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)
Condition: Advanced Non Small Cell Lung Cancer; Advanced (Inoperable) Non Small Cell Lung Cancer
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: Pharmacokinetic sampling; AZD9291; Itraconazole
Intervention description: Blood samples taken pre and post dosing with AZD9291+/- itraconazole; AZD9291 tablets: Part A 80mg od, days 1 and 10 only. Part B 80mg od for 12 months.; Itraconazole tablets: 2x100mg bd, Part A days 6 to 19 only
Intervention MeSH terms: Itraconazole; Osimertinib
Phase: Phase 1
Study type: Interventional
Primary purpose: Other
Allocation: Non-Randomized
Masking: None (Open Label)
Enrollment: 39.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: oncology, cancer, non small cell lung cancer, anticancer drug, pharmacokinetics, AZD9291, intraconazole, EGFR sensitivity mutation

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
    

Eligibility 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.