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

Phase 1TerminatedNCT04959266

AstraZeneca5 enrolled

Overview

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.

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

Allocation

NON_RANDOMIZED

Purpose

OTHER

Masking

NONE

Enrollment

Conditions

Advanced Solid Tumours

Interventions

AdavosertibDRUG

Patients will receive a single dose of Adavosertib orally in arm A, B, and C.

ItraconazoleDRUG

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

RifampicinDRUG

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

Eligibility

Sex: ALLMin age: 18 YearsMax age: 130 Years

Medical Language ↔ Plain English

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.

Locations (5)

Research Site

Portland, Oregon, United States

Research Site

Austin, Texas, United States

Research Site

Dallas, Texas, United States

Research Site

Madrid, Spain

Research Site

Málaga, Spain

Outcomes

Primary Outcomes

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.

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

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.

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

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.

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

Secondary Outcomes

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).

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

Descriptive statistics of Cmax

Data from ClinicalTrials.gov

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