Clinical trial NCT05008913: Human Absorption, Distribution, Metabolism, and Excretion Study of [14C]Adavosertib
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Advanced Solid Tumors
Keywords: Absorption
Distribution
Metabolism
Excretion
Pharmacokinetics
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2021-08-17
Enrollment: 2
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

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.

Eligibility criteria: Inclusion Criteria:

1. Patient must be ≥ 18 years of age.
2. 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.
3. Eastern Cooperative Oncology Group performance status score of 0 to 1.
4. Life expectancy ≥ 12 weeks.
5. Patients must have normal organ and marrow function at baseline, within 7 days prior to study drug administration.
6. 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.
7. Body weight within 50-100 kg and BMI within the range 18-30 kg/m\^2 (inclusive).
8. Regular bowel movements (i.e., on average production of at least 1 faeces per day).
9. Males and females of childbearing potential who agree to use contraceptive measures consistent with local regulations for clinical studies.

Exclusion Criteria:

1. Persistent toxicities (Common Terminology Criteria for Adverse Events \[CTCAE\] Grade \> 2) caused by previous anticancer therapy, excluding alopecia and CTCAE Grade 2 peripheral neuropathy.
2. 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.
3. Patients who have participated in another absorption, distribution, metabolism and excretion study within 1 year prior to screening.
4. Any significant cardiac diseases currently or within the last 6 months such as:

   1. unstable angina pectoris
   2. acute myocardial infarction, congestive heart failure
   3. conduction abnormality not controlled with pacemaker or medication
   4. significant ventricular or supraventricular arrhythmias
5. 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.
6. Known to have tested positive for human immunodeficiency virus or active tuberculosis infection.
7. Known active hepatitis infection, positive hepatitis C antibody, hepatitis B virus surface antigen or hepatitis B virus core antibody, at screening.
8. 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.
9. Spinal cord compression or brain metastases unless asymptomatic, stable, and not requiring steroids for at least 4 weeks prior to start of study intervention.
10. 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.
11. 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.
12. 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.
13. Any known hypersensitivity or contraindication to the components of the study intervention adavosertib.
14. Currently pregnant (confirmed with positive pregnancy test) or breast feeding.

Primary outcomes:
measure: 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
timeFrame: Urine and fecal samples collected from pre-dose to 168 hours post-dose
measure: Renal clearance of radioactivity (CLR)
timeFrame: From pre-dose to 168 hours post-dose
measure: Maximum observed plasma concentration (Cmax)
timeFrame: From pre-dose to 168 hours post-dose
measure: Area under plasma concentration-time curve from time zero to infinity (AUCinf)
timeFrame: From pre-dose to 168 hours post-dose
measure: Area under the plasma concentration-time curve from zero to time of last quantifiable concentration (AUClast)
timeFrame: From pre-dose to 168 hours post-dose
measure: Time to reach peak or maximum observed concentration following drug administration (tmax)
timeFrame: From pre-dose to 168 hours post-dose
measure: Terminal elimination rate constant (λz)
timeFrame: From pre-dose to 168 hours post-dose
measure: Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½λz)
timeFrame: From pre-dose to 168 hours post-dose
measure: Apparent total body clearance of drug from plasma after extravascular administration (CL/F)
timeFrame: From pre-dose to 168 hours post-dose
measure: Mean Residence Time of the unchanged drug in the systemic circulation (MRTinf)
timeFrame: From pre-dose to 168 hours post-dose
measure: Volume of distribution (apparent) at steady state following extravascular administration (Vss/F)
timeFrame: From pre-dose to 168 hours post-dose
measure: Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F)
timeFrame: From pre-dose to 168 hours post-dose
measure: Ratio of AUCinf of plasma adavosertib relative to AUCinf of plasma total radioactivity [AUCinf Plasma:Total Plasma Ratio]
timeFrame: From pre-dose to 168 hours post-dose
measure: Ratio of AUCinf of whole blood total radioactivity to AUCinf of plasma total radioactivity [AUCinf Blood:Plasma Ratio]
timeFrame: From pre-dose to 168 hours post-dose
measure: Amount, cumulative amount, and cumulative percentage of unchanged adavosertib excreted into urine from time t1 to time t2
timeFrame: Urine collected from pre-dose to 168 hours post-dose
measure: Renal clearance of adavosertib from plasma (CLR)
timeFrame: From pre-dose to 168 hours post-dose
Secondary outcomes:
measure: Number of patients with adverse events (AE) and serious AEs (SAE)
timeFrame: From screening (Day -28 to Day -1) until end of study (within 30 [±7] days of adavosertib dose)
Other outcomes:
Locations:
city: Manchester
country: United Kingdom
facility: Research Site
Study officials:
References: