Study to Assess the Effect of Itraconazole (a CYP3A4 Inhibitor) on the Pharmacokinetics of AZD9291, in Patients With EGFR Positive Non-small Cell Lung Cancer. Patients Will be Chosen From Those Who Have Already Been Prescribed an EGFR TKI Medicine (Such as Iressa or Tarceva)

A Phase I, Open-label, Non-randomised Study to Assess the Effect of Itraconazole (a CYP3A4 Inhibitor) on the Pharmacokinetics of a Single Oral Dose of AZD9291 in Patients With EGFRm Positive NSCLC Whose Disease Has Progressed on an EGFR TKI

This is a 2 part study in patients with EGFRm+ non small cell lung cancer (NSCLC), whose disease has progressed on an EGFRm TKI, who are refractory or resistant to standard therapy. Part A will assess the effect of multiple oral doses of itraconazole on the single dose pharmacokinetic (PK) parameters of AZD9291. On completion of Part A, patients may continue to take AZD9291 tablets (Part B) following the collection of the 216 hour sample on Day 19 if they and the Investigator deem it appropriate, until such time as their disease progresses, the Investigator believes they are no longer deriving clinical benefit, or they stop taking AZD9291 for any other reason

Study Overview

• Status: Completed
• Conditions: Advanced Non Small Cell Lung Cancer; Advanced (Inoperable) Non Small Cell Lung Cancer
• Intervention / Treatment: Procedure: Pharmacokinetic sampling; Drug: AZD9291; Drug: Itraconazole

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Edegem, Belgium, 2650
    • Research Site
  • Gent, Belgium, 9000
    • Research Site
• Korea, Republic of
  • Seongnam-si, Korea, Republic of, 13620
    • Research Site
  • Seoul, Korea, Republic of, 03722
    • Research Site
  • Seoul, Korea, Republic of, 05505
    • Research Site
  • Seoul, Korea, Republic of, 06351
    • Research Site
  • lJongno-gu, Korea, Republic of, 03080
    • Research Site
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Research Site
  • Maastricht, Netherlands, 6229 HX
    • Research Site
  • Rotterdam, Netherlands, 3015 GD
    • Research Site
• Taiwan
  • Taipei, Taiwan, 10002
    • Research Site
  • Taipei City, Taiwan, 11217
    • Research Site
• United Kingdom
  • London, United Kingdom, SE1 9RT
    • Research Site
  • Manchester, United Kingdom, M20 4BX
    • Research Site
• United States
  • California
    • San Diego, California, United States, 92123
      • Research Site
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

For inclusion in the study, patients should fulfil the following criteria:

1. Male or female, aged at least 18 years.
2. Histological or cytological confirmation diagnosis of NSCLC.
3. Radiological documentation of disease progression while on a previous continuous treatment with an EGFR TKI, eg, gefitinib or erlotinib. In addition, other lines of therapy may have been given. All patients must have documented radiological progression on the last treatment administered prior to enrolling in the study.
4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q).
5. ECOG performance status 0-1 with no deterioration over the previous 2 weeks.
6. Patients must have a life expectancy of ≥12 weeks as estimated at the time of screening.
7. Evidence of non-childbearing status for women of childbearing potential, or post-menopausal status: negative urine or serum pregnancy test within 28 days of study treatment, confirmed prior to treatment on Day 1 of Part A, or post menopausal status. Females should be using adequate contraceptive measures and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments; women under 50 years old would be consider postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with LH and FSH levels in the post-menopausal range for the institution; documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
8. Male patients should be willing to use barrier contraception, ie, condoms, until 6 months after last study drug is taken.

Patients should not enter the study if any of the following exclusion criteria are fulfilled:

1. 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).
2. Treatment with any of the following: Treatment with 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) within 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 CYP2C8 and of CYP3A4 (at least 1 week prior) and potent inducers of CYP3A4 (at least 3 week prior). All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer/inhibitory effects on CYP3A4, CYP2C8, and/ or CYP1A2.
3. 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.
4. 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 the end of Part A.
5. Spinal cord compression or brain metastases unless asymptomatic, stable and not requiring steroids for at least 4 weeks prior to start of study treatment.
6. 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.
7. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: ANC <1.5 x 10^9/L; Platelet count <100 x 10^9/L; Haemoglobin <90 g/L; ALT >2.5 x the institutional ULN if no demonstrable liver metastases or >5 x institutional ULN in the presence of liver metastases; AST >2.5 x institutional ULN if no demonstrable liver metastases or >5 x institutional ULN in the presence of liver metastases; Total bilirubin >1.5 x institutional ULN if no liver metastases or >3 x institutional ULN in the presence of documented Gilbert's Syndrome or liver metastases; Creatinine >1.5 x institutional ULN concurrent with creatinine clearance <50 mL/min (measured or calculated by Cockcroft-Gault formula); confirmation of creatinine clearance is only required when creatinine is >1.5 x institutional ULN.
8. Any of the following cardiac criteria: Mean resting corrected QT interval corrected for heart rate using Fridericia's correction factor (QTcF) >450 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 >250 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.
9. Patients unable to swallow oral medication or patients with GI disorders or significant GI resection likely to interfere with the absorption of AZD9291.
10. Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
11. Women who are breastfeeding.
12. Patients with a known hypersensitivity to AZD9291 or itranconazole or any of their excipients.

12. Concomitant medication contraindicated for use with itraconazole (including, but not limited to): cisapride, oral midazolam, nisoldipine, pimozide, quinidine, dofetilide, triazolam, levacetylmethadol (levomethadyl), 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA)- reductase inhibitors metabolized by CYP3A4, such as lovastatin and simvastatin, ergot alkaloids metabolized by CYP3A4, such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine).

13. For optional genetic research: Previous allogenic bone marrow transplant or non-leukocyte depleted whole blood transfusion within 120 days of sample collection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AZD9291 alone, AZD9291+itraconozole; Sequential treatments of AZD9291 alone followed by AZD9291+itraconazole, with a washout period in between.	Procedure: Pharmacokinetic sampling; Blood samples taken pre and post dosing with AZD9291+/- itraconazole; Drug: AZD9291; AZD9291 tablets: Part A 80mg od, days 1 and 10 only. Part B 80mg od for 12 months.; Drug: Itraconazole; Itraconazole tablets: 2x100mg bd, Part A days 6 to 19 only

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax of AZD9291	Pharmacokinetics of AZD9291 by assessment of maximum plasma AZD9291 concentration	Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.
AUC of AZD9291	Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration time curve from zero to infinity	Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC(0-120) of AZD9291	Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration time curve from zero to 120 hours	Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.
AUC(0-t) of AZD9291	Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration curve from time zero to last quantifiable dose	Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.
Tmax of AZD9291	Pharmacokinetics of AZD9291 by assessment of time to Cmax	Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.
t1/2 of AZD9291	Pharmacokinetics of AZD9291 by assessment of the terminal half-life	Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.
CL/F of AZD9291	Rate and extent of absorption of AZD9291 by assessment of apparent clearance following oral administration	Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.
Vz/F of AZD9291	Rate and extent of absorption of AZD9291 by assessment of the apprarent volume of distribution	Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.
Cmax of AZ5104	Pharmacokinetics of AZ5104 (metabolite to AZD9291) by assessment of maximum plasma AZ5104 concentration	Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.
AUC of AZ5104	Pharmacokinetics of AZ5104 (metabolite to AZD9291) by assessment of area under the plasma concentration time curve from zero to infinity	Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.
Cmax of AZ7550	Pharmacokinetics of AZ7550 (metabolite to AZD9291) by assessment of maximum plasma AZ7550 concentration	Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.
AUC of AZ7550	Pharmacokinetics of AZ7550 (metabolite to AZD9291) by assessment of area under the plasma concentration time curve from zero to infinity	Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Study Director: Serban Ghiorghiu, MSD, AstraZeneca

Publications and helpful links

General Publications

• Vishwanathan K, Dickinson PA, So K, Thomas K, Chen YM, De Castro Carpeno J, Dingemans AC, Kim HR, Kim JH, Krebs MG, Chih-Hsin Yang J, Bui K, Weilert D, Harvey RD. The effect of itraconazole and rifampicin on the pharmacokinetics of osimertinib. Br J Clin Pharmacol. 2018 Jun;84(6):1156-1169. doi: 10.1111/bcp.13534. Epub 2018 Mar 23.

Helpful Links

• StudyD5160C00012

Study record dates

Study Major Dates

• Study Start (Actual): November 6, 2014
• Primary Completion (Actual): April 3, 2015
• Study Completion (Actual): May 17, 2023

Study Registration Dates

• First Submitted: June 5, 2014
• First Submitted That Met QC Criteria: June 5, 2014
• First Posted (Estimated): June 6, 2014

Study Record Updates

• Last Update Posted (Actual): March 19, 2024
• Last Update Submitted That Met QC Criteria: March 12, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: oncology, cancer, non small cell lung cancer, anticancer drug, pharmacokinetics, AZD9291, intraconazole, EGFR sensitivity mutation
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Protein Kinase Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Tyrosine Kinase Inhibitors; Osimertinib; Itraconazole
• Other Study ID Numbers: D5160C00012; 2014-001557-16 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing 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 rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• IPD Sharing 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
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP