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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)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02157883
Recruitment Status : Active, not recruiting
First Posted : June 6, 2014
Results First Posted : April 14, 2016
Last Update Posted : June 11, 2020
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Advanced Non Small Cell Lung Cancer Advanced (Inoperable) Non Small Cell Lung Cancer Procedure: Pharmacokinetic sampling Drug: AZD9291 Drug: Itraconazole Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 39 participants
Allocation: N/A
Intervention Model: Single Group 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) on the Pharmacokinetics of a Single Oral Dose of AZD9291 in Patients With EGFRm Positive NSCLC Whose Disease Has Progressed on an EGFR TKI
Actual Study Start Date : November 6, 2014
Actual Primary Completion Date : April 3, 2015
Estimated Study Completion Date : March 5, 2021

Resource links provided by the National Library of Medicine


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




Primary Outcome Measures :
  1. Cmax of AZD9291 [ Time Frame: 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. ]
    Pharmacokinetics of AZD9291 by assessment of maximum plasma AZD9291 concentration

  2. AUC of AZD9291 [ Time Frame: 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. ]
    Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration time curve from zero to infinity


Secondary Outcome Measures :
  1. AUC(0-120) of AZD9291 [ Time Frame: 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. ]
    Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration time curve from zero to 120 hours

  2. AUC(0-t) of AZD9291 [ Time Frame: 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. ]
    Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration curve from time zero to last quantifiable dose

  3. Tmax of AZD9291 [ Time Frame: 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. ]
    Pharmacokinetics of AZD9291 by assessment of time to Cmax

  4. t1/2 of AZD9291 [ Time Frame: 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. ]
    Pharmacokinetics of AZD9291 by assessment of the terminal half-life

  5. CL/F of AZD9291 [ Time Frame: 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. ]
    Rate and extent of absorption of AZD9291 by assessment of apparent clearance following oral administration

  6. Vz/F of AZD9291 [ Time Frame: 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. ]
    Rate and extent of absorption of AZD9291 by assessment of the apprarent volume of distribution

  7. Cmax of AZ5104 [ Time Frame: 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. ]
    Pharmacokinetics of AZ5104 (metabolite to AZD9291) by assessment of maximum plasma AZ5104 concentration

  8. AUC of AZ5104 [ Time Frame: 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. ]
    Pharmacokinetics of AZ5104 (metabolite to AZD9291) by assessment of area under the plasma concentration time curve from zero to infinity

  9. Cmax of AZ7550 [ Time Frame: 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. ]
    Pharmacokinetics of AZ7550 (metabolite to AZD9291) by assessment of maximum plasma AZ7550 concentration

  10. AUC of AZ7550 [ Time Frame: 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. ]
    Pharmacokinetics of AZ7550 (metabolite to AZD9291) by assessment of area under the plasma concentration time curve from zero to infinity



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02157883


Locations
Layout table for location information
United States, California
Research Site
San Diego, California, United States, 92123
United States, Ohio
Research Site
Cleveland, Ohio, United States, 44106-4950
Belgium
Research Site
Edegem, Belgium, 2650
Research Site
Gent, Belgium, 9000
Korea, Republic of
Research Site
Seongnam-si, Korea, Republic of, 13620
Research Site
Seoul, Korea, Republic of, 03080
Research Site
Seoul, Korea, Republic of, 03722
Research Site
Seoul, Korea, Republic of, 06351
Research Site
Seoul, Korea, Republic of, 138-736
Netherlands
Research Site
Amsterdam, Netherlands, 1066 CX
Research Site
Maastricht, Netherlands, 6229 HX
Research Site
Rotterdam, Netherlands, 3015 CE
Taiwan
Research Site
Taipei City, Taiwan, 11217
Research Site
Taipei, Taiwan, 10002
United Kingdom
Research Site
London, United Kingdom, SE1 9RT
Research Site
Manchester, United Kingdom, M20 4BX
Sponsors and Collaborators
AstraZeneca
Investigators
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Study Director: Serban Ghiorghiu, MSD AstraZeneca
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02157883    
Other Study ID Numbers: D5160C00012
2014-001557-16 ( EudraCT Number )
First Posted: June 6, 2014    Key Record Dates
Results First Posted: April 14, 2016
Last Update Posted: June 11, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
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
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
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home
Keywords provided by AstraZeneca:
oncology, cancer, non small cell lung cancer, anticancer drug, pharmacokinetics, AZD9291, intraconazole, EGFR sensitivity mutation
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Itraconazole
Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 CYP3A Inhibitors