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

NCT05008913 | Terminated Phase 1 FDA Drug

• 1 other identifier: D601HC00004
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief Summary

This is a non-randomised study in patients with advanced solid malignancies

Conditions

Advanced Solid Tumors

Keywords

Absorption; Distribution; Metabolism; Excretion; Pharmacokinetics

Outcome Measures

Primary Outcomes (16)

• 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 Outcomes (1)

• Number of patients with adverse events (AE) and serious AEs (SAE)

  From screening (Day -28 to Day -1) until end of study (within 30 [±7] days of adavosertib dose)

Study Arms (1)

[14C]Adavosertib

EXPERIMENTAL

Patients will receive a single administration of \[14C\]adavosertib as an oral solution on Day 1.

Drug: [14C]Adavosertib

Interventions

[14C]Adavosertib DRUG

Patients will receive a single administration of \[14C\]Adavosertib as an oral solution on Day 1.

Also known as: AZD1775

[14C]Adavosertib

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator

Study Sites (1)

Research Site

Manchester, M20 4BX, United Kingdom

Location

MeSH Terms

Interventions

adavosertib

Study Design

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

Study Record Dates

• First Submitted: August 10, 2021
• First Posted: August 17, 2021
• Study Start: October 1, 2021
• Primary Completion: November 16, 2021
• Study Completion: November 16, 2021
• Last Updated: September 6, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will share
• 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 refer 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 de-identified 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 SAS MSE to gain access. For additional details, please review the Disclosure Statements at: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

Locations

GB (1)