Solid Tumors
Conditions
Keywords
Solid tumors, Small-molecule kinase inhibitor
Brief summary
This is a phase I, open-label, 3 treatment period, fixed-sequence study in healthy non-Japanese male subjects, aged 18 to 65 years (inclusive), performed at a single study centre. Treatment Period 1 will establish the single dose pharmacokinetic (PK) profile of savolitinib. Dosing of daily rifampicin during Treatment Period 2 will result in maximal induction of the CYP450 enzymes including CYP3A4. Treatment Period 3 will then establish the single dose PK profile of savolitinib under maximum CYP450 induction conditions. Comparison of the PK profile of savolitinib between Treatment Period 1 and Treatment Period 3 will quantify the effect of CYP450 enzyme induction.
Detailed description
The treatment starts with a single dose of savolitinib (Treatment Period 1), followed by a washout period at least of 14 days after savolitinib dosing and before the start of Treatment Period 2, followed by rifampicin administration for 5 days (Treatment Period 2), and lastly, a combination of savolitinib + rifampicin (Treatment Period 3). Overall, all subjects will receive 2 single doses of 600 mg savolitinib and 7 daily doses of 600 mg rifampicin. Subjects will be resident in the study centre when receiving study drug administrations (savolitinib \[Treatment Period 1\], rifampicin \[Treatment Period 2\] and savolitinib+rifampicin \[Treatment Period 3\]). Subjects are required to fast overnight before each dosing day. Rifampicin will be administered 1 hour before breakfast with 240 mL water. The subjects will need to complete high-fat, high calorie breakfast before administration of savolitinib in Treatment Period 1, Day 1 (Study Day 1) and Treatment Period 3 Day 1 (Study Day 20).
Interventions
DRUGSavolitinib
Patients will receive a single dose on Study Day 1 and Study Day 20. Savolitinib will be administrated after a high fat, high calorie breakfast to reduce the risk of adverse events.
DRUGRifampicin
Patients will receive Rifampicin once daily on Study Day 15, 16, 17, 18, 19, 20 and 21. Rifampicin will be administered 1 hour before breakfast.
Sponsors
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
For inclusion in the study subjects should fulfil the following criteria: 1. Provision of signed and dated, written informed consent prior to any study specific procedures. 2. Healthy male subjects with suitable veins for cannulation or repeated venipuncture: non Japanese male subjects aged 18 to 65 years (inclusive). 3. Have a body mass index between 18 and 30 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive. 4. Alanine aminotransferase, AST and total bilirubin less than or equal to the upper limit of normal for the institution. 5. Have a calculated creatinine clearance greater than 80 mL/min using the Cockcroft-Gault formula at screening. 6. Provision of signed, written and dated informed consent for optional genetic/biomarker research. If a subject declines to participate in the genetic component of the study, there will be no penalty or loss of benefit to the subject. The subject will not be excluded from other aspects of the study described in this clinical study protocol.
Exclusion criteria
Subjects will not enter the study if any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Savolitinib: Maximum plasma concentration (Cmax) ratios of geometric means of test treatment (savolitinib+rifampicin), relative to reference treatment (savolitinib alone) | Treatment Period 1 (Study Days 1 to 14) and Treatment Period 3 (Study Days 20 to 22) at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours after study drug administration | To assess the effect of rifampicin on the PK of savolitinib |
| Area under the curve (AUC) ratios of geometric means of test treatment (savolitnib+rifampicin) relative to reference treatment (savolitinib alone) | Treatment Period 1 (Study Days 1 to 14) and Treatment Period 3 (Study Days 20 to 22) at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours after study drug administration | To assess the effect of rifampicin on the PK of savolitinib |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of subjects with abnormal findings in diastolic BP | At Screening, and from Study Days 1 to 14 and Days 20 to 22 | To assess vital sign as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of subjects with abnormal findings in pulse rate | At Screening, and from Study Days 1 to 14 and Study Days 20 to 22 | To assess vital sign as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of subjects with abnormal findings in electrocardiograms (ECGs) (12-lead ECGs) | At Screening, and from Study Days 1 to 34 | To assess any clinically important abnormalities in cardiovascular function based on the 12-lead ECGs as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of subjects with abnormal findings in physical examinations | At Screening, from Study Days -1 to 22 (brief) and Study Day 34 | To assess any clinically important abnormal findings in physical conditions as a variable of safety and tolerability of savolitinib in combination with rifampicin. The complete physical examinations will include an assessment of the general appearance, respiratory, cardiovascular, abdomen, skin, head and neck, lymph nodes, thyroid, musculoskeletal and neurological systems. The brief physical examinations will include an assessment of the general appearance, skin, abdomen, cardiovascular system and respiratory. |
| Number of subjects with abnormal findings in white blood cell (WBC) count | From Screening to Study Day 34 | To assess the WBC count as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of subjects with abnormal findings in red blood cell (RBC) count | From Screening to Study Day 34 | To assess the RBC count as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of subjects with abnormal findings in hemoglobin (Hb) | From Screening to Study Day 34 | To assess Hb as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of subjects with abnormal findings in hematocrit (HCT) | From Screening to Study Day 34 | To assess HCT as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of subjects with abnormal findings in mean corpuscular volume (MCV) | From Screening to Study Day 34 | To assess MCV as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of subjects with abnormal findings in mean corpuscular hemoglobin (MCH) | From Screening to Study Day 34 | To assess MCH as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of subjects with abnormal findings in mean corpuscular hemoglobin concentration (MCHC) | From Screening to Study Day 34 | To assess MCHC as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of subjects with abnormal findings in neutrophils absolute count | From Screening to Study Day 34 | To assess the neutrophils absolute count as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of subjects with abnormal findings in lymphocytes absolute count | From Screening to Study Day 34 | To assess the lymphocytes absolute count as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of subjects with abnormal findings in monocytes absolute count | From Screening to Study Day 34 | To assess the monocytes absolute count as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of subjects with abnormal findings in eosinophils absolute count | From Screening to Study Day 34 | To assess the eosinophils absolute count as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of subjects with abnormal findings in basophils absolute count | From Screening to Study Day 34 | To assess the basophils absolute count as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of subjects with abnormal findings in platelets | From Screening to Study Day 34 | To assess platelets as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of subjects with abnormal findings in reticulocytes absolute count | From Screening to Study Day 34 | To assess the reticulocytes absolute count as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of subjects with abnormal findings in sodium | From Screening to Study Day 34 | To assess the clinical chemistry value (sodium) as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of subjects with abnormal findings in potassium | From Screening to Study Day 34 | To assess the clinical chemistry value (potassium) as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of subjects with abnormal findings in urea | From Screening to Study Day 34 | To assess the clinical chemistry value (urea) as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of subjects with abnormal findings in creatinine | From Screening to Study Day 34 | To assess the clinical chemistry value (creatinine) as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of subjects with abnormal findings in albumin | From Screening to Study Day 34 | To assess the clinical chemistry value (albumin) as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of subjects with abnormal findings in calcium | From Screening to Study Day 34 | To assess the clinical chemistry value (calcium) as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of subjects with abnormal findings in phosphate | From Screening to Study Day 34 | To assess the clinical chemistry value (phosphate) as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of subjects with abnormal findings in glucose (fasting) | From Screening to Study Day 34 | To assess the clinical chemistry value (glucose \[fasting\]) as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of subjects with abnormal findings in c-reactive protein (CRP) | From Screening to Study Day 34 | To assess the clinical chemistry value (CRP) as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of participants with abnormal findings in liver enzymes | From Screening to Study Day 34 | To assess the clinical chemistry value of liver enzymes as a variable of safety and tolerability of savolitinib in combination with rifampicin. The laboratory variables to be measured are: alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transpeptidase (GGT) |
| Number of subjects with abnormal findings in total bilirubin | From Screening to Study Day 34 | To assess the clinical chemistry value (total bilirubin) as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of subjects with abnormal findings in unconjugated bilirubin | From Screening to Study Day 34 | To assess the clinical chemistry value (unconjugated bilirubin) as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Number of subjects with abnormal findings in urinalysis | From Screening to Study Day 34 | To assess the urinalysis as a variable of safety and tolerability of savolitinib in combination with rifampicin. The laboratory variables to be measured are protein, glucose, and blood. |
| Number of subjects with abnormal findings in urinalysis (microscopy) | From Screening to Study Day 34 | To assess the urinalysis microscopy (if positive for protein or blood) as a variable of safety and tolerability of savolitinib in combination with rifampicin. The laboratory variables to be measures are RBC, WBC, casts (cellular, granular, hyaline). |
| Savolitinib: Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUC[0-t]) ratios of geometric means of test treatment (savolitinib+rifampicin), relative to reference treatment (savolitinib alone) | Treatment Period 1 (Study Days 1 to 14) and Treatment Period 3 (Study Days 20 to 22) at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours after study drug administration | To assess the effect of rifampicin on the PK of metabolites N-desmethyl savolitinib or 3-\[(1S)-1-imidazo\[1,2-a\]pyridin-6-ylethyl\]-5-(1H-pyrazol-4-yl)triazolo\[4,5-b\]pyrazine (M2) and 1-\[(1S)-1-imidazo\[1,2-a\]pyridin-6-ylethyl\]-6-(1 methylpyrazol-4-yl)triazolo\[4,5-b\]pyrazin-5-ol (M3) |
| M2 and M3: Cmax ratios of geometric means of test treatment (savolitinib+rifampicin), relative to reference treatment (savolitinib alone) | Treatment Period 1 (Study Days 1 to 14) and Treatment Period 3 (Study Days 20 to 22) at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours after study drug administration | To describe the PK parameters and the PK profiles for savolitinib, M2 and M3 when savolitinib is administered alone and in combination with rifampicin |
| M2 and M3: AUC ratios of geometric means of test treatment (savolitinib+rifampicin), relative to reference treatment (savolitinib alone) | Treatment Period 1 (Study Days 1 to 14) and Treatment Period 3 (Study Days 20 to 22) at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours after study drug administration | To describe the PK parameters and the PK profiles for savolitinib, M2 and M3 when savolitinib is administered alone and in combination with rifampicin |
| M2 and M3: AUC(0-t) ratios of geometric means of test treatment (savolitinib+rifampicin), relative to reference treatment (savolitinib alone) | Treatment Period 1 (Study Days 1 to 14) and Treatment Period 3 (Study Days 20 to 22) at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours after study drug administration | To describe the PK parameters and the PK profiles for savolitinib, M2 and M3 when savolitinib is administered alone and in combination with rifampicin |
| Savolitinib, M2 and M3: summary PK profiles and descriptive statistics of Cmax | Treatment Period 1 (Study Days 1 to 14) and Treatment Period 3 (Study Days 20 to 22) at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours after study drug administration | To describe the PK parameters and the PK profiles for savolitinib, M2 and M3 when savolitinib is administered alone and in combination with rifampicin |
| Savolitinib, M2 and M3: summary PK profiles and descriptive statistics of AUC | Treatment Period 1 (Study Days 1 to 14) and Treatment Period 3 (Study Days 20 to 22) at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours after study drug administration | To describe the PK parameters and the PK profiles for savolitinib, M2 and M3 when savolitinib is administered alone and in combination with rifampicin |
| Savolitinib, M2 and M3: summary PK profiles and descriptive statistics of AUC(0 t) | Treatment Period 1 (Study Days 1 to 14) and Treatment Period 3 (Study Days 20 to 22) at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours after study drug administration | To describe the PK parameters and the PK profiles for savolitinib, M2 and M3 when savolitinib is administered alone and in combination with rifampicin |
| Savolitinib, M2 and M3: Ratio of metabolite AUC to parent AUC (MRCAUC) | Treatment Period 1 (Study Days 1 to 14) and Treatment Period 3 (Study Days 20 to 22) at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours after study drug administration | To describe the PK parameters and the PK profiles for savolitinib, M2 and M3 when savolitinib is administered alone and in combination with rifampicin |
| Savolitinib, M2 and M3: Ratio of metabolite AUC(0-t) to parent AUC(0-t) (MRCAUC[0-t]) | Treatment Period 1 (Study Days 1 to 14) and Treatment Period 3 (Study Days 20 to 22) at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours after study drug administration | To describe the PK parameters and the PK profiles for savolitinib, M2 and M3 when savolitinib is administered alone and in combination with rifampicin |
| Savolitinib, M2 and M3: metabolite-to-parent ratios for Time to reach maximum observed plasma concentration (tmax) | Treatment Period 1 (Study Days 1 to 14) and Treatment Period 3 (Study Days 20 to 22) at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours after study drug administration | To describe the PK parameters and the PK profiles for savolitinib, M2 and M3 when savolitinib is administered alone and in combination with rifampicin |
| Number of subjects with adverse events | Only SAEs at Screening; AEs from Study Days 1 to 34 | To assess the adverse events as a variable of safety and tolerability of savolitinib in combination with rifampicin |
| Savolitinib, M2 and M3: metabolite-to-parent ratios for terminal elimination rate constant (λz) | Treatment Period 1 (Study Days 1 to 14) and Treatment Period 3 (Study Days 20 to 22) at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours after study drug administration | To describe the PK parameters and the PK profiles for savolitinib, M2 and M3 when savolitinib is administered alone and in combination with rifampicin |
| Savolitinib: Apparent total body clearance of drug from plasms after extravascular administration (parent drug only)CL/F | Treatment Period 1 (Study Days 1 to 14) and Treatment Period 3 (Study Days 20 to 22) at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours after study drug administration | To describe the PK parameters and the PK profiles for savolitinib, when it is administered alone and in combination with rifampicin |
| Savolitinib, M2 and M3: Ratio of metabolite Cmax to parent Cmax (MRCmax) | Treatment Period 1 (Study Days 1 to 14) and Treatment Period 3 (Study Days 20 to 22) at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours after study drug administration | To describe the PK parameters and the PK profiles for savolitinib, M2 and M3 when savolitinib is administered alone and in combination with rifampicin |
| Savolitinib: Apparent volume of distribution during the terminal phase after extravascular administration (parent drug only) (Vz/F) | Treatment Period 1 (Study Days 1 to 14) and Treatment Period 3 (Study Days 20 to 22) at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours after study drug administration | To describe the PK parameters and the PK profiles for savolitinib it is administered alone and in combination with rifampicin |
| Savolitinib, M2 and M3: metabolite-to-parent ratios for Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t1/2,λz) | Treatment Period 1 (Study Days 1 to 14) and Treatment Period 3 (Study Days 20 to 22) at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours after study drug administration | To describe the PK parameters and the PK profiles for savolitinib, M2 and M3 when savolitinib is administered alone and in combination with rifampicin |
| Number of subjects with abnormal findings in systolic blood pressure (BP) | At Screening, and from Study Days 1 to 14 and Study Days 20 to 22 | To assess vital sign as a variable of safety and tolerability of savolitinib in combination with rifampicin |
Countries
United States
Outcome results
None listed