Study to Assess the Effect of AZD9291 on the Blood Levels of Simvastatin in Patients With EGFRm+ NSCLC
Condition: Non Small Cell Lung Cancer
MeSH terms: Carcinoma, Non-Small-Cell Lung
Intervention: Pharmacokinetic sampling - AZD9291; Simvastatin; AZD9291 tablet dosing; Pharmacokinetic sampling - simvastatin; Pharmacokinetic sampling - AZ5140 and AZ7550
Intervention description: Blood sampling to measure AZD9291; 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.; Blood sampling to measure simvastatin levels; Blood samples to measure levels of AZ5140 and AZ7550
Intervention MeSH terms: Osimertinib; Simvastatin
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Masking: None (Open Label)
Enrollment: 52.0
Sex: All
Minimum age: 18 Years
Maximum age: 130 Years
Healthy volunteers: No
Keywords: oncology, cancer, non small cell lung cancer, anticancer drug, pharmacokinetics, AZD9291, simvastatin, EGFR genes

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.
    

Eligibility 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.