Human Absorption, Distribution, Metabolism, and Excretion Study of [14C]Adavosertib

Study Overview
=================
Brief Summary
-----------------
This is a non-randomised study in patients with advanced solid malignancies

Detailed Description
-----------------
The aim is to recruit approximately 8 patients with a minimum number of 4 pharmacokinetics (PK) evaluable patients. Each patient will be admitted to the study site pre-dose on Day -1 and will remain at the study site until at least Day 8. Patients will receive a single administration of [14C]adavosertib as an oral solution on Day 1. During this study, whole blood, plasma, urine, faeces, and vomit samples (if presented) will be collected at various time points to characterise the absorption, distribution, metabolism, excretion and PK of adavosertib. The duration of the residential period will be evaluated following treatment of the first patient and may be adjusted to ensure recovery of at least 90% of the total radioactivity following the dose of [14C]adavosertib and/or until less than 1% of dose is recovered in urine and/or faeces within a 24-hour period.

Official Title
-----------------
A Phase I, Open-Label, Non-Randomised Study of the Absorption, Distribution, Metabolism, and Excretion of Adavosertib After a Single Oral Dose of [14C]Adavosertib to Patients With Advanced Solid Tumours

Conditions
-----------------
Advanced Solid Tumors

Intervention / Treatment
-----------------
* Drug: [14C]Adavosertib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient must be ≥ 18 years of age. Histologically or cytologically documented, locally advanced or metastatic solid tumour, excluding lymphoma, for which standard therapy does not exist or has proven ineffective or intolerable. Eastern Cooperative Oncology Group performance status score of 0 to 1. Life expectancy ≥ 12 weeks. Patients must have normal organ and marrow function at baseline, within 7 days prior to study drug administration. Able and willing to stay in hospital for approximately 9 days (first patient; to be evaluated and possibly adjusted for subsequent patients) for the collection of samples following a single oral dose of [14C]-adavosertib. Body weight within 50-100 kg and BMI within the range 18-30 kg/m^2 (inclusive). Regular bowel movements (i.e., on average production of at least 1 faeces per day). Males and females of childbearing potential who agree to use contraceptive measures consistent with local regulations for clinical studies. Exclusion Criteria: Persistent toxicities (Common Terminology Criteria for Adverse Events [CTCAE] Grade > 2) caused by previous anticancer therapy, excluding alopecia and CTCAE Grade 2 peripheral neuropathy. Refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of 14C-adavosertib oral solution. Patients who have participated in another absorption, distribution, metabolism and excretion study within 1 year prior to screening. Any significant cardiac diseases currently or within the last 6 months such as: unstable angina pectoris acute myocardial infarction, congestive heart failure conduction abnormality not controlled with pacemaker or medication significant ventricular or supraventricular arrhythmias Any of the following: History or current evidence of congenital long QT syndrome; concomitant medications known to prolong QT interval or history of medication-related QT prolongation. Known to have tested positive for human immunodeficiency virus or active tuberculosis infection. Known active hepatitis infection, positive hepatitis C antibody, hepatitis B virus surface antigen or hepatitis B virus core antibody, at screening. Any evidence of diseases (such as severe or uncontrolled systemic diseases, including uncontrolled hypertension, renal transplant, active infections, and active bleeding diseases) which prohibit participating in the study. Spinal cord compression or brain metastases unless asymptomatic, stable, and not requiring steroids for at least 4 weeks prior to start of study intervention. Use of an anti-cancer treatment drug ≤ 21 days (≤ 6 weeks for nitroureas or mitomycin C) or use of an investigational product within 5 half-lives prior to the first dose of adavosertib. Patient uses drugs that are sensitive to CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index, or are moderate to strong inhibitors/inducers of CYP3A4 which cannot be discontinued 2 weeks or 5 halflives (whichever is longer) prior to Day 1 of dosing. Receipt of live virus and live bacterial vaccines whilst the patient is receiving the study intervention and during the 30-day follow-up period. Inactivated flu vaccines are permitted. Any known hypersensitivity or contraindication to the components of the study intervention adavosertib. Currently pregnant (confirmed with positive pregnancy test) or breast feeding.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: [14C]Adavosertib<br>Patients will receive a single administration of [14C]adavosertib as an oral solution on Day 1. | Drug: [14C]Adavosertib<br>* Patients will receive a single administration of [14C]Adavosertib as an oral solution on Day 1.<br>* Other names: AZD1775;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amount and cumulative amount excreted and expressed as the percentage of the administered dose into the urine and faeces from time t1 to time t2 | Assessment of the mass balance of total radioactivity, including the routes and rates of elimination following a single oral dose [14C]adavosertib. | Urine and fecal samples collected from pre-dose to 168 hours post-dose | 
| Renal clearance of radioactivity (CLR) | Assessment of renal clearance of adavosertib, including the routes and rates of elimination following a single oral dose [14C]adavosertib. | From pre-dose to 168 hours post-dose | 
| Maximum observed plasma concentration (Cmax) | Assessment of Cmax of adavosertib and total radioactivity following a single oral dose of [14C]adavosertib. | From pre-dose to 168 hours post-dose | 
| Area under plasma concentration-time curve from time zero to infinity (AUCinf) | Assessment of AUCinf of adavosertib and total radioactivity following a single oral dose of [14C]adavosertib. | From pre-dose to 168 hours post-dose | 
| Area under the plasma concentration-time curve from zero to time of last quantifiable concentration (AUClast) | Assessment of AUClast of adavosertib and total radioactivity following a single oral dose of [14C]adavosertib. | From pre-dose to 168 hours post-dose | 
| Time to reach peak or maximum observed concentration following drug administration (tmax) | Assessment of tmax of adavosertib and total radioactivity following a single oral dose of [14C]adavosertib. | From pre-dose to 168 hours post-dose | 
| Terminal elimination rate constant (λz) | Assessment of λz of adavosertib and total radioactivity following a single oral dose of [14C]adavosertib. | From pre-dose to 168 hours post-dose | 
| Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½λz) | Assessment of t½λz of adavosertib and total radioactivity following a single oral dose of [14C]adavosertib. | From pre-dose to 168 hours post-dose | 
| Apparent total body clearance of drug from plasma after extravascular administration (CL/F) | Assessment of CL/F of adavosertib and total radioactivity following a single oral dose of [14C]adavosertib. | From pre-dose to 168 hours post-dose | 
| Mean Residence Time of the unchanged drug in the systemic circulation (MRTinf) | Assessment of MRTinf of adavosertib and total radioactivity following a single oral dose of [14C]adavosertib. | From pre-dose to 168 hours post-dose | 
| Volume of distribution (apparent) at steady state following extravascular administration (Vss/F) | Assessment of Vss/F of adavosertib and total radioactivity following a single oral dose of [14C]adavosertib. | From pre-dose to 168 hours post-dose | 
| Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F) | Assessment of Vz/F of adavosertib and total radioactivity following a single oral dose of [14C]adavosertib. | From pre-dose to 168 hours post-dose | 
| Ratio of AUCinf of plasma adavosertib relative to AUCinf of plasma total radioactivity [AUCinf Plasma:Total Plasma Ratio] | Assessment of AUCinf plasma adavosertib:Total plasma radioactivity ratio following a single oral dose of [14C]adavosertib. | From pre-dose to 168 hours post-dose | 
| Ratio of AUCinf of whole blood total radioactivity to AUCinf of plasma total radioactivity [AUCinf Blood:Plasma Ratio] | Assessment of AUCinf Blood:Plasma Ratio total radioactivity following a single oral dose of [14C]adavosertib. | From pre-dose to 168 hours post-dose | 
| Amount, cumulative amount, and cumulative percentage of unchanged adavosertib excreted into urine from time t1 to time t2 | Assessment of unchanged adavosertib following a single oral dose of [14C]adavosertib. | Urine collected from pre-dose to 168 hours post-dose | 
| Renal clearance of adavosertib from plasma (CLR) | Assessment of CLR of adavosertib and total radioactivity following a single oral dose of [14C]adavosertib. | From pre-dose to 168 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with adverse events (AE) and serious AEs (SAE) | Assessment of the safety and tolerability of adavosertib following oral dosing in patients with advanced solid tumours. | From screening (Day -28 to Day -1) until end of study (within 30 [±7] days of adavosertib dose) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Absorption, Distribution, Metabolism, Excretion, Pharmacokinetics