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

NCT04959266 | Terminated Phase 1 FDA Drug

• 1 other identifier: D601HC00006
• Study Type: interventional
• Target: 5
• Locations: 2 countries
• Sites: 5

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.

Conditions

Advanced Solid Tumours

Keywords

Proton Pump Inhibitor; Cytochrome P450 3A4 Inhibitor; Cytochrome P450 3A4 Inducer; Pharmacokinetics

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (12)

• Summary of Adavosertib plasma concentrations with time

  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

  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

  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

  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)

  Arm A: Days 1-4 and 9-12; Arm B: Days 1-4 and 14-17; Arm C: Days 1-4 and 9-12

Study Arms (3)

Arm A

EXPERIMENTAL

Patients will receive a single oral dose of adavosertib alone, and a single oral dose of adavosertib concomitantly with itraconazole.

Drug: Adavosertib; Drug: Itraconazole

Arm B

EXPERIMENTAL

Patients will receive a single oral dose of adavosertib alone, and a single oral dose of adavosertib concomitantly with rifampicin.

Drug: Adavosertib; Drug: Rifampicin

Arm C

EXPERIMENTAL

Patients will receive a single oral dose of adavosertib alone, and a single oral dose of adavosertib concomitantly with omeprazole.

Drug: Adavosertib; Drug: Omeprazole

Interventions

Adavosertib DRUG

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

Arm A; Arm B; Arm C

Itraconazole DRUG

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

Arm A

Rifampicin DRUG

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

Arm B

Omeprazole DRUG

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

Arm C

Eligibility Criteria

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

You may qualify if:

• 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 or 1.
• Predicted life expectancy ≥ 12 weeks.
• Patients must have normal organ and marrow function at baseline, within 7 days prior to study drug administration.
• Males and females of childbearing potential who agree to use contraceptive measures must be consistent with clinical study protocol.

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 adavosertib, itraconazole, rifampicin, and omeprazole.
• 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.
• Any of the following:
• History or current evidence of congenital long QT syndrome;
• concomitant medications known to prolong QT interval or history of medicationrelated 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.
• 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.
• 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.
• Patients with a known hypersensitivity to adavosertib, itraconazole, rifampicin, and omeprazole or any of the excipients of the product.
• Currently pregnant (confirmed with positive pregnancy test) or breast-feeding.

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator

Study Sites (5)

Research Site

Portland, Oregon, 97213, United States

Location

Research Site

Austin, Texas, 78758, United States

Location

Research Site

Dallas, Texas, 75230, United States

Location

Research Site

Madrid, 28041, Spain

Location

Research Site

Málaga, 29010, Spain

Location

MeSH Terms

Interventions

adavosertib; Itraconazole; Rifampin; Omeprazole

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Piperazines; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; 2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Organic Chemicals; Pyridines; Benzimidazoles; Heterocyclic Compounds, 2-Ring

Study Design

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

Study Record Dates

• First Submitted: June 8, 2021
• First Posted: July 13, 2021
• Study Start: June 28, 2021
• Primary Completion: June 1, 2022
• Study Completion: June 1, 2022
• Last Updated: September 16, 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

ES (2); US (3)