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

Advanced Solid Tumours Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04959266
• Other study ID #: D601HC00006
• Status: Terminated
• Phase: Phase 1
• Start date: June 28, 2021
• Est. completion date: June 1, 2022

Study information

• Verified date: August 2022
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 5
• Est. completion date: June 1, 2022
• Est. primary completion date: June 1, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 130 Years

Eligibility

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.

Related Conditions & MeSH terms

• Advanced Solid Tumours

Intervention

Drug:
• Adavosertib
Patients will receive a single dose of Adavosertib orally in arm A, B, and C.
• Itraconazole
Patients will receive Itraconazole orally once daily for 7 days in arm A.
• Rifampicin
Patients will receive Rifampicin orally once daily for 13 days in arm B.
• Omeprazole
Patients will receive Omeprazole orally once daily for 5 days in arm C.

Locations

Country	Name	City	State
Spain	Research Site	Madrid
Spain	Research Site	Malaga
United States	Research Site	Austin	Texas
United States	Research Site	Dallas	Texas
United States	Research Site	Portland	Oregon

Sponsors (2)

Lead Sponsor	Collaborator
AstraZeneca	Parexel

Countries where clinical trial is conducted

United States,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Descriptive statistics of ?z (Terminal elimination rate constant)	Assessment of ?z 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
Secondary	Descriptive statistics of t½?z (Half-life associated with terminal slope (?z) of a semi-logarithmic concentration-time curve)	Assessment of t½?z 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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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]