Study to Assess the Effect of AZD9291 on the Blood Levels of Simvastatin in Patients With EGFRm+ NSCLC

NCT02197234 | Completed Phase 1 Results

• 2 other identifiers: D5160C000142014-002070-36
• Study Type: interventional
• Target: 52
• Locations: 5 countries
• Sites: 16

Brief Summary

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.

Conditions

Non Small Cell Lung Cancer

Keywords

oncology, cancer, non small cell lung cancer, anticancer drug, pharmacokinetics, AZD9291, simvastatin, EGFR genes

Outcome Measures

Primary Outcomes (2)

• Cmax of Simvastatin

  Pharmacokinetics of simvastatin by assessment of maximum plasma simvastatin concentration

  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

• AUC of Simvastatin

  Pharmacokinetics of simvastatin by assessment of area under the plasma concentration time curve from zero to infinity

  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

Secondary Outcomes (5)

• Tmax of Simvastatin and Simvastatin Acid

  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

• CL/F of Simvastatin

  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

• Cmax of Simvastatin Acid

  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

• AUC of Simvastatin Acid

  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

• AUC(0-t) of Simvastatin and Simvastatin Acid

  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

Study Arms (1)

AZD9291 and simvastatin

EXPERIMENTAL

Sequential treatments of simvastatin alone followed by AZD9291 alone, followed by simvastatin + AZD9291.

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

Interventions

Pharmacokinetic sampling - AZD9291 PROCEDURE

Blood sampling to measure AZD9291

AZD9291 and simvastatin

Simvastatin DRUG

Simvastatin (CYP substrate) 40mg taken once daily on Days 1 and 31 (Part A)

AZD9291 and simvastatin

AZD9291 tablet dosing DRUG

AZD9291 80mg tablet taken from Days 3 to 32. (Part B) AZD9291 80mg tablet taken daily for 12 months.

AZD9291 and simvastatin

Pharmacokinetic sampling - simvastatin PROCEDURE

Blood sampling to measure simvastatin levels

AZD9291 and simvastatin

Pharmacokinetic sampling - AZ5140 and AZ7550 PROCEDURE

Blood samples to measure levels of AZ5140 and AZ7550

AZD9291 and simvastatin

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (16)

Research Site

Atlanta, Georgia, 30322, United States

Location

Research Site

Leuven, 3000, Belgium

Location

Research Site

Angers, 49055, France

Location

Research Site

Dijon, 21079, France

Location

Research Site

Marseille, 13385, France

Location

Research Site

Rennes, 35033, France

Location

Research Site

Saint-Herblain, 44805, France

Location

Research Site

Seongnam-si, 13620, South Korea

Location

Research Site

Seoul, 03080, South Korea

Location

Research Site

Seoul, 03722, South Korea

Location

Research Site

Seoul, 05505, South Korea

Location

Research Site

Seoul, 06351, South Korea

Location

Research Site

Badalona, 08916, Spain

Location

Research Site

Barcelona, 08041, Spain

Location

Research Site

Madrid, 28046, Spain

Location

Research Site

Seville, 41013, Spain

Location

Related Publications (1)

• Harvey RD, Aransay NR, Isambert N, Lee JS, Arkenau T, Vansteenkiste J, Dickinson PA, Bui K, Weilert D, So K, Thomas K, Vishwanathan K. Effect of multiple-dose osimertinib on the pharmacokinetics of simvastatin and rosuvastatin. Br J Clin Pharmacol. 2018 Dec;84(12):2877-2888. doi: 10.1111/bcp.13753. Epub 2018 Oct 10.

  PMID: 30171779 DERIVED

Related Links

• CSR Synopsis\_Redacted

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Neoplasms

Interventions

Simvastatin

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Lovastatin; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds

Limitations and Caveats

At end of Part B, the CAP allowed patients to continue receiving AZD9291 if still deriving clinical benefit. No clinical data was databased during the CAP; thus AE data is presented to end of Part B only.

Results Point of Contact

• Title: Dr Karen So
• Organization: AstraZeneca

ClinicalTrialTransparency@astrazeneca.com

Study Officials

• Serban Ghiorghiu, MSD

  AstraZeneca

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 21, 2014
• First Posted: July 22, 2014
• Study Start: December 22, 2014
• Primary Completion: April 30, 2015
• Study Completion: June 3, 2024
• Last Updated: November 20, 2025
• Results First Posted: June 22, 2016

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, 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.

Locations

BE (1); US (1); KR (5); FR (5); ES (4)