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

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

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.

Study Overview

• Status: Terminated
• Conditions: Advanced Solid Tumours
• Intervention / Treatment: Drug: Adavosertib; Drug: Itraconazole; Drug: Rifampicin; Drug: Omeprazole

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.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 1

Contacts and Locations

Study Locations

• Spain
  • Madrid, Spain, 28041
    • Research Site
  • Malaga, Spain, 29010
    • Research Site
• United States
  • Oregon
    • Portland, Oregon, United States, 97213
      • Research Site
  • Texas
    • Austin, Texas, United States, 78758
      • Research Site
    • Dallas, Texas, United States, 75230
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 130 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ratios of geometric means of Cmax (maximum observed plasma concentration) when administered in combination with itraconazole/rifampicin/omeprazole relative to adavosertib alone	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.	Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12
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	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.	Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12
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	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.	Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Summary of Adavosertib plasma concentrations with time	Assessment of pharmacokinetics (PK) for adavosertib when administered alone and in combination with itraconazole (arm A) /rifampicin (arm B) /omeprazole (arm C).	Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12
Descriptive statistics of Cmax	Assessment of Cmax for adavosertib when administered alone and in combination with itraconazole (arm A) /rifampicin (arm B) /omeprazole (arm C).	Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12
Descriptive statistics of AUCinf	Assessment of AUCinf for adavosertib when administered alone and in combination with itraconazole (arm A) /rifampicin (arm B) /omeprazole (arm C).	Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12
Descriptive statistics of AUClast	Assessment of AUClast for adavosertib when administered alone and in combination with itraconazole (arm A) /rifampicin (arm B) /omeprazole (arm C).	Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12
Descriptive statistics of tmax (Time to reach maximum observed concentration following drug administration)	Assessment of tmax for adavosertib when administered alone and in combination with itraconazole (arm A) /rifampicin (arm B) /omeprazole (arm C).	Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12
Descriptive statistics of λz (Terminal elimination rate constant)	Assessment of λz for adavosertib when administered alone and in combination with itraconazole (arm A) /rifampicin (arm B) /omeprazole (arm C).	Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12
Descriptive statistics of t½λz (Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve)	Assessment of t½λz for adavosertib when administered alone and in combination with itraconazole (arm A) /rifampicin (arm B) /omeprazole (arm C).	Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12
Descriptive statistics of CL/F (Apparent total body clearance of drug from plasma after extravascular administration)	Assessment of CL/F for adavosertib when administered alone and in combination with itraconazole (arm A) /rifampicin (arm B) /omeprazole (arm C).	Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12
Descriptive statistics of Vss/F (Volume of distribution (apparent) at steady state following extravascular administration)	Assessment of Vss/F for adavosertib when administered alone and in combination with itraconazole (arm A) /rifampicin (arm B) /omeprazole (arm C).	Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12
Descriptive statistics of Vz/F (Apparent volume of distribution during the terminal phase after extravascular administration)	Assessment of Vz/F for adavosertib when administered alone and in combination with itraconazole (arm A) /rifampicin (arm B) /omeprazole (arm C).	Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12
Descriptive statistics of Ctrough (Observed lowest drug concentration reached before the next dose is administered)	Assessment of Ctrough for itraconazole, rifampicin and omeprazole when administered in combination with adavosertib.	Arm A: Days 9-11; Arm B: Days 14-17; Arm C: Day 9
Number of patients with serious and non-serious adverse events	Assessment of the safety and tolerability of adavosertib when dosed with itraconazole (arm A), rifampicin (arm B), and omeprazole (arm C).	From screening to end of study [within 30 (±7) days of last adavosertib dose]

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Parexel

Study record dates

Study Major Dates

• Study Start (Actual): June 28, 2021
• Primary Completion (Actual): June 1, 2022
• Study Completion (Actual): June 1, 2022

Study Registration Dates

• First Submitted: June 8, 2021
• First Submitted That Met QC Criteria: June 30, 2021
• First Posted (Actual): July 13, 2021

Study Record Updates

• Last Update Posted (Actual): September 16, 2022
• Last Update Submitted That Met QC Criteria: September 15, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Proton Pump Inhibitor; Cytochrome P450 3A4 Inhibitor; Cytochrome P450 3A4 Inducer
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Gastrointestinal Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Bacterial Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Leprostatic Agents; Hormone Antagonists; Cytochrome P-450 Enzyme Inducers; Antifungal Agents; Steroid Synthesis Inhibitors; Anti-Ulcer Agents; Proton Pump Inhibitors; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; 14-alpha Demethylase Inhibitors; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Rifampin; Itraconazole; Omeprazole; Adavosertib
• Other Study ID Numbers: D601HC00006

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD 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.

• IPD Sharing 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

IPD Sharing 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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No