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

Sponsor
AstraZeneca (Industry)
Overall Status
Recruiting
CT.gov ID
NCT04959266
Collaborator
Parexel (Industry)
70
13
3
16.4
5.4
0.3

Study Details

Study Description

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
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.

Study Design

Study Type:
Interventional
Anticipated 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 :
Jun 28, 2021
Anticipated Primary Completion Date :
Nov 9, 2022
Anticipated Study Completion Date :
Nov 9, 2022

Arms and Interventions

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.

Outcome Measures

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 [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 [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 [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 [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 [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 [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 [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) [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) [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) [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) [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) [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) [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) [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 [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).

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years to 130 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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 >
  1. caused by previous anticancer therapy, excluding alopecia and CTCAE Grade 2 peripheral neuropathy.
  1. 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.

  2. 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.

  3. Any of the following:

  4. History or current evidence of congenital long QT syndrome;

  5. concomitant medications known to prolong QT interval or history of medicationrelated QT prolongation.

  6. Known to have tested positive for human immunodeficiency virus or active tuberculosis infection.

  7. Known active hepatitis infection, positive hepatitis C antibody, hepatitis B virus surface antigen or hepatitis B virus core antibody, at screening.

  8. 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.

  9. Spinal cord compression or brain metastases unless asymptomatic, stable, and not requiring steroids for at least 4 weeks prior to start of study intervention.

  10. 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.

  11. Use of an anti-cancer treatment drug ≤ 21 days (≤ 6 weeks for nitroureas or mitomycin

  1. or use of an investigational product within 5 half-lives prior to the first dose of adavosertib.
  1. 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.

  2. Patients with a known hypersensitivity to adavosertib, itraconazole, rifampicin, and omeprazole or any of the excipients of the product.

  3. Currently pregnant (confirmed with positive pregnancy test) or breast-feeding.

Contacts and Locations

Locations

Site City State Country Postal Code
1 Research Site New Haven Connecticut United States 06510
2 Research Site Newnan Georgia United States 30265
3 Research Site Lebanon New Hampshire United States 03756
4 Research Site Portland Oregon United States 97213
5 Research Site Austin Texas United States 78758
6 Research Site Dallas Texas United States 75230
7 Research Site Madrid Spain 28029
8 Research Site Madrid Spain 28031
9 Research Site Madrid Spain 28034
10 Research Site Madrid Spain 28040
11 Research Site Madrid Spain 28041
12 Research Site Malaga Spain 29010
13 Research Site Pozuelo de Alarcon Spain 28223

Sponsors and Collaborators

  • AstraZeneca
  • Parexel

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
AstraZeneca
ClinicalTrials.gov Identifier:
NCT04959266
Other Study ID Numbers:
  • D601HC00006
First Posted:
Jul 13, 2021
Last Update Posted:
Jun 30, 2022
Last Verified:
Jun 1, 2022
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by AstraZeneca
Additional relevant MeSH terms:

Study Results

No Results Posted as of Jun 30, 2022