Study to Assess the Blood Levels and Safety of AZD9291 in Patients With Advanced Solid Tumours and Normal Liver Function or Mild or Moderate Liver Impairment

NCT02161770 | Completed Phase 1

• 2 other identifiers: D5160C000082014-001515-39
• Study Type: interventional
• Target: 30
• Locations: 6 countries
• Sites: 19

Brief Summary

This is a 2-part study in patients with advanced solid tumours. Part A will investigate the pharmacokinetics (PK) of AZD9291 in patients with mild or moderate hepatic impairment compared to patients with normal hepatic function; Part B will allow any patient with mild or moderate hepatic impairment or normal hepatic function, who completes Part A, continued access to AZD9291 after the PK phase and will provide additional safety data.

Conditions

Solid Tumours

Keywords

oncology, cancer, neoplasm, anticancer drug, pharmacokinetics, area under curve, AZD9291, solid tumour, mild hepatic impairment, moderate hepatic impairment

Outcome Measures

Primary Outcomes (2)

• Pharmacokinetics of AZD9291 by assessment of maximum plasma AZD9291 concentration (Cmax)

  Rate and extent of absorption of AZD9291 following single oral doses of AZD9291 tablet formulation by assessment of maximum plasma AZD9291 concentration (Cmax).

  Blood samples are collected at the following timepoints post AZD9291 dose on Day 1: pre-dose, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours

• Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration time curve from zero to infinity (AUC)

  Rate and extent of absorption of AZD9291 following single oral doses of AZD9291 tablet formulation by assessment of area under the plasma concentration time curve from zero to infinity (AUC).

  Blood samples are collected at the following timepoints post AZD9291 dose on Day 1: pre-dose, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours

Secondary Outcomes (13)

• Pharmacokinetics of AZD9291, AZ5104, and AZ7550 by assessment of AUC(0-t)

  Blood samples are collected at the following timepoints post AZD9291 dose on Day 1: pre-dose, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours

• Pharmacokinetics of AZ5104 and AZ7550 by assessment of Cmax

  Blood samples are collected at the following timepoints post AZD9291 dose on Day 1: pre-dose, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours

• Assessment of the safety and tolerability of AZD9291

  Parts A and B, approximately seven months

• Pharmacokinetics of AZD9291, AZ5104, and AZ7550 by assessment of tmax

  Blood samples are collected at the following timepoints post AZD9291 dose on Day 1: pre-dose, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours

• Pharmacokinetics of AZD9291, AZ5104, and AZ7550 by assessment of AUC(0-24)

  Blood samples are collected at the following timepoints post AZD9291 dose on Day 1: pre-dose, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours

Study Arms (3)

Normal hepatic function

OTHER

Patients without a history or presence of hepatic disease

Drug: AZD9291 tablet dosing; Procedure: Pharmacokinetic sampling - AZD9291; Procedure: Pharmacokinetic sampling - AZ5140 and AZ7550

Mild hepatic impairment

OTHER

Patients defined by the Child-Pugh classification system to be Child-Pugh A

Drug: AZD9291 tablet dosing; Procedure: Pharmacokinetic sampling - AZD9291; Procedure: Pharmacokinetic sampling - AZ5140 and AZ7550

Moderate hepatic impairment

OTHER

Patients defined by the Child-Pugh classification system to be Child-Pugh B

Drug: AZD9291 tablet dosing; Procedure: Pharmacokinetic sampling - AZD9291; Procedure: Pharmacokinetic sampling - AZ5140 and AZ7550

Interventions

AZD9291 tablet dosing DRUG

Part A - single 80mg oral dose AZD9291 (administered as 1 80mg tablet). Part B - 80mg oral dose AZD9291 od.

Mild hepatic impairment; Moderate hepatic impairment; Normal hepatic function

Pharmacokinetic sampling - AZD9291 PROCEDURE

Blood sampling to measure AZD9291 pharmacokinetic parameters.

Mild hepatic impairment; Moderate hepatic impairment; Normal hepatic function

Pharmacokinetic sampling - AZ5140 and AZ7550 PROCEDURE

Blood samples to measure the pharmacokinetic parameters of AZ5104 and AZ7550.

Mild hepatic impairment; Moderate hepatic impairment; Normal hepatic function

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• Participation in another clinical study with an IP during the last 14 days (or a longer period depending on the defined characteristics of the agents used).
• Treatment in the previous 3 months before dosing in this study with any drug known to have a well-defined potential for fulminant hepatotoxicity (eg, halothane and methotrexate).
• Treatment with any of the following: an EGFR TKI w/in 8 days or approximately 5x half-life, whichever is the longer, of the first dose of study treatment; Any cytotoxic chemotherapy, investigational agents or other anticancer drugs w/in 14 days of the first dose of study treatment; Major surgery (excluding placement of vascular access) w/in 4 weeks of the first dose; Radiotherapy with a limited field of radiation for palliation within 1 week of the first dose of study treatment, with the exception of patients receiving radiation to more than 30% of the bone marrow or with a wide field of radiation which must be completed within 4 weeks of the first dose of study treatment; Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inhibitors of CYP3A4 (at least 1 week prior) and potent inducers of CYP3A4 (at least 3 week prior) (Appendix H). All patients in Part B and continued access must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known potent inducer/inhibitory effects on CYP3A4 (Appendix H).
• Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment with the exception of alopecia and Grade 2 prior platinum-therapy related neuropathy.
• Any intake of grapefruit, grapefruit juice, Seville oranges, Seville orange marmalade, or other products containing grapefruit or Seville oranges within 7 days of the first administration of the IP until final PK sample collection on Day 22.
• Spinal cord compression or brain metastases unless asymptomatic, stable and not requiring steroids for at least 4 weeks prior to start of study treatment.
• Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the Investigator's opinion makes it undesirable for the patient to participate in the study or which would jeopardise compliance with the protocol, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
• Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: ANCless than1.5x10.9/L; platelet count less than100x10.9/L; haemoglobinless than90 g/L; Creatinine greater than1.5 x institutional ULN concurrent with creatinine clearance less than50 mL/min (measured or calculated by Cockcroft-Gault formula); confirmation of creatinine clearance is only required when creatinine is greater than1.5 x institutional ULN.
• Any of the following cardiac criteria: Mean resting corrected QT interval corrected for heart rate using Fridericia's correction factor (QTcF) greater than470 msec obtained from 3 ECGs; Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG eg, complete left bundle branch block, third degree heart block, second degree heart block, PR interval greater than250 msec; Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval.
• Patients unable to swallow oral medication or patients with GI disorders or significant GI resection likely to interfere with the absorption of AZD9291.
• Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
• Women who are breastfeeding.
• Patients with a known hypersensitivity to AZD9291 or any of its excipients. Patients with normal hepatic function should not have a history or presence of hepatic disease known to interfere with the absorption, distribution, metabolism or excretion of AZD9291.
• Patients with mild or moderate hepatic function should not enter if the following are fulfilled:
• Patients with hepatic encephalopathy within the last 4 weeks prior to Day 1.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (19)

Research Site

San Diego, California, 92123, United States

Location

Research Site

Atlanta, Georgia, 30322, United States

Location

Research Site

Detroit, Michigan, 48202, United States

Location

Research Site

Cleveland, Ohio, 44106-4948, United States

Location

Research Site

San Antonio, Texas, 78229, United States

Location

Research Site

Ghent, 9000, Belgium

Location

Research Site

Woluwé-St-Lambert, 1200, Belgium

Location

Research Site

Angers, Angers Cedex 9, France

Location

Research Site

Marseille, 13915, France

Location

Research Site

Pierre-Bénite, 69495, France

Location

Research Site

Rennes, 35000, France

Location

Research Site

Saint-Herblain, 44805, France

Location

Research Site

Toulouse, 31059, France

Location

Research Site

Seoul, 05505, South Korea

Location

Research Site

Madrid, 28034, Spain

Location

Research Site

Madrid, 28040, Spain

Location

Research Site

Madrid, 28046, Spain

Location

Research Site

Madrid, 28050, Spain

Location

Research Site

Newcastle upon Tyne, NE7 7DN, United Kingdom

Location

Related Publications (1)

• Grande E, Harvey RD, You B, Batlle JF, Galbraith H, Sarantopoulos J, Ramalingam SS, Mann H, So K, Johnson M, Vishwanathan K. Pharmacokinetic Study of Osimertinib in Cancer Patients with Mild or Moderate Hepatic Impairment. J Pharmacol Exp Ther. 2019 May;369(2):291-299. doi: 10.1124/jpet.118.255919. Epub 2019 Mar 14.

  PMID: 30872388 DERIVED

MeSH Terms

Conditions

Neoplasms

Study Officials

• Yuri Rukazenkov

  AstraZeneca

  STUDY CHAIR

Study Design

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

Study Record Dates

• First Submitted: May 29, 2014
• First Posted: June 12, 2014
• Study Start: December 22, 2014
• Primary Completion: May 16, 2017
• Study Completion: August 22, 2017
• Last Updated: March 8, 2019

Record last verified: 2019-03

Locations

BE (2); US (5); GB (1); FR (6); ES (4); KR (1)