Solid TumorsPhase 1NCT04187456
A Study in Healthy Male Subjects to Understand How Savolitinib When Taken With Midazolam Behaves Inside the Body
A Phase 1 study testing Savolitinib and Midazolam in people with Solid Tumors, run by AstraZeneca at 1 site in United States.
Trial summary
This study will be an open label, 2 period, fixed sequence study in healthy male subjects, performed at a single study center in the Unites States of America. The purpose of this study is to evaluate the effect of savolitinib on the PK of midazolam, a known cytochrome P450 (CYP) 3A substrate. Read more about this study
- Who is it for?
- Ages 18 to 65 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Solid Tumors
- What is being tested?
- Savolitinib and Midazolam
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 14 participants
- Where
- 1 siteUnited States
- Study dates
- 27 Dec 2019to 6 Mar 2020
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- Men only
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Provision of signed and dated, written informed consent prior to any study specific procedures.
- Healthy male subjects, aged 18 - 65 years (inclusive) , with suitable veins for cannulation or repeated venipuncture.
- Have a body mass index (BMI) between 18 and 35 kg/m2 inclusive and body weight greater than 50 kg and no more than 100 kg.
- Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and Total Bilirubin (TBL) less than or equal to upper limit of normal for the institution at screening.
- Have a calculated creatinine clearance (CrCL) greater than 80 mL/min using the Cockcroft-Gault formula at screening.
- Provision of a signed, written and dated informed consent for optional genetic/biomarker research. If a subject decline 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 the protocol..
Who cannot join
- Healthy subjects of Japanese ethnicity and any healthy subject that has 1 parent or grandparent (maternal or paternal) of Japanese ethnicity.
- History of any clinically significant disease or disorder which, in the opinion of the PI, may either put the volunteer at risk because of participation in the study, or influence the results or the volunteer's ability to participate in the study.
- History or presence of gastrointestinal (GI), hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
- Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP.
- Planned in-patient surgery, dental procedure or hospitalizing during the study.
- Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, as judged by the PI.
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- Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus (HIV) antibody.
- Abnormal vital signs, after 5 minutes supine rest, defined as any of the following:
- 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 significant 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:
- Abnormal ST-T-wave morphology, particularly in the protocol defined primary lead (V2) or left ventricular hypertrophy.
- PR interval shortening < 120 ms (PR > 110 ms but < 120 ms is acceptable if there is no evidence of ventricular pre-excitation).
- PR interval prolongation (> 200 ms). Intermittent second (Type 1 second degree block [Wenckebach Phenomenon] while asleep is not exclusive) or third degree atrioventricular (AV) block, or AV dissociation.
- Persistent or intermittent complete bundle branch block (BBB), incomplete bundle branch block (IBBB), or intraventricular conduction delay (IVCD) with QRS > 110 ms. Subjects with QRS > 110 ms but < 115 ms are acceptable if there is no evidence of e.g., ventricular hypertrophy or pre-excitation.
- Mean resting correct QT interval (QTcF) > 450 ms for men on screening obtained from 3 ECGs or history or factors that may increase the risk of QTcF prolongation such as chronic hypokalemia not correctable with supplements, congenital or familial long QT syndrome, or family history of unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval and cause Torsade de Pointes (TdP).
- 10 Known or suspected history of drug abuse, as judged by the Principal Investigator.
- 11 Current smokers or those who have smoked or used nicotine products within the previous 30 days.
- 12 History of alcohol abuse, as judged by the PI, or excessive intake of alcohol (defined as an average weekly intake of > 21 units or an average daily intake of > 3 units).
- 13 Excessive intake of caffeine-containing drinks or food (e.g., coffee, tea, chocolate) as judged by the Investigator.
- 14 Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the administration of 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 firs 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 first dosing day until final follow-up visit, herbal remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks prior to the first administration of IMP or longer (5 times half-life) if the medication has a long half-life.
- 17 Positive screen for drugs of abuse, cotinine (nicotine) and/or alcohol at screening and at admission to the Study Center and/or positive screen for alcohol on admission to the Study Center (Day -1, Treatment Period 1).
- 18 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 midazolam.
- 19 Plasma donation within 1 month of screening or any blood donation/loss more than 500 mL during the 3 months prior to screening.
- 20 Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of the administration of IMP in this study. The period of exclusion begins 3 months after the final dose or one month after the last visit, whichever is the longest.
- Note: subjects consented and screened, but not randomized in this study or a previous phase I study, are not excluded.
- 21 Known or suspected history of alcohol abuse or excessive intake of alcohol as judged by the PI.
- 22 Involvement of any AstraZeneca, Parexel or study site employee or their close relatives.
- 23 Subjects who have previously received savolitinib or midazolam. 24 Judgement 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: An Open Label, 2 Period, Fixed-sequence Study to Assess the Effect of Savolitinib on the Pharmacokinetics of Oral Midazolam (a CYP450 3A Probe) in Healthy Subjects
This study will be an open label, 2 period, fixed sequence study in healthy male subjects, performed at a single study center in the Unites States of America. The purpose of this study is to evaluate the effect of savolitinib on the PK of midazolam, a known cytochrome P450 (CYP) 3A substrate.
Read the detailed description
This study is designed as an open-label, 2 treatment period, fixed sequence study in healthy male subjects, performed at a single study center.
The study will comprise:
- A screening period of maximum 28 days;
- Two treatment periods:
Treatment Period 1 consists of 5 days (Study Days -1 to 4), starting with admission to the Study Center on Study Day -1, dosing of midazolam alone on Study Day 1 and ending on Study Day 4, after a 3 day washout period.
Treatment Period 2 consists of 2 days (Study Days 5 and 6), with administration of midazolam in combination with savolitinib on Study Day 5. Subjects will be discharged from the Study Center on Study Day 6, after the last PK sample is collected.
- The Follow up Visit will occur at least 14 days (Study Day 19 or after) after the administration of savolitinib in Treatment Period 2.
- Subjects will be admitted to the Study Center on Study Day -1, prior to the evening meal the night before dosing with midazolam alone (Study Day 1) and will stay in house until at least 24 hours after dosing with midazolam in combination with savolitinib (Study Day 5). Subjects will thus be discharged on Study Day 6, after the last PK sample has been collected.
Each subject will be involved in the study between 21 and approximately 48 days.
- Conditions
- Solid Tumors
- Being tested
- Savolitinib, Midazolam
- Keywords
- Pharmacokinetics, Safety, Small molecule kinase inhibitor, Open-label
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SavolitinibDrug
Single dose (together with midazolam) on Study Day 5 after a high fat, high calorie breakfast.
MidazolamDrug
Single dose (alone) on Study Day 1 and single dose (together with savolitinib) on Study Day 5, both after a high fat, high calorie breakfast.
| Study group | Role | What they receive |
|---|---|---|
| Midazolam + Savolitinib | Experimental | * Treatment Period 1: Single administration of midazolam (1 mg) will occur on Study Day 1, after a high fat, high calorie breakfast, followed by PK sampling for 24 hours.
* Treatment Period 2: Single administration of midazolam 1 mg in combination with a single administration of savolitinib (600 mg), after a high fat, high calorie breakfast will occur on Study Day 5 and PK sampling will occur for 24 hours. Receives: Drug: Savolitinib; Drug: Midazolam |
What is being measured
The primary outcome is the main question the study is designed to answer.
Midazolam: Area under the plasma concentration-time curve from time zero to infinity (AUC) ratio of geometric means of test treatment (midazolam + savolitinib), relative to reference treatment (midazolam alone).
To assess the effect of savolitinib on the PK of midazolam.
Measured: Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.
Midazolam: Maximum observed plasma concentration (Cmax) ratio of geometric means of test treatment (midazolam + savolitinib), relative to reference treatment (midazolam alone).
To assess the effect of savolitinib on the PK of midazolam.
Measured: Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.
Secondary outcomes (45)
Midazolam: 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 (midazolam + savolitinib), relative to reference treatment (midazolam alone).
To describe the PK of midazolam in the presence and absence of savolitinib.
Measured: Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.
Midazolam: Cmax
To describe the PK of midazolam in the presence and absence of savolitinib.
Measured: Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.
Midazolam: [AUC(0-t)]
To describe the PK of midazolam in the presence and absence of savolitinib.
Measured: Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.
Midazolam: Time to reach maximum observed plasma concentration (tmax)
To describe the PK of midazolam in the presence and absence of savolitinib.
Measured: Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.
Midazolam: Half-life associated with terminal slope (λz) of a semi-logarithmic concentration time curve (t½,λz)
To describe the PK of midazolam in the presence and absence of savolitinib.
Measured: Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.
Midazolam: Terminal elimination rate constant (λz)
To describe the PK of midazolam in the presence and absence of savolitinib.
Measured: Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.
Midazolam and savolitinib: Apparent total body clearance of drug from plasma after extravascular administration (CL/F)
To describe the PK of midazolam in the presence and absence of savolitinib.
Measured: Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.
Midazolam and savolitinib: Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F)
To describe the PK of midazolam in the presence and absence of savolitinib.
Measured: Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.
Number of subjects with adverse events
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day -1, 1, 2, 3, 4, 5, 6, 19
Number of subjects with abnormal systolic blood pressure (BP)
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day -1, 1, 2, 5, 6, 19. Vital signs on dosing days will be collected at pre dose, 0.5, 1, 2, 3, 4, 8 and 24 hours post dose.
Number of subjects with abnormal diastolic blood pressure (BP)
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day -1, 1, 2, 5, 6, 19. Vital signs on dosing days will be collected at pre dose, 0.5, 1, 2, 3, 4, 8 and 24 hours post dose.
Number of subjects with abnormal findings in pulse rate
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day -1, 1, 2, 5, 6, 19. Vital signs on dosing days will be collected at pre dose, 0.5, 1, 2, 3, 4, 8 and 24 hours post dose.
Number of subjects with abnormal findings in physical examination
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day -1, 1, 2, 3, 4, 5, 6 and 19
Number of subjects with abnormal findings in White blood cell (WBC) count
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Red blood cell (RBC) count
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Hemoglobin (Hb)
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Hematocrit (HCT)
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Mean corpuscular volume (MCV)
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Mean corpuscular hemoglobin (MCH)
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Mean corpuscular hemoglobin concentration (MCHC)
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Neutrophils absolute count
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Monocytes absolute count
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Eosinophils absolute count
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Basophils absolute count
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Platelets
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Reticulocytes absolute count
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in sodium
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in pottasium
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in urea
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in creatinine
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in albumin
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in calcium
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in phosphate
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in glucose (fasting)
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in C-reactive protein (CRP)
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in T4
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening
Number of subjects with abnormal findings in Thyroid-Stimulating Hormone (TSH)
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening
Number of subjects with abnormal findings in Alkaline phosphatase (ALP)
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Alanine aminotransferase (ALT)
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Aspartate aminotransferase (AST)
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Gamma glutamyl transpeptidase (GGT)
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in total bilirubin
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in unconjugated bilirubin
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in urinalysis
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in pulse oximetry
To examine the safety and tolerability of midazolam alone and in combination with savolitinib.
Measured: Day 1 and 5
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Dec 2019
- Study start27 Dec 2019
- Primary completion6 Mar 2020
- Study completion6 Mar 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Solid TumorsStudies of the same condition, open and under way.
- More trials run by AstraZenecaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 14 participants (actual)
Sponsor and investigators
- Lead sponsor
- AstraZeneca
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Parexel
- Responsible party
- Sponsor
- Investigators
- Ronald Goldwater, MD, Principal investigator, PAREXEL Early Phase Clinical Unit Baltimore
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04187456
- Sponsor's protocol ID
- D5084C00004
- Status last verified
- Aug 2020
- First submitted
- 3 Dec 2019
- Last updated
- 19 Aug 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 19 Aug 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open Label, 2 Period, Fixed-sequence Study to Assess the Effect of Savolitinib on the Pharmacokinetics of Oral Midazolam (a CYP450 3A Probe) in Healthy Subjects
- ClinicalTrials.gov ID
- NCT04187456
- Acronym / sponsor ID
- D5084C00004
- Conditions
- Solid Tumors
- Keywords
- Pharmacokinetics, Safety, Small molecule kinase inhibitor, Open-label
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 14 participants (actual)
- Lead sponsor
- AstraZenecaIndustry (pharma, biotech, devices)
- Collaborators
- Parexel
- Study start
- 27 Dec 2019 (actual)
- Primary completion
- 6 Mar 2020 (actual)
- Study completion
- 6 Mar 2020 (actual)
- First posted
- 5 Dec 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study will be an open label, 2 period, fixed sequence study in healthy male subjects, performed at a single study center in the Unites States of America. The purpose of this study is to evaluate the effect of savolitinib on the PK of midazolam, a known cytochrome P450 (CYP) 3A substrate.
Detailed description
This study is designed as an open-label, 2 treatment period, fixed sequence study in healthy male subjects, performed at a single study center.
The study will comprise:
- A screening period of maximum 28 days;
- Two treatment periods:
Treatment Period 1 consists of 5 days (Study Days -1 to 4), starting with admission to the Study Center on Study Day -1, dosing of midazolam alone on Study Day 1 and ending on Study Day 4, after a 3 day washout period.
Treatment Period 2 consists of 2 days (Study Days 5 and 6), with administration of midazolam in combination with savolitinib on Study Day 5. Subjects will be discharged from the Study Center on Study Day 6, after the last PK sample is collected.
- The Follow up Visit will occur at least 14 days (Study Day 19 or after) after the administration of savolitinib in Treatment Period 2.
- Subjects will be admitted to the Study Center on Study Day -1, prior to the evening meal the night before dosing with midazolam alone (Study Day 1) and will stay in house until at least 24 hours after dosing with midazolam in combination with savolitinib (Study Day 5). Subjects will thus be discharged on Study Day 6, after the last PK sample has been collected.
Each subject will be involved in the study between 21 and approximately 48 days.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Midazolam + Savolitinib | Experimental | Drug: Savolitinib, Drug: Midazolam* Treatment Period 1: Single administration of midazolam (1 mg) will occur on Study Day 1, after a high fat, high calorie breakfast, followed by PK sampling for 24 hours. * Treatment Period 2: Single administration of midazolam 1 mg in combination with a single administration of savolitinib (600 mg), after a high fat, high calorie breakfast will occur on Study Day 5 and PK sampling will occur for 24 hours. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Provision of signed and dated, written informed consent prior to any study specific procedures.
- Healthy male subjects, aged 18 - 65 years (inclusive) , with suitable veins for cannulation or repeated venipuncture.
- Have a body mass index (BMI) between 18 and 35 kg/m2 inclusive and body weight greater than 50 kg and no more than 100 kg.
- Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and Total Bilirubin (TBL) less than or equal to upper limit of normal for the institution at screening.
- Have a calculated creatinine clearance (CrCL) greater than 80 mL/min using the Cockcroft-Gault formula at screening.
Key exclusion criteria (31 listed)
- Healthy subjects of Japanese ethnicity and any healthy subject that has 1 parent or grandparent (maternal or paternal) of Japanese ethnicity.
- History of any clinically significant disease or disorder which, in the opinion of the PI, may either put the volunteer at risk because of participation in the study, or influence the results or the volunteer's ability to participate in the study.
- History or presence of gastrointestinal (GI), hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
- Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP.
- Planned in-patient surgery, dental procedure or hospitalizing during the study.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| SavolitinibSingle dose (together with midazolam) on Study Day 5 after a high fat, high calorie breakfast. | Drug | Midazolam + Savolitinib |
| MidazolamSingle dose (alone) on Study Day 1 and single dose (together with savolitinib) on Study Day 5, both after a high fat, high calorie breakfast. | Drug | Midazolam + Savolitinib |
Primary outcome
Midazolam: Area under the plasma concentration-time curve from time zero to infinity (AUC) ratio of geometric means of test treatment (midazolam + savolitinib), relative to reference treatment (midazolam alone).
Time frame: Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.
To assess the effect of savolitinib on the PK of midazolam.
Midazolam: Maximum observed plasma concentration (Cmax) ratio of geometric means of test treatment (midazolam + savolitinib), relative to reference treatment (midazolam alone).
Time frame: Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.
To assess the effect of savolitinib on the PK of midazolam.
45 secondary outcomes
Midazolam: 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 (midazolam + savolitinib), relative to reference treatment (midazolam alone).
Time frame: Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.
Midazolam: Cmax
Time frame: Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.
Midazolam: [AUC(0-t)]
Time frame: Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.
Midazolam: Time to reach maximum observed plasma concentration (tmax)
Time frame: Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.
Midazolam: Half-life associated with terminal slope (λz) of a semi-logarithmic concentration time curve (t½,λz)
Time frame: Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.
Midazolam: Terminal elimination rate constant (λz)
Time frame: Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.
Midazolam and savolitinib: Apparent total body clearance of drug from plasma after extravascular administration (CL/F)
Time frame: Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.
Midazolam and savolitinib: Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F)
Time frame: Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.
Number of subjects with adverse events
Time frame: At screening, Day -1, 1, 2, 3, 4, 5, 6, 19
Number of subjects with abnormal systolic blood pressure (BP)
Time frame: At screening, Day -1, 1, 2, 5, 6, 19. Vital signs on dosing days will be collected at pre dose, 0.5, 1, 2, 3, 4, 8 and 24 hours post dose.
Number of subjects with abnormal diastolic blood pressure (BP)
Time frame: At screening, Day -1, 1, 2, 5, 6, 19. Vital signs on dosing days will be collected at pre dose, 0.5, 1, 2, 3, 4, 8 and 24 hours post dose.
Number of subjects with abnormal findings in pulse rate
Time frame: At screening, Day -1, 1, 2, 5, 6, 19. Vital signs on dosing days will be collected at pre dose, 0.5, 1, 2, 3, 4, 8 and 24 hours post dose.
Number of subjects with abnormal findings in physical examination
Time frame: At screening, Day -1, 1, 2, 3, 4, 5, 6 and 19
Number of subjects with abnormal findings in White blood cell (WBC) count
Time frame: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Red blood cell (RBC) count
Time frame: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Hemoglobin (Hb)
Time frame: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Hematocrit (HCT)
Time frame: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Mean corpuscular volume (MCV)
Time frame: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Mean corpuscular hemoglobin (MCH)
Time frame: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Mean corpuscular hemoglobin concentration (MCHC)
Time frame: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Neutrophils absolute count
Time frame: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Monocytes absolute count
Time frame: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Eosinophils absolute count
Time frame: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Basophils absolute count
Time frame: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Platelets
Time frame: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Reticulocytes absolute count
Time frame: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in sodium
Time frame: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in pottasium
Time frame: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in urea
Time frame: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in creatinine
Time frame: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in albumin
Time frame: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in calcium
Time frame: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in phosphate
Time frame: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in glucose (fasting)
Time frame: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in C-reactive protein (CRP)
Time frame: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in T4
Time frame: At screening
Number of subjects with abnormal findings in Thyroid-Stimulating Hormone (TSH)
Time frame: At screening
Number of subjects with abnormal findings in Alkaline phosphatase (ALP)
Time frame: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Alanine aminotransferase (ALT)
Time frame: At screening, Day 1, 4, 5 and 19
Number of subjects with abnormal findings in Aspartate aminotransferase (AST)
Time frame: At screening, Day 1, 4, 5 and 19
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Aug 2021.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ronald Goldwater, MD principal investigator
PAREXEL Early Phase Clinical Unit Baltimore
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Savolitinib and Midazolam in people with Solid Tumors, run by AstraZeneca at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 31 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Aug 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Midazolam: Area under the plasma concentration-time curve from time zero to infinity (AUC) ratio of geometric means of test treatment (midazolam + savolitinib), relative to reference treatment (midazolam alone). (time frame: Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Aug 2021.