A Phase 1 interventional study of Savolitinib and Rifampicin in Solid Tumors, sponsored by AstraZeneca. Completed at 1 site in United States. Open to male participants aged 18 Years to 65 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2020-04-03.
Sponsored by AstraZeneca · Phase 1, Interventional, and Basic science
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.
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).
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For inclusion in the study subjects should fulfil the following criteria:
Exclusion Criteria:
Subjects will not enter the study if any of the following exclusion criteria are fulfilled:
(1) Systolic BP \< 90 mmHg or ≥ 140 mmHg (2) Diastolic BP \< 50 mmHg or ≥ 90 mmHg (3) Heart rate \< 45 or > 85 beats per minute. 9 Any clinically important abnormalities in rhythm, conduction or morphology of the 12 lead resting ECG that may interfere with the interpretation of QTc interval changes. These include healthy subjects with any of the following:
10 Known or suspected history of drug abuse, as judged by the PI. 11 Current smokers or those who have smoked or used nicotine products within the previous 30 days.
12 History of alcohol abuse or excessive intake of alcohol as judged by the PI. 13 Excessive intake of caffeine-containing drinks or food (e.g., coffee, tea, chocolate,) as judged by the PI.
14 Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks prior to the first administration of the IMP.
15 Any intake of grapefruit, grapefruit juice, Seville oranges, Seville orange marmalade, or other products containing grapefruit or Seville oranges within 7 days of the first admission on Day -1.
16 Use of any prescribed or non-prescribed medication including antacids, analgesics (other than use of ibuprofen up to 72 hours before dosing day), herbal remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks before the first administration of the IMP or longer (5 times the half-life) if the medication has a long half-life. No medications known to prolong the QT/QTc interval and cause TdP are allowed.
17 Positive screen for drugs of abuse, cotinine (nicotine) and/or alcohol at screening and at admission to the Study Centre (Day -1 [Period 1] and Day 14 [Period 2]) to the Study Centre.
18 History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the PI.
19 History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the PI or history of hypersensitivity to drugs with a similar chemical structure or class to savolitinib or rifampicin.
20 Plasma donation within 1 month of screening or any blood donation/blood loss > 500 mL during the 3 months prior to screening.
21 Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of the first administration of IMP in this study. The period of exclusion begins 3 months after the final dose or 1 month after the last visit whichever is the longest.
Note: subjects consented and screened, but not enrolled in this study or a previous phase I study, are not excluded.
22 Involvement of any AstraZeneca, Parexel or study site employee or their close relatives 23 Subjects who have previously received savolitinib. 24 Judgment by the PI that the subject should not participate in the study if they have any ongoing or recent (i.e., during the screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions, and requirements.
25 Subjects who are vegans, vegetarians or have medical dietary restrictions and who are lactose intolerant.
26 Subjects who cannot communicate reliably with the PI. 27 Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.
28 Subjects who wear soft contact lenses, unless the subject is prepared to refrain from wearing soft lenses throughout Period 2 until after the last PK sample collection in Period 3.
Treatment Period 1 consists of 16 days starting with admission on Study Day -1, followed by a single dose administration of savolitinib on Day 1, followed by a washout period of at least 14 days. Subjects will be discharged from the Study Centre on Study Day 3, after the last PK sample is collected Treatment Period 2 consists of 6 days, starting with admission on Study Day 14, followed by QD dose administrations of rifampicin for 5 consecutive days (Study Day 15 to Study Day 19) Treatment Period 3 consists of 4 days, starting immediately after Treatment Period 2, comprising of a single dose administration of savolitinib on Study Day 20 and QD dose administration of rifampicin on Study Day 20 and Study Day 21. Subjects will be discharged from the Study Centre on Study Day 22, after the last PK sample is collected
Drug: Savolitinib · Drug: Rifampicin
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.
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.
Also known as: Rifampin
Savolitinib: Maximum plasma concentration (Cmax) ratios of geometric means of test treatment (savolitinib+rifampicin), relative to reference treatment (savolitinib alone)
To assess the effect of rifampicin on the PK of savolitinib
Time frame: 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
Area under the curve (AUC) ratios of geometric means of test treatment (savolitnib+rifampicin) relative to reference treatment (savolitinib alone)
To assess the effect of rifampicin on the PK of savolitinib
Time frame: 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
Number of subjects with adverse events
To assess the adverse events as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: Only SAEs at Screening; AEs from Study Days 1 to 34
Number of subjects with abnormal findings in systolic blood pressure (BP)
To assess vital sign as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: At Screening, and from Study Days 1 to 14 and Study Days 20 to 22
Number of subjects with abnormal findings in diastolic BP
To assess vital sign as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: At Screening, and from Study Days 1 to 14 and Days 20 to 22
Number of subjects with abnormal findings in pulse rate
To assess vital sign as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: At Screening, and from Study Days 1 to 14 and Study Days 20 to 22
Number of subjects with abnormal findings in electrocardiograms (ECGs) (12-lead ECGs)
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
Time frame: At Screening, and from Study Days 1 to 34
Number of subjects with abnormal findings in physical examinations
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.
Time frame: At Screening, from Study Days -1 to 22 (brief) and Study Day 34
Number of subjects with abnormal findings in white blood cell (WBC) count
To assess the WBC count as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: From Screening to Study Day 34
Number of subjects with abnormal findings in red blood cell (RBC) count
To assess the RBC count as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: From Screening to Study Day 34
Number of subjects with abnormal findings in hemoglobin (Hb)
To assess Hb as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: From Screening to Study Day 34
Number of subjects with abnormal findings in hematocrit (HCT)
To assess HCT as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: From Screening to Study Day 34
Number of subjects with abnormal findings in mean corpuscular volume (MCV)
To assess MCV as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: From Screening to Study Day 34
Number of subjects with abnormal findings in mean corpuscular hemoglobin (MCH)
To assess MCH as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: From Screening to Study Day 34
Number of subjects with abnormal findings in mean corpuscular hemoglobin concentration (MCHC)
To assess MCHC as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: From Screening to Study Day 34
Number of subjects with abnormal findings in neutrophils absolute count
To assess the neutrophils absolute count as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: From Screening to Study Day 34
Number of subjects with abnormal findings in lymphocytes absolute count
To assess the lymphocytes absolute count as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: From Screening to Study Day 34
Number of subjects with abnormal findings in monocytes absolute count
To assess the monocytes absolute count as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: From Screening to Study Day 34
Number of subjects with abnormal findings in eosinophils absolute count
To assess the eosinophils absolute count as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: From Screening to Study Day 34
Number of subjects with abnormal findings in basophils absolute count
To assess the basophils absolute count as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: From Screening to Study Day 34
Number of subjects with abnormal findings in platelets
To assess platelets as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: From Screening to Study Day 34
Number of subjects with abnormal findings in reticulocytes absolute count
To assess the reticulocytes absolute count as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: From Screening to Study Day 34
Number of subjects with abnormal findings in sodium
To assess the clinical chemistry value (sodium) as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: From Screening to Study Day 34
Number of subjects with abnormal findings in potassium
To assess the clinical chemistry value (potassium) as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: From Screening to Study Day 34
Number of subjects with abnormal findings in urea
To assess the clinical chemistry value (urea) as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: From Screening to Study Day 34
Number of subjects with abnormal findings in creatinine
To assess the clinical chemistry value (creatinine) as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: From Screening to Study Day 34
Number of subjects with abnormal findings in albumin
To assess the clinical chemistry value (albumin) as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: From Screening to Study Day 34
Number of subjects with abnormal findings in calcium
To assess the clinical chemistry value (calcium) as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: From Screening to Study Day 34
Number of subjects with abnormal findings in phosphate
To assess the clinical chemistry value (phosphate) as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: From Screening to Study Day 34
Number of subjects with abnormal findings in glucose (fasting)
To assess the clinical chemistry value (glucose \[fasting\]) as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: From Screening to Study Day 34
Number of subjects with abnormal findings in c-reactive protein (CRP)
To assess the clinical chemistry value (CRP) as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: From Screening to Study Day 34
Number of participants with abnormal findings in liver enzymes
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)
Time frame: From Screening to Study Day 34
Number of subjects with abnormal findings in total bilirubin
To assess the clinical chemistry value (total bilirubin) as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: From Screening to Study Day 34
Number of subjects with abnormal findings in unconjugated bilirubin
To assess the clinical chemistry value (unconjugated bilirubin) as a variable of safety and tolerability of savolitinib in combination with rifampicin
Time frame: From Screening to Study Day 34
Number of subjects with abnormal findings in urinalysis
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.
Time frame: From Screening to Study Day 34
Number of subjects with abnormal findings in urinalysis (microscopy)
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).
Time frame: From Screening to Study Day 34
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)
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)
Time frame: 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
M2 and M3: Cmax ratios of geometric means of test treatment (savolitinib+rifampicin), relative to reference treatment (savolitinib alone)
To describe the PK parameters and the PK profiles for savolitinib, M2 and M3 when savolitinib is administered alone and in combination with rifampicin
Time frame: 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
M2 and M3: AUC ratios of geometric means of test treatment (savolitinib+rifampicin), relative to reference treatment (savolitinib alone)
To describe the PK parameters and the PK profiles for savolitinib, M2 and M3 when savolitinib is administered alone and in combination with rifampicin
Time frame: 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
M2 and M3: AUC(0-t) ratios of geometric means of test treatment (savolitinib+rifampicin), relative to reference treatment (savolitinib alone)
To describe the PK parameters and the PK profiles for savolitinib, M2 and M3 when savolitinib is administered alone and in combination with rifampicin
Time frame: 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
Savolitinib, M2 and M3: summary PK profiles and descriptive statistics of Cmax
To describe the PK parameters and the PK profiles for savolitinib, M2 and M3 when savolitinib is administered alone and in combination with rifampicin
Time frame: 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
Savolitinib, M2 and M3: summary PK profiles and descriptive statistics of AUC
To describe the PK parameters and the PK profiles for savolitinib, M2 and M3 when savolitinib is administered alone and in combination with rifampicin
Time frame: 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
Savolitinib, M2 and M3: summary PK profiles and descriptive statistics of AUC(0 t)
To describe the PK parameters and the PK profiles for savolitinib, M2 and M3 when savolitinib is administered alone and in combination with rifampicin
Time frame: 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
Savolitinib, M2 and M3: Ratio of metabolite AUC to parent AUC (MRCAUC)
To describe the PK parameters and the PK profiles for savolitinib, M2 and M3 when savolitinib is administered alone and in combination with rifampicin
Time frame: 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
Savolitinib, M2 and M3: Ratio of metabolite AUC(0-t) to parent AUC(0-t) (MRCAUC[0-t])
To describe the PK parameters and the PK profiles for savolitinib, M2 and M3 when savolitinib is administered alone and in combination with rifampicin
Time frame: 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
Savolitinib, M2 and M3: metabolite-to-parent ratios for Time to reach maximum observed plasma concentration (tmax)
To describe the PK parameters and the PK profiles for savolitinib, M2 and M3 when savolitinib is administered alone and in combination with rifampicin
Time frame: 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
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)
To describe the PK parameters and the PK profiles for savolitinib, M2 and M3 when savolitinib is administered alone and in combination with rifampicin
Time frame: 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
Savolitinib, M2 and M3: metabolite-to-parent ratios for terminal elimination rate constant (λz)
To describe the PK parameters and the PK profiles for savolitinib, M2 and M3 when savolitinib is administered alone and in combination with rifampicin
Time frame: 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
Savolitinib: Apparent total body clearance of drug from plasms after extravascular administration (parent drug only)CL/F
To describe the PK parameters and the PK profiles for savolitinib, when it is administered alone and in combination with rifampicin
Time frame: 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
Savolitinib, M2 and M3: Ratio of metabolite Cmax to parent Cmax (MRCmax)
To describe the PK parameters and the PK profiles for savolitinib, M2 and M3 when savolitinib is administered alone and in combination with rifampicin
Time frame: 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
Savolitinib: Apparent volume of distribution during the terminal phase after extravascular administration (parent drug only) (Vz/F)
To describe the PK parameters and the PK profiles for savolitinib it is administered alone and in combination with rifampicin
Time frame: 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
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