Subjects from the Safety Population who had GSK PK parameter estimates from any portion of the study. Cohort 1 (N=8)

Transcription

1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. GSK Medicine: Study Number: Title: A Phase 1, Randomized, -Controlled, Double-Blind, Ascending Dose Escalating, 4 Period Crossover Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Food Effect of Single Doses of, a REarranged during Transfection (RET) Growth Factor Receptor Tyrosine Kinase Inhibitor, in Normal Healthy Volunteers Rationale: This study was the first administration of to humans. Phase: I Study Period: 26-NOV-1016 to 18-MAR-2016 Study Design: This was a randomized, double-blind (sponsor unblind), placebo-controlled, dose escalating, fourperiod, single-dose crossover, first time in human study. The study was composed of 2 cohorts, each having Screening, Treatment, and Follow-up Periods. The Treatment Period included up to 4 Dosing Periods. A subject s total time involved in the study was approximately 10 weeks. Subjects participated in either Cohort 1 or Cohort 2. Subjects assigned to Cohort 1 participated in 1 placebo and 3 dose escalating periods. Subjects assigned to Cohort 2 participated in a pilot food effect study in Periods 1 and 2. Within each cohort, subjects returned for their next scheduled dosing period approximately 14 days after administration of the single dose of study drug during the prior dosing period. Cohort 2 proceeded after completion of the treatment periods in Cohort 1. Centres: Conducted at a single site in Australia Indication: No applicable Treatment: (5, 25, ) and matched placebo (manufactured by Aptuit/GSK) were provided as uncoated, white to slightly colored round or oblong tablets. Objectives: To evaluate the safety and tolerability of escalating single oral doses of under fasting conditions in healthy adult subjects To evaluate the pharmacokinetic parameters of escalating single oral doses of under fasting and fed (for one dose only) conditions in healthy adult subjects Primary Endpoints: The primary endpoints were clinical safety and tolerability data including spontaneous AE reporting, clinical observations, physical examination findings, 12-lead electrocardiograms (ECG), vital signs, Bristol Stool Form Scores (BSFS), and clinical laboratory tests.. Secondary Endpoints: The secondary endpoints were pharmacokinetic (PK) data generated from plasma drug concentrations obtained at various times following administration. PK parameters including area under the plasma concentration versus time curve [AUC(0-t), AUC(0 ), AUC(0-24h)] Cmax, (tmax), terminal half-life (t1/2), CL/F, V/F, and Ka as data permitted Statistical Methods: Safety Analyses: No formal statistical analyses were performed; these data were descriptively summarized. PK analyses: There was no formal hypothesis testing; however, there were statistical analyses done for dose proportionality and a food effect comparison. The PK data were descriptively summarized.. Study Population: Key eligibility criteria included healthy, non smoking, males and females 18 to 55 years of age. Women were of nonchildbearing potential. Number of Subjects: Population Definition Cohort 1 Cohort 2 Intent-to-Treat (ITT) All randomized subjects 8 (100%) 8 (100%) Safety Subjects who received at least one dose of study treatment 8 (100%) 8 (100%) PK Subjects from the Safety Population who had PK parameter estimates from any portion of the study 8 (100%) 6 (75%) Demographics Cohort 1 Cohort 2 All Subjects (N=16) Age (years) Mean (SD) (13.34) (15.65) (14.12) Median Min, Max 18.0, , ,

2 Gender Male 7 (87.5%) 7 (87.5%) 14 (87.5%) Female 1 (12.5%) 1 (12.5%) 2 (12.5%) Non-Child Bearing Potential Surgically sterilized 1 (100.0%) 0 1 (50.0%) Post-menopausal with last menses > 12 months 0 1 (100.0%) 1 (50.0%) Race White 8 (100.0%) 8 (100.0%) 16 (100.0%) Ethnicity Hispanic or Latino 0 1 (12.5%) 1 (6.3%) Not Hispanic or Latino 8 (100.0%) 7 (87.5%) 15 (93.8%) Pharmacokinetic Results: Summary of Selected Plasma Pharmacokinetic Parameters (PK Population) Cohort 1 and 2 (fasted) Parameter Treatment n Geometric Mean (CVb%) 95% CI (645) 0.378, (68.2) 13.6, 49.7 AUC LST (h*ng/ml) 100mg (52.6) 27.9, 78.8 (common name: AUC last) (113) 29.1, (60.0) 114, 364 AUC INT (h*ng/ml) (common name: AUC(0-24)) CMAX (ng/ml) TMAX (h) 1 MRT EVLST (h) (common name: MRT last) AUC IFO (h*ng/ml) (common name: AUC infinity) LAMZHL (h) (common name: t1/2) NA: Not applicable 1. median (range) 2 NA NA 4 NA NA 100mg (24.5) 29.4, (25.1) 43.5, (35.5) 78.4, (41.3) 1.10, (25.5) 1.77, mg (31.8) 2.11, (21.9) 2.93, (33.0) 5.26, ( ) NA ( ) NA 100mg ( ) NA ( ) NA ( ) NA (58.5) 3.50, (44.8) 6.93, mg (33.2) 10.8, (81.6) 7.98, (27.8) 17.5, (56.0) 148, (46.1) 13.0, 32.8 Summary of Plasma Pharmacokinetic Parameters for the Pilot Food Effect (PK Population) Cohort 2 (100mg fasted and 100mg fed) Parameter Treatment n Geometric Mean (CVb%) 95% CI AUC LST (h*ng/ml) 100mg fasted (52.6) 27.9, 78.8 (common name: AUC last) 100mg fed (28.2) 354, 633 AUC IFO (h*ng/ml) 100mg fasted 6 NA NA (common name: AUC infinity) 100mg fed (27.0) 382, 662 CMAX (ng/ml) 100mg fasted (31.8) 2.11, mg fed (20.7) 18.5, 28.4 TMAX (h) 1 100mg fasted ( ) NA 100mg fed ( ) NA 2

3 TLAG (h) 1 MRT EVLST (h) (common name: MRT last) LAMZHL (h) (common name: t1/2) 100mg fasted ( ) NA 100mg fed ( ) NA 100mg fasted (33.2) 10.8, mg fed (9.66) 20.0, mg fasted 6 NA NA 100mg fed (11.9) 13.5, 17.3 NA: Not applicable 1. median (range) Safety Results: AEs were collected from the start of Study Treatment until the follow-up contact. Cohort 1 Subjects with at least one TEAE 3 (37.5%)11 4 (66.7%)11 2 (33.3%)2 4 (66.7%) 9 3 (50.0%) 4 Gastrointestinal disorders 1 (12.5%)2 1 (16.7%)1 2 (33.3%)2 1 (16.7%)1 0 Flatulence 1 (12.5%)2 1 (16.7%)1 0 1 (16.7%)1 0 Abdominal discomfort Chapped lips (16.7%)1 0 0 Diarrhoea (16.7%)1 0 0 General disorders and administration site conditions 0 2 (33.3%) (33.3%)2 1 (16.7%)1 Catheter site pain 0 1 (16.7%)2 0 1 (16.7%)1 0 Catheter site erythema (16.7%)1 Catheter site bruise 0 1 (16.7%) Catheter site swelling 0 1 (16.7%) Fatigue (16.7%)1 0 Nervous system disorders 0 1 (16.7%)1 0 1 (16.7%)1 0 Headache 0 1 (16.7%)1 0 1 (16.7%)1 0 Paraesthesia Injury, poisoning and procedural complications 0 2 (33.3%) (16.7%)1 1 (16.7%)2 Contusion 0 2 (33.3%) (16.7%)1 Arthropod bite Joint injury 0 1 (16.7%) Skin abrasion (16.7%)1 Sunburn (16.7%)1 0 Respiratory, thoracic and mediastinal disorders 1 (12.5%)2 1 (16.7%)1 0 2 (33.3%) 3 0 Nasal congestion 1 (12.5%) Dry throat 1 (12.5%) Epistaxis (16.7%)1 0 Productive cough 0 1 (16.7%) Rhinorrhoea (16.7%)1 0 Tonsillolith (16.7%)1 0 Musculoskeletal and connective tissue disorders 1 (12.5%) Back pain 1 (12.5%) Musculoskeletal discomfort 1 (12.5%)

4 Neck pain 1 (12.5%) Pain in extremity Infections and infestations 1 (12.5%) (16.7%)1 0 Pharyngitis 1 (12.5%) Rhinitis (16.7%)1 0 Upper respiratory tract infection Skin and subcutaneous tissue disorders 1 (12.5%)1 1 (16.7%) (16.7%)1 Dermatitis contact 0 1 (16.7%) (16.7%)1 Papule 1 (12.5%) Ear and labyrinth disorders 1 (12.5%) Eustachian tube dysfunction 1 (12.5%) Vascular disorders 1 (12.5%) Thrombophlebitis superficial 1 (12.5%) Cohort 2 + Food Subjects with at least one TEAE 1 (50.0%) 2 1 (50.0%) 3 3 (50.0%) 6 2 (33.3%) 2 Gastrointestinal disorders 0 1 (50.0%) 1 1 (16.7%) 1 0 Flatulence Abdominal discomfort 0 1 (50.0%) 1 1 (16.7%) 1 0 Chapped lips Diarrhoea General disorders and administration site conditions (16.7%) 1 Catheter site pain Catheter site erythema (16.7%) 1 Catheter site bruise Catheter site swelling Fatigue Nervous system disorders 1 (50.0% ) (33.3%) 4 0 Headache 1 (50.0% ) (33.3% ) 3 0 Paraesthesia (16.7% ) Food Injury, poisoning and procedural complications (16.7% ) 1 Contusion Arthropod bite (16.7% ) 1 Joint injury Skin abrasion Sunburn

5 Most Frequent Adverse Events On-Therapy Headache 0 1 (16.7%)1 0 1 (16.7%)1 0 + Food All Subjects (N=16) Headache 1 (50.0% ) (33.3% ) (31.3%) 7 Serious Adverse Events - On-Therapy: There were no deaths, other serious TEAEs, or withdrawals due to TEAEs. Conclusion: Single dose administration of ranging from to in the fasted state and 100mg in the fed state was in general safe and well tolerated in healthy adult men and women. In the fasted state, AUCLST increased with increasing doses however significantly less than dose proportional. CMAX increased only slightly with increasing doses and was significantly less than dose proportional. These parameters were variable. The median TMAX was consistently 5.0 hours for all dose groups. With fasted and fed dose levels, the geometric mean plasma half-lives were 20.7 and 15.3 hours, respectively. There was a significant food effect on a 100mg dose of administered 30 minutes after a highfat, high-calorie FDA breakfast meal on AUCLST and CMAX. The geometric mean ratio comparing fed to fasted for AUCLST and CMAX was approximately 10-fold and 8-fold, respectively. To appropriately use this template, the Legal Review-Rejected and Exempt Manuscript Guidance for Summary Writers document (see below) must be reviewed and used in conjunction with this template. Please delete these instructions and guidance document below prior to loading into VCTR. 5