Metabolites, Capmatinib, and Buparlisib: Part II(C1 D15: at the end of a dosing interval at steady-state (24 hour ± 2 hour), taken directly before next administration)
• Number of Participants With Dose Limiting Toxicities (DLTs) in Cycle 1: Part II(Cycle 1 (21 days following the first dose of the combination treatment with buparlisib and capmatinib; 28 days for the combination with ribociclib and infigratinib))
• Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs): Part I(Day 1 up to 30 days after last dose (maximum treatment exposure for Part I was 403.7 weeks))
• Number of Participants With AEs and SAEs: Part II(Day 1 up to 30 days after last dose (maximum treatment exposure for Part II was 97.0 weeks))
• Number of Participants With At Least One Dose Interruption: Part II(During study treatment (maximum treatment exposure for Part II was 97.0 weeks))
• Number of Participants With At Least One Dose Reduction: Part I(During study treatment (maximum treatment exposure for Part I was 403.7 weeks))
• Actual Dose Intensity: Part II(During study treatment (maximum treatment exposure for Part II was 97.0 weeks))
• Duration of Response (DOR): Part I(From date of first documented response (CR or PR) till the date of first documented progression or death due to underlying cancer or censoring date (maximum treatment exposure for Part I was 403.7 weeks))
• Number of Participants With Worst Post-baseline Serum Chemistry Results Based on CTCAE v4.03 Grade: Part I(Baseline up to last dose (maximum treatment exposure for Part I was 403.7 weeks))
• Number of Participants With Newly Occurring Notably Abnormal Vital Signs: Part I(During study treatment (maximum treatment exposure for Part I was 403.7 weeks))
• Number of Participants With Newly Occurring Notably Abnormal Vital Signs: Part II(During study treatment (maximum treatment exposure for Part II was 97.0 weeks))
• Number of Participants With Notable Electrocardiograms (ECG) Values: Part I(During study treatment (maximum treatment exposure for Part I was 403.7 weeks))
• Number of Participants With Notable ECG Values: Part II(During study treatment (maximum treatment exposure for Part II was 97.0 weeks))
• Number of Participants With At Least One Dose Interruption: Part I(During study treatment (maximum treatment exposure for Part I was 403.7 weeks))
• Progression-Free Survival (PFS): Part I(From start of study drug until documented PD or death due to any cause or censoring date (maximum treatment exposure for Part I was 403.7 weeks))
• PFS: Part II(From start of study drug until documented PD or death due to any cause or censoring date (maximum treatment exposure for Part II was 97.0 weeks))
• TTR: Part II(From start date of study drug till first documented response (CR or PR) (maximum treatment exposure for Part II was 97.0 weeks))
• Summary of Genomic Biomarkers From Tumor Samples: Part I(Baseline up to end of treatment (EOT) (maximum treatment exposure for Part I was 403.7 weeks))
• Plasma Concentration for Encorafenib (LGX): Part II(C1 (1.5, 4 hrs post-dose on D1; pre-dose on D8; pre-dose, 0.5, 1.5, 2.5, 4, 6, 8 hrs post-dose on D15; 24 hrs post-dose on D16; pre-dose on D21); C2 (pre-dose on D1 and D15); C3 pre-dose on D1; C4 pre-dose on D1; C5 pre-dose on D1; EOT)
• Plasma Concentration for Binimetinib (MEK) and Its Metabolite: Part I(C1 (1.5 hrs post-dose on D1; pre-dose, 1.5 hrs post-dose on D15); C2 (pre-dose on D8 and D21); C3 pre-dose on D15; C4 pre-dose on D15; C5 pre-dose on D15; EOT)
• DOR: Part II(From date of first documented response (CR or PR) till the date of first documented progression or death due to underlying cancer or censoring date (maximum treatment exposure for Part II was 97.0 weeks))
• Time to Response (TTR): Part I(From start date of study drug till first documented response (CR or PR) (maximum treatment exposure for Part I was 403.7 weeks))
• Apparent Volume of Distribution at Steady State (Vz, ss/F) of Encorafenib, Binimetinib, Ribociclib, Capmatinib, and Buparlisib: Part II(C1 D15: 0.5 hour ± 10 min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2 hour)
• Disease Control Rate (DCR): Part I(From start date of study drug till first documented response (CR or PR or SD) (maximum treatment exposure for Part I was 403.7 weeks))
• DCR: Part II(From start date of study drug till first documented response (CR or PR or SD) (maximum treatment exposure for Part II was 97.0 weeks))
• Overall Survival (OS): Part II(From date of start of treatment to date of death due to any cause or censoring date (maximum treatment exposure for Part II was 97.0 weeks))
• Plasma Concentration for Encorafenib (LGX): Part I(C1 (1.5 hrs post-dose on D1; pre-dose, 1.5 hrs post-dose on D15); C2 (pre-dose on D8 and D21); C3 pre-dose on D15; C4 pre-dose on D15; C5 pre-dose on D15; EOT)
• Plasma Concentration for Binimetinib (MEK) and Its Metabolite: Part II(C1 (1.5, 4 hrs post-dose on D1; pre-dose on D8; pre-dose, 0.5, 1.5, 2.5, 4, 6, 8 hrs post-dose on D15; 24 hrs post-dose on D16; pre-dose on D21); C2 (pre-dose on D1 and D15); C3 pre-dose on D1; C4 pre-dose on D1; C5 pre-dose on D1; EOT)
• Plasma Concentration for Ribociclib (LEE) and Its Metabolite: Part II(C1 (1.5, 4 hrs post-dose on D1; pre-dose on D8; pre-dose, 0.5, 1.5, 2.5, 4, 6, 8 hrs post-dose on D15; 24 hrs post-dose on D16; pre-dose on D21); C2 (pre-dose on D1 and D15); C3 pre-dose on D1; C4 pre-dose on D1; C5 pre-dose on D1; EOT)
• Plasma Concentration for Infigratinib (BGJ) and Its Metabolites: Part II(C1 (1.5 hrs post-dose on D1; pre-dose on D8; pre-dose, 0.5, 1.5, 2.5, 4, 6 hrs post-dose on D15; 24 hrs post-dose on D16; pre-dose on D21); C2 (pre-dose on D1 and D15); C3 pre-dose on D1; EOT)
• Plasma Concentration for Capmatinib (INC): Part II(C1 (1.5 hrs post-dose on D1; pre-dose on D8; pre-dose, 0.5, 1.5, 2.5, 4, 6, 8 hrs post-dose on D15; 24 hrs post-dose on D16); C2 (pre-dose on D1 and D15); C3 pre-dose on D1; C4 pre-dose on D1; C5 pre-dose on D1; EOT)
• Plasma Concentration for Buparlisib (BKM): Part II(C1 (1.5 hrs post-dose on D1; pre-dose on D8; pre-dose, 0.5, 1.5, 2.5, 4, 6, 8 hrs post-dose on D15; 24 hrs post-dose on D16); C2 (pre-dose on D1 and D15); C3 pre-dose on D1; C4 pre-dose on D1; C5 pre-dose on D1; EOT)
• Maximum Observed Plasma Concentration at Steady State (Cmax,ss) for Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Infigratinib, Infigratinib Metabolites, Capmatinib, and Buparlisib: Part II(C1 D15: 0.5 hour ± 10 (minutes) min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2 hour)
• Apparent Total Plasma Clearance at Steady State (Cl, ss/F) of Encorafenib, Binimetinib, Ribociclib, Capmatinib, and Buparlisib: Part II(C1 D15: 0.5 hour ± 10 min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2 hour)
• Time to Reach Cmax at Steady State (Tmax, ss) for Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Infigratinib, Infigratinib Metabolites, Capmatinib, and Buparlisib: Part II(C1 D15: 0.5 hour ± 10 min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2 hour)
• Area Under the Concentration-time Curve From Time Zero to Time Tau at Steady-State (AUCtau,ss) for Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Capmatinib, and Buparlisib: Part II(C1 D15: 0.5 hour ± 10 min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2 hour)
• Elimination Half-life at Steady State (t1/2, ss) of Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Capmatinib, and Buparlisib: Part II(C1 D15: 0.5 hour ± 10 min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2 hour)