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A Study to Assess the Effects of Itraconazole, Rifampicin, and Omeprazole on Pharmacokinetics of Adavosertib

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04959266
Recruitment Status : Recruiting
First Posted : July 13, 2021
Last Update Posted : June 30, 2022
Sponsor:
Collaborator:
Parexel
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:
This is a Phase 1, open-label, non-randomised, 3-arm (A, B, and C), drug-drug interaction study in patients with advanced solid tumours.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumours Drug: Adavosertib Drug: Itraconazole Drug: Rifampicin Drug: Omeprazole Phase 1

Detailed Description:

The study will include 3 arms consisting of a screening period of up to 28 days (Day -28 to Day -1), an intervention period (12 days for arm A, 17 days for arm B, and 12 days for arm C), and a follow-up end of treatment [EOT] visit (within 3 days after a 4-day washout period relative to the last dose of adavosertib).

Arm A of this study follows a non-randomised, open-label, 2-intervention design. Patients will receive the following 2 study interventions: a single oral dose of adavosertib alone, and a single oral dose of adavosertib administered concomitantly with itraconazole.

Arm B of this study follows a non-randomised, open-label, 2-intervention design. Patients will receive the following 2 study interventions: a single oral dose of adavosertib alone, and a single oral dose of adavosertib administered concomitantly with rifampicin.

Arm C of this study follows a non-randomised, open-label, 2-intervention design. Patients will receive the following 2 study interventions: a single oral dose of adavosertib alone, and a single oral dose of adavosertib administered concomitantly with omeprazole.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: A Phase I, Open-label, Non-randomised Study to Assess the Effect of Itraconazole (a CYP3A4 Inhibitor), Rifampicin (a CYP3A4 Inducer), and Omeprazole (a Proton Pump Inhibitor) on the Pharmacokinetics of a Single Oral Dose of Adavosertib in Patients With Advanced Solid Tumours
Actual Study Start Date : June 28, 2021
Estimated Primary Completion Date : November 9, 2022
Estimated Study Completion Date : November 9, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm A
Patients will receive a single oral dose of adavosertib alone, and a single oral dose of adavosertib concomitantly with itraconazole.
Drug: Adavosertib
Patients will receive a single dose of Adavosertib orally in arm A, B, and C.

Drug: Itraconazole
Patients will receive Itraconazole orally once daily for 7 days in arm A.

Experimental: Arm B
Patients will receive a single oral dose of adavosertib alone, and a single oral dose of adavosertib concomitantly with rifampicin.
Drug: Adavosertib
Patients will receive a single dose of Adavosertib orally in arm A, B, and C.

Drug: Rifampicin
Patients will receive Rifampicin orally once daily for 13 days in arm B.

Experimental: Arm C
Patients will receive a single oral dose of adavosertib alone, and a single oral dose of adavosertib concomitantly with omeprazole.
Drug: Adavosertib
Patients will receive a single dose of Adavosertib orally in arm A, B, and C.

Drug: Omeprazole
Patients will receive Omeprazole orally once daily for 5 days in arm C.




Primary Outcome Measures :
  1. Ratios of geometric means of Cmax (maximum observed plasma concentration) when administered in combination with itraconazole/rifampicin/omeprazole relative to adavosertib alone [ Time Frame: Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12 ]
    Assessment of the effect of itraconazole (arm A)/rifampicin (arm B)/omeprazole (arm C) on the Cmax of adavosertib following oral dosing in patients with advanced solid tumours.

  2. Ratios of geometric means of AUCinf (Area under plasma concentration-time curve from time zero to infinity) when administered in combination with itraconazole/rifampicin/omeprazole relative to adavosertib alone [ Time Frame: Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12 ]
    Assessment of the effect of itraconazole (arm A)/rifampicin (arm B)/omeprazole (arm C) on the AUCinf of adavosertib following oral dosing in patients with advanced solid tumours.

  3. Ratios of geometric means of AUClast (Area under the plasma concentration-time curve from zero to time of last quantifiable concentration) when administered in combination with itraconazole/rifampicin/omeprazole relative to adavosertib alone [ Time Frame: Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12 ]
    Assessment of the effect of itraconazole (arm A)/rifampicin (arm B)/omeprazole (arm C) on the AUClast of adavosertib following oral dosing in patients with advanced solid tumours.


Secondary Outcome Measures :
  1. Summary of Adavosertib plasma concentrations with time [ Time Frame: Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12 ]
    Assessment of pharmacokinetics (PK) for adavosertib when administered alone and in combination with itraconazole (arm A) /rifampicin (arm B) /omeprazole (arm C).

  2. Descriptive statistics of Cmax [ Time Frame: Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12 ]
    Assessment of Cmax for adavosertib when administered alone and in combination with itraconazole (arm A) /rifampicin (arm B) /omeprazole (arm C).

  3. Descriptive statistics of AUCinf [ Time Frame: Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12 ]
    Assessment of AUCinf for adavosertib when administered alone and in combination with itraconazole (arm A) /rifampicin (arm B) /omeprazole (arm C).

  4. Descriptive statistics of AUClast [ Time Frame: Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12 ]
    Assessment of AUClast for adavosertib when administered alone and in combination with itraconazole (arm A) /rifampicin (arm B) /omeprazole (arm C).

  5. Descriptive statistics of tmax (Time to reach maximum observed concentration following drug administration) [ Time Frame: Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12 ]
    Assessment of tmax for adavosertib when administered alone and in combination with itraconazole (arm A) /rifampicin (arm B) /omeprazole (arm C).

  6. Descriptive statistics of λz (Terminal elimination rate constant) [ Time Frame: Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12 ]
    Assessment of λz for adavosertib when administered alone and in combination with itraconazole (arm A) /rifampicin (arm B) /omeprazole (arm C).

  7. Descriptive statistics of t½λz (Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve) [ Time Frame: Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12 ]
    Assessment of t½λz for adavosertib when administered alone and in combination with itraconazole (arm A) /rifampicin (arm B) /omeprazole (arm C).

  8. Descriptive statistics of CL/F (Apparent total body clearance of drug from plasma after extravascular administration) [ Time Frame: Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12 ]
    Assessment of CL/F for adavosertib when administered alone and in combination with itraconazole (arm A) /rifampicin (arm B) /omeprazole (arm C).

  9. Descriptive statistics of Vss/F (Volume of distribution (apparent) at steady state following extravascular administration) [ Time Frame: Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12 ]
    Assessment of Vss/F for adavosertib when administered alone and in combination with itraconazole (arm A) /rifampicin (arm B) /omeprazole (arm C).

  10. Descriptive statistics of Vz/F (Apparent volume of distribution during the terminal phase after extravascular administration) [ Time Frame: Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12 ]
    Assessment of Vz/F for adavosertib when administered alone and in combination with itraconazole (arm A) /rifampicin (arm B) /omeprazole (arm C).

  11. Descriptive statistics of Ctrough (Observed lowest drug concentration reached before the next dose is administered) [ Time Frame: Arm A: Days 9-11; Arm B: Days 14-17; Arm C: Day 9 ]
    Assessment of Ctrough for itraconazole, rifampicin and omeprazole when administered in combination with adavosertib.

  12. Number of patients with serious and non-serious adverse events [ Time Frame: From screening to end of study [within 30 (±7) days of last adavosertib dose] ]
    Assessment of the safety and tolerability of adavosertib when dosed with itraconazole (arm A), rifampicin (arm B), and omeprazole (arm C).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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.
  2. Eastern Cooperative Oncology Group performance status score of 0 or 1.
  3. Predicted life expectancy ≥ 12 weeks.
  4. Patients must have normal organ and marrow function at baseline, within 7 days prior to study drug administration.
  5. Males and females of childbearing potential who agree to use contraceptive measures must be consistent with clinical study protocol.

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 adavosertib, itraconazole, rifampicin, and omeprazole.
  3. Any significant cardiac diseases currently or within the last 6 months such as: (a) unstable angina pectoris (b) acute myocardial infarction, congestive heart failure (c) conduction abnormality not controlled with pacemaker or medication (d) significant ventricular or supraventricular arrhythmias.
  4. Any of the following:

    1. History or current evidence of congenital long QT syndrome;
    2. concomitant medications known to prolong QT interval or history of medicationrelated QT prolongation.
  5. Known to have tested positive for human immunodeficiency virus or active tuberculosis infection.
  6. Known active hepatitis infection, positive hepatitis C antibody, hepatitis B virus surface antigen or hepatitis B virus core antibody, at screening.
  7. 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.
  8. Spinal cord compression or brain metastases unless asymptomatic, stable, and not requiring steroids for at least 4 weeks prior to start of study intervention.
  9. 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.
  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. Patients with a known hypersensitivity to adavosertib, itraconazole, rifampicin, and omeprazole or any of the excipients of the product.
  13. Currently pregnant (confirmed with positive pregnancy test) or breast-feeding.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04959266


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
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United States, Connecticut
Research Site Withdrawn
New Haven, Connecticut, United States, 06510
United States, Georgia
Research Site Not yet recruiting
Newnan, Georgia, United States, 30265
United States, New Hampshire
Research Site Not yet recruiting
Lebanon, New Hampshire, United States, 03756
United States, Oregon
Research Site Recruiting
Portland, Oregon, United States, 97213
United States, Texas
Research Site Recruiting
Austin, Texas, United States, 78758
Research Site Recruiting
Dallas, Texas, United States, 75230
Spain
Research Site Not yet recruiting
Madrid, Spain, 28029
Research Site Not yet recruiting
Madrid, Spain, 28031
Research Site Recruiting
Madrid, Spain, 28034
Research Site Not yet recruiting
Madrid, Spain, 28040
Research Site Recruiting
Madrid, Spain, 28041
Research Site Not yet recruiting
Malaga, Spain, 29010
Research Site Not yet recruiting
Pozuelo de Alarcon, Spain, 28223
Sponsors and Collaborators
AstraZeneca
Parexel
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT04959266    
Other Study ID Numbers: D601HC00006
First Posted: July 13, 2021    Key Record Dates
Last Update Posted: June 30, 2022
Last Verified: June 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

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

URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
Proton Pump Inhibitor
Cytochrome P450 3A4 Inhibitor
Cytochrome P450 3A4 Inducer
Pharmacokinetics
Additional relevant MeSH terms:
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Itraconazole
Rifampin
Omeprazole
Adavosertib
Anti-Ulcer Agents
Gastrointestinal Agents
Proton Pump Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 CYP3A Inhibitors
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP2C8 Inducers
Cytochrome P-450 CYP2C19 Inducers
Cytochrome P-450 CYP2C9 Inducers
Cytochrome P-450 CYP3A Inducers