Study to Assess the Effect of AZD9291 on the Blood Levels of Simvastatin in Patients With EGFRm+ NSCLC
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|ClinicalTrials.gov Identifier: NCT02197234|
Recruitment Status : Active, not recruiting
First Posted : July 22, 2014
Results First Posted : June 22, 2016
Last Update Posted : March 21, 2023
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This is a Phase I, open-label, 2-part study in patients with a confirmed diagnosis of epidermal growth factor receptor (EGFR) mutation positive (EGFRm+) non-small cell lung cancer (NSCLC), who have progressed following prior therapy with an approved EGFR tyrosine kinase inhibitor (TKI) agent.
Part A will assess the effect of AZD9291 on the pharmacokinetic (PK) parameters of simvastatin and simvastatin acid, following multiple oral dosing of AZD9291 in a fasted state.
Part B will allow patients further access to AZD9291 after the PK phase (Part A) and will provide for additional safety data collection. All patients from Part A who completed treatment may continue to receive AZD9291 80 mg once daily until: disease progression; they are no longer deriving clinical benefit; or any other reason.
|Condition or disease||Intervention/treatment||Phase|
|Non Small Cell Lung Cancer||Procedure: Pharmacokinetic sampling - AZD9291 Drug: Simvastatin Drug: AZD9291 tablet dosing Procedure: Pharmacokinetic sampling - simvastatin Procedure: Pharmacokinetic sampling - AZ5140 and AZ7550||Phase 1|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||52 participants|
|Masking:||None (Open Label)|
|Official Title:||A Phase I, Open-Label, Non-Randomised, Multicentre Study to Assess the Effect of AZD9291 on the Pharmacokinetics of Simvastatin (a Sensitive CYP3A4 Substrate) in Patients With EGFRm Positive NSCLC Whose Disease Has Progressed on an EGFR TKI|
|Actual Study Start Date :||December 22, 2014|
|Actual Primary Completion Date :||April 30, 2015|
|Estimated Study Completion Date :||December 29, 2023|
Experimental: AZD9291 and simvastatin
Sequential treatments of simvastatin alone followed by AZD9291 alone, followed by simvastatin + AZD9291.
Procedure: Pharmacokinetic sampling - AZD9291
Blood sampling to measure AZD9291
Simvastatin (CYP substrate) 40mg taken once daily on Days 1 and 31 (Part A)
Drug: AZD9291 tablet dosing
AZD9291 80mg tablet taken from Days 3 to 32. (Part B) AZD9291 80mg tablet taken daily for 12 months.
Procedure: Pharmacokinetic sampling - simvastatin
Blood sampling to measure simvastatin levels
Procedure: Pharmacokinetic sampling - AZ5140 and AZ7550
Blood samples to measure levels of AZ5140 and AZ7550
- Cmax of Simvastatin [ Time Frame: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A ]Pharmacokinetics of simvastatin by assessment of maximum plasma simvastatin concentration
- AUC of Simvastatin [ Time Frame: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A ]Pharmacokinetics of simvastatin by assessment of area under the plasma concentration time curve from zero to infinity
- Tmax of Simvastatin and Simvastatin Acid [ Time Frame: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A ]Pharmacokinetics of simvastatin and simvastatin acid by time to Cmax
- CL/F of Simvastatin [ Time Frame: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A ]Rate and extent of absorption of simvastatin by assessment of apparent clearance following oral administration
- Cmax of Simvastatin Acid [ Time Frame: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A ]Pharmacokinetics of simvastatin acid by assessment of maximum plasma simvastatin acid concentration
- AUC of Simvastatin Acid [ Time Frame: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A ]Pharmacokinetics of simvastatin acid by assessment of area under the plasma concentration time curve from zero to infinity
- AUC(0-t) of Simvastatin and Simvastatin Acid [ Time Frame: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A ]Pharmacokinetics of simvastatin and simvastatin acid by assessment of area under the plasma concentration time curve from time zero to last quantifiable dose
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.
|Ages Eligible for Study:||18 Years to 130 Years (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
For inclusion in the study patient should fulfil the following criteria:
- Male or female, aged at least 18 years.
- Histological or cytological confirmation diagnosis of NSCLC.
- Radiological documentation of disease progression while on a previous continuous treatment with an EGFR TKI, eg gefitinib, afatinib 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.
- Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q).
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1 with no deterioration over the previous 2 weeks (Appendix G).
- Patients must have a life expectancy of ≥12 weeks as estimated at the time of screening.
- 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 considered post-menopausal 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.
- Male patients should be willing to use barrier contraception, ie, condoms, until 6 months after last study drug is taken.
- Participation in another study with an IP during the last 14 days (or a longer period depending on the defined characteristics of the agents used).
- Treatment with any of the following: Treatment with an EGFR TKI (eg, erlotinib or gefitinib) within 8 days or approx. 5 x half-life, whichever is the longer, of the first dose of study treatment; any cytotoxic chemotherapy, investigational agents or other anticancer drugs from a previous treatment regimen or clinical study within 14 days of the first dose; major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study treatment; 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; 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). All patients must avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer/inhibitory effects on CYP3A4.
- 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 the final PK sample collection on Day 32 of Part A.
- 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 PI'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 HIV. Screening for chronic conditions not required.
- 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 times ULN if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases; Aspartate aminotransferase (AST) >2.5 times ULN if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases; total bilirubin >1.5 times ULN if no liver metastases or >3 times ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia) or liver metastases; creatinine >1.5 times ULN concurrent with creatinine clearance <50 ml/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is >1.5 times ULN.
- Any of the following cardiac criteria: mean resting corrected QT interval corrected for heart rate using Fridericia's correction factor (QTcF) >470 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 age of 40 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 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, simvastatin, or any of the excipients of the products.
- Concomitant medication contraindicated for use with simvastatin due to drug interaction associated with increased risk of rhabdomyolysis (including, but not limited to): itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (eg, nelfinavir), nefazodone, cyclosporine, danazol, gemfibrozil, amiodarone, amlodipine.
- 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA)-reductase inhibitors, such as lovastatin and simvastatin.
- For optional genetic research: Previous allogenic bone marrow transplant or non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection.
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): NCT02197234
|United States, Georgia|
|Atlanta, Georgia, United States, 30322|
|Leuven, Belgium, 3000|
|Angers Cedex 9, France, 49055|
|Dijon cedex, France, 21079|
|Marseille, France, 13385|
|Rennes, France, 35033|
|Saint Herblain, France, 44805|
|Korea, Republic of|
|Seongnam-si, Korea, Republic of, 13620|
|Seoul, Korea, Republic of, 03080|
|Seoul, Korea, Republic of, 03722|
|Seoul, Korea, Republic of, 05505|
|Seoul, Korea, Republic of, 06351|
|Badalona, Spain, 08916|
|Barcelona, Spain, 08041|
|Madrid, Spain, 28046|
|Sevilla, Spain, 41013|
|Study Director:||Serban Ghiorghiu, MSD||AstraZeneca|
|Other Study ID Numbers:||
|First Posted:||July 22, 2014 Key Record Dates|
|Results First Posted:||June 22, 2016|
|Last Update Posted:||March 21, 2023|
|Last Verified:||March 2023|
|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.|
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.|
oncology, cancer, non small cell lung cancer, anticancer drug, pharmacokinetics, AZD9291, simvastatin, EGFR genes
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Neoplasms by Site
Respiratory Tract Diseases
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Protein Kinase Inhibitors