Absolute Bioavailability and ADME Study of Savolitinib in Healthy Male Subjects

NCT04675021 | Completed Phase 1

• 1 other identifier: D5084C00010
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief Summary

The Sponsor is developing the test medicine, AZD6094 (Savolitinib) for the potential treatment of cancer. Cancer is a condition where cells in a specific part of the body grow and reproduce uncontrollably, causing a growth called a tumour. The test medicine works to inhibit a pathway within the body which promotes tumours to grow and spread. The study involves radiolabelling (labelling the molecule with radioactive 14C) which is used to locate the molecule within the body. The study will evaluate the absolute bioavailability of the test medicine (amount of the oral test medicine that enters the blood stream relative to the dose given into the vein), along with the mass balance (how much radioactivity can be recovered from the urine and faeces) and the rates and routes of elimination of \[14C\]savolitinib. It will also look to identify the breakdown products (metabolites) of the test medicine. The safety and tolerability of the test medicine will be assessed. The study will consist of two parts, involving a minimum of eight healthy male volunteers. In Part one, following a high fat breakfast, volunteers will receive a single oral dose of the test medicine, followed by an intravenous infusion (solution into the vein) of radiolabelled test medicine. Volunteers will remain resident in the clinical unit until 72 hours post-oral dose. There will then be a washout period of at least 14 days, after which the volunteers will return to the clinical unit for Part two. Volunteers will receive a single oral dose of radiolabelled test medicine as an oral solution. Blood, urine and faecal samples will be collected from volunteers whilst they are resident in the clinical unit for up to 168 hours postdose (Day 8). Volunteers will return for a follow-up visit at least 14 days after their last dose for safety assessments.

Conditions

Cancer

Keywords

Cancer

Outcome Measures

Primary Outcomes (6)

• Absolute Bioavailability (F) of savolitinib

  Absolute bioavailability based on AUC0-inf of oral formulation compared to IV adjusted for dose

  Collection of plasma samples from pre-dose to 72 hours post-dose

• The cumulative amount of AZD6094 (savolitinib) excreted (CumAe)

  Assessment of the total radioactivity by measuring the cumulative amount of AZD6094 (savolitinib) excreted (CumAe)

  Urine and faecal samples collected from pre-dose until 168 hours post-dose

• The cumulative amount of AZD6094 (savolitinib) excreted and expressed as a percentage of the administered dose (CumFe)

  Assessment of the total radioactivity by measuring the cumulative amount of AZD6094 (savolitinib) excreted and expressed as a percentage of the administered dose (CumFe)

  Urine and faecal samples collected from pre-dose until 168 hours post-dose

• Assessment of metabolites in plasma by liquid chromatography-radiochemical-detection and subsequent mass spectrometry

  Assessment of metabolites in plasma by liquid chromatography-radiochemical-detection and subsequent mass spectrometry

  Plasma samples collected until 168 hours post-dose

• Assessment of metabolites in urine by liquid chromatography-radiochemical-detection and subsequent mass spectrometry

  Assessment of metabolites in urine by liquid chromatography-radiochemical-detection and subsequent mass spectrometry

  Urine samples collected until 168 hours post-dose

• Assessment of metabolites in faeces by liquid chromatography-radiochemical-detection and subsequent mass spectrometry

  Assessment of metabolites in faeces by liquid chromatography-radiochemical-detection and subsequent mass spectrometry

  Faeces samples collected until 168 hours post-dose

Secondary Outcomes (11)

• Number of AE's experienced by subjects

  AEs recorded from the time of informed consent until the follow up visit (approx 10 weeks)

• Time to maximum concentration (tmax) for AZD6094 (savolitinib) and total radioactivity

  Collection of plasma samples from pre-dose to 168 hours post-dose

• Maximum observed concentration for AZD6094 and total radioactivity

  Collection of plasma samples from pre-dose to 168 hours post-dose

• Area under the curve from time 0 to the time of last measurable concentration for AZD6094 (savolitinib) and total radioactivity

  Collection of plasma samples from pre-dose to 168 hours post-dose

• Area under the curve from time 0 extrapolated to infinity for AZD6094 (savolitinib) and total radtioactivity

  Collection of plasma samples from pre-dose to 168 hours post-dose

Other Outcomes (4)

• Identification of the chemical structure of major metabolite(s) in plasma

  Plasma samples collected until 168 hours post-dose

• Identification of the chemical structure of major metabolite(s) in urine

  Urine samples collected until 168 hours post-dose

• Identification of the chemical structure of major metabolite(s) in faeces

  Faeces samples collected until 168 hours post-dose

Study Arms (1)

AZD6094 (Savolitinib) D5084C00010

EXPERIMENTAL

All volunteers will receive either a single dose or two doses of AZD6094 (Savolitinib) D5084C00010

Drug: AZD6094 (Savolitinib) film coated tablets 600 mg; Drug: [14C]-AZD6094 (Savolitinib) Solution for Infusion, 20 μg/mL (NMT 37.0 kBq/5 mL); Drug: [14C] AZD6094 (Savolitinib) Oral Solution, 300 mg (NMT 4.1 MBq)

Interventions

AZD6094 (Savolitinib) film coated tablets 600 mg DRUG

AZD6094 (Savolitinib) ilm Coated Tablet 200 mg x 3

Also known as: AZD6094 (Savolitinib) Film Coated Tablet 200 mg x 3

AZD6094 (Savolitinib) D5084C00010

[14C]-AZD6094 (Savolitinib) Solution for Infusion, 20 μg/mL (NMT 37.0 kBq/5 mL) DRUG

14C AZD6094 (Savolitinib) Solution for Infusion (20 μg/mL (NMT 37.0 kBq/5 mL)

Also known as: 14C AZD6094 (Savolitinib) Solution for Infusion (20 μg/mL (NMT 37.0 kBq/5 mL)

AZD6094 (Savolitinib) D5084C00010

[14C] AZD6094 (Savolitinib) Oral Solution, 300 mg (NMT 4.1 MBq) DRUG

14CAZD6094 (Savolitinib) Oral Solution (300 mg NMT 4.1MBq)

Also known as: 14CAZD6094 (Savolitinib) Oral Solution (300 mg NMT 4.1MBq)

AZD6094 (Savolitinib) D5084C00010

Eligibility Criteria

• Age: 30 Years - 65 Years
• Gender Eligibility Details: Healthy male subjects aged 30 to 65 years at the time of signing informed consent
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of signed and dated, written informed consent prior to any study specific procedures.
• Healthy male subjects aged 30 to 65 years at the time of signing informed consent with suitable veins for cannulation or repeated venepuncture.
• Body mass index (BMI) of 18.0 to 32.0 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive, as measured at screening.
• Must be willing and able to communicate and participate in the whole study
• Must have regular bowel movements (i.e., average stool production of ≥1 and
• ≤3 stools per day).
• Adequate coagulation parameters, defined as: International Normalisation Ratio (INR) \<1.5 x ULN and activated partial thromboplastin time (aPTT) \<1.5 x ULN.
• Must agree to adhere to the contraception requirements defined in Section 9.4. Subjects aged under 45 years must have had a vasectomy. Subjects must be willing to agree to not father children for a further 6 months after the study follow-up visit.

You may not qualify if:

• History of any clinically significant disease or disorder which, in the opinion of the investigator, 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 GI, hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
• Acute diarrhoea or constipation in the 7 days before administration of IMP in the study. If screening occurs \>7 days before the first study day, this criterion will be determined on first study day.
• Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP.
• Any clinically significant abnormalities in clinical chemistry, haematology, or urinalysis results, as judged by the investigator. Subjects with Gilbert's Syndrome are not allowed.
• Any clinically significant abnormal findings in vital signs, as judged by the investigator.
• Any clinically significant abnormalities on 12-lead ECG, as judged by the investigator. Mean resting corrected QT interval (QTcF) \>450 msec on screening or pre-dose (Part 1 only) obtained from 3 ECGs or factors that may increase the risk of QTcF prolongation or any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiograms (ECGs), e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval \>250 msec.
• Any factors that may increase the risk of QTcF prolongation such as chronic hypokalaemia 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.
• Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus (HIV) antibody.
• Known or suspected history of drug abuse, as judged by the investigator.
• Plasma donation within 1 month of screening or any blood donation/loss more than 500 mL during the 3 months prior to screening.
• History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the investigator or history of hypersensitivity to drugs with a similar chemical structure or class to savolitinib. Hay fever is allowed unless it is active
• Evidence of current SARS-CoV-2 infection.
• History of any alcohol abuse in the past 2 years.
• Regular alcohol consumption in males \>21 units per week (1 unit = ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 Units = 125 mL glass of wine, depending on type).

Sponsors & Collaborators

• AstraZeneca: lead
• Quotient Sciences: collaborator

Study Sites (1)

Research Site

Ruddington, NG11 6JS, United Kingdom

Location

Related Publications (1)

• Miah K, Vishwanathan K, Scarfe G, Li Y, Hara I, Cantarini M, Argue J, Menakuru SR. A Phase 1 Study to Evaluate Absolute Bioavailability and Absorption, Distribution, Metabolism, and Excretion of Savolitinib in Healthy Male Volunteers. Clin Pharmacol Drug Dev. 2023 Apr;12(4):424-435. doi: 10.1002/cpdd.1224. Epub 2023 Feb 19.

  PMID: 36808891 DERIVED

MeSH Terms

Conditions

Neoplasms

Interventions

1-(1-(imidazo(1,2-a)pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-(1,2,3)triazolo(4,5-b)pyrazine; Solutions

Intervention Hierarchy (Ancestors)

Pharmaceutical Preparations

Study Officials

• Somasekhara Menakuru, MBBS MS MRCS

  Quotient Sciences

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 12, 2020
• First Posted: December 19, 2020
• Study Start: November 13, 2020
• Primary Completion: January 11, 2021
• Study Completion: January 11, 2021
• Last Updated: January 26, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the AZ approved data access tool to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

GB (1)