Non Small Cell Lung Cancer
Conditions
Keywords
oncology, cancer, non small cell lung cancer, anticancer drug, pharmacokinetics, AZD9291, simvastatin, EGFR genes
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.
Interventions
PROCEDUREPharmacokinetic sampling - AZD9291
Blood sampling to measure AZD9291
DRUGSimvastatin
Simvastatin (CYP substrate) 40mg taken once daily on Days 1 and 31 (Part A)
AZD9291 80mg tablet taken from Days 3 to 32. (Part B) AZD9291 80mg tablet taken daily for 12 months.
PROCEDUREPharmacokinetic sampling - simvastatin
Blood sampling to measure simvastatin levels
Blood samples to measure levels of AZ5140 and AZ7550
Sponsors
AstraZeneca
Study design
Allocation
NA
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
For inclusion in the study patient 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, 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. 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. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 with no deterioration over the previous 2 weeks (Appendix G). 6. Patients must have a life expectancy of ≥12 weeks as estimated at the time of screening. 7. 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. 8. Male patients should be willing to use barrier contraception, ie, condoms, until 6 months after last study drug is taken.
Exclusion criteria
1. 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). 2. 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. 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 final PK sample collection on Day 32 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 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. 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 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. 8. 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. 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 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, simvastatin, or any of the excipients of the products. 13. 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. 14. 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA)-reductase inhibitors, such as lovastatin and simvastatin. 15. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax 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 | Pharmacokinetics of simvastatin by assessment of maximum plasma simvastatin concentration |
| AUC 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 | Pharmacokinetics of simvastatin by assessment of area under the plasma concentration time curve from zero to infinity |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Pharmacokinetics of simvastatin acid by assessment of maximum plasma simvastatin acid concentration |
| 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 | Pharmacokinetics of simvastatin and simvastatin acid by time to Cmax |
| 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 | Pharmacokinetics of simvastatin and simvastatin acid by assessment of area under the plasma concentration time curve from time zero to last quantifiable dose |
| 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 | Pharmacokinetics of simvastatin acid by assessment of area under the plasma concentration time curve from zero to infinity |
| 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 | Rate and extent of absorption of simvastatin by assessment of apparent clearance following oral administration |
Countries
Belgium, France, South Korea, Spain, United States
Participant flow
Recruitment details
First patient enrolled: 22 December 2014; Last Subject Last Visit Part A: 30 April 2015 and Part B: 13 May 2016. Study performed at 17 sites across Asia, North America and Western Europe. Part A assessed effect of multiple doses of AZD9291 on PK of simvastatin; Part B allowed subjects further access to AZD9291 and provided additional safety data.
Pre-assignment details
57 patients were enrolled (signed informed consent). Patients were assigned to treatment if they met all the inclusion and none of the exclusion criteria. 5 patients were enrolled but failed inclusion/exclusion criteria and so were not eligible to be assigned treatment. The remaining 52 patients started Period 1 and received treatment.
Participants by arm
| Arm | Count |
|---|---|
| Simvastatin and AZD9291 (Part A); AZD9291 Alone (Part B) In Part A of the study, sequential treatments of simvastatin alone followed by AZD9291 alone, followed by simvastatin + AZD9291. Each patient received 80 mg oral doses of AZD9291 tablets once daily for 30 days (Days 3 to 32) and single 40 mg oral doses of simvastatin on Day 1 and Day 31.
In Part B of the study, each patient received 80 mg oral AZD9291 tablet formulation once daily, for the duration of their participation. | 52 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Part A: Day 3-30 (AZD9291 Alone) | Condition under investigation worsened | 1 |
| Part A: Day 3-30 (AZD9291 Alone) | Withdrawal by Subject | 1 |
| Part B: Day 33 to End Part B (AZD9291) | Adverse Event | 1 |
| Part B: Day 33 to End Part B (AZD9291) | Condition under investigation worsened | 22 |
| Part B: Day 33 to End Part B (AZD9291) | Death | 6 |
| Part B: Day 33 to End Part B (AZD9291) | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Simvastatin and AZD9291 (Part A); AZD9291 Alone (Part B) |
|---|---|
| Age, Continuous | 63.5 years STANDARD_DEVIATION 11.28 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 17 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 35 Participants |
| Sex: Female, Male Female | 37 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 52 | 0 / 52 | 8 / 50 |
| other Total, other adverse events | 50 / 52 | 39 / 52 | 45 / 50 |
| serious Total, serious adverse events | 11 / 52 | 4 / 52 | 8 / 50 |
Outcome results
Primary
AUC of Simvastatin
Pharmacokinetics of simvastatin by assessment of area under the plasma concentration time curve from zero to infinity
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
Population: Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Simvastatin Alone | AUC of Simvastatin | 80.25 ng.h/mL |
| AZD9291 + Simvastatin | AUC of Simvastatin | 73.54 ng.h/mL |
Comparison: Study sized so experiment-wise power for the 90% CIs of geometric mean ratios for both AUC and Cmax of AUC9291 being within 70-143% was 90% (95% for each parameter). Within patient CV assumed to be 45%. No change in exposure was also assumed.90% CI: [77.16, 108.41]
Primary
Cmax of Simvastatin
Pharmacokinetics of simvastatin by assessment of maximum plasma simvastatin concentration
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
Population: Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Simvastatin Alone | Cmax of Simvastatin | 24.54 ng/mL |
| AZD9291 + Simvastatin | Cmax of Simvastatin | 18.65 ng/mL |
Comparison: Study sized so experiment-wise power for the 90% CIs of geometric mean ratios for both AUC and Cmax of AUC9291 being within 70-143% was 90% (95% for each parameter). Within patient CV assumed to be 45%. No change in exposure was also assumed.90% CI: [63.41, 93.7]
Secondary
AUC(0-t) of Simvastatin and Simvastatin Acid
Pharmacokinetics of simvastatin and simvastatin acid by assessment of area under the plasma concentration time curve from time zero to last quantifiable dose
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
Population: Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Simvastatin Alone | AUC(0-t) of Simvastatin and Simvastatin Acid | Simvastatin | 77.97 ng.h/mL |
| Simvastatin Alone | AUC(0-t) of Simvastatin and Simvastatin Acid | Simvastatin acid | 29.25 ng.h/mL |
| AZD9291 + Simvastatin | AUC(0-t) of Simvastatin and Simvastatin Acid | Simvastatin | 70.17 ng.h/mL |
| AZD9291 + Simvastatin | AUC(0-t) of Simvastatin and Simvastatin Acid | Simvastatin acid | 29.60 ng.h/mL |
Secondary
AUC of Simvastatin Acid
Pharmacokinetics of simvastatin acid by assessment of area under the plasma concentration time curve from zero to infinity
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
Population: Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Simvastatin Alone | AUC of Simvastatin Acid | 31.18 ng.h/mL |
| AZD9291 + Simvastatin | AUC of Simvastatin Acid | 30.16 ng.h/mL |
Secondary
CL/F of Simvastatin
Rate and extent of absorption of simvastatin by assessment of apparent clearance following oral administration
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
Population: Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Simvastatin Alone | CL/F of Simvastatin | 498.3 L/h |
| AZD9291 + Simvastatin | CL/F of Simvastatin | 543.9 L/h |
Secondary
Cmax of Simvastatin Acid
Pharmacokinetics of simvastatin acid by assessment of maximum plasma simvastatin acid concentration
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
Population: Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Simvastatin Alone | Cmax of Simvastatin Acid | 4.187 ng/mL |
| AZD9291 + Simvastatin | Cmax of Simvastatin Acid | 4.161 ng/mL |
Secondary
Tmax of Simvastatin and Simvastatin Acid
Pharmacokinetics of simvastatin and simvastatin acid by time to Cmax
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
Population: Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Simvastatin Alone | Tmax of Simvastatin and Simvastatin Acid | Simvastatin | 1.50 hours |
| Simvastatin Alone | Tmax of Simvastatin and Simvastatin Acid | Simvastatin acid | 3.08 hours |
| AZD9291 + Simvastatin | Tmax of Simvastatin and Simvastatin Acid | Simvastatin | 1.50 hours |
| AZD9291 + Simvastatin | Tmax of Simvastatin and Simvastatin Acid | Simvastatin acid | 3.08 hours |