Phase I, Study in Chinese NSCLC Patients
Condition: Carcinoma, Non-Small-Cell Lung With EGFR Mutation Positive
MeSH terms: Carcinoma, Non-Small-Cell Lung
Intervention: AZD9291 40 mg; AZD9291 80 mg
Intervention description: This is a two parts (Part A and Part B) study to determine the pharmacokinetics of AZD9291 administered orally at two dose levels (40 mg Cohort 1 and 80 mg Cohort 2) in patients with locally advanced or metastatic NSCLC who have progressed following prior therapy with an EGFR TKI agent (+/- additional chemotherapy regimens).; This is a two parts (Part A and Part B) study to determine the pharmacokinetics of AZD9291 administered orally at two dose levels (40 mg Cohort 1 and 80 mg Cohort 2) in patients with locally advanced or metastatic NSCLC who have progressed following prior therapy with an EGFR TKI agent (+/- additional chemotherapy regimens).
Intervention MeSH terms: Osimertinib
Phase: Phase 1
Study type: Interventional
Primary purpose: Other
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 31.0
Sex: All
Minimum age: 18 Years
Maximum age: 130 Years
Healthy volunteers: No

Summary:

      A Phase I, Open-Label, Two Parts Study to Assess the Safety, Tolerability,Pharmacokinetics
      and Preliminary Anti-tumour Activity of AZD9291 in Chinese Patients with Advanced Non-Small
      Cell Lung Cancer who have Progressed Following Prior Therapy with an Epidermal Growth Factor
      Receptor Tyrosine Kinase Inhibitor Agent

      Study Objective: 1, Primary Objective To characterise the pharmacokinetics (PK) of AZD9291
      and its metabolites (AZ5104 and AZ7550) after single then multiple doses of AZD9291
      administered orally once daily in Chinese patients with locally advanced or metastatic non
      small cell lung Cancer (NSCLC) who have progressed following prior therapy with an approved
      Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) agent.

      2, Secondary objective(s) To investigate the safety and tolerability of AZD9291 when given
      orally to Chinese patients with locally advanced or metastatic NSCLC who have progressed
      following prior therapy with an approved EGFR TKI agent. To obtain a preliminary assessment
      of the anti-tumour activity of AZD9291 by evaluation of tumour response using Response
      Evaluation Criteria in Solid Tumours (RECIST) version 1.1.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Provision informed consent

          2. Aged at least 18 years

          3. Histological or cytological confirmation diagnosis of NSCLC

          4. Locally advanced or metastatic NSCLC

          5. Radiological documentation of disease progression while on a previous continuous
             treatment with an approved EGFR TKI. In addition other lines of therapy may have been
             given

               -  Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known
                  to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion,
                  L858R, L861Q)

          6. World Health Organisation (WHO) performance status 0-1

          7. At least one lesion suitable for accurate repeated measurements

          8. Females

               -  Child bearing potential : should not be breast feeding, use adequate
                  contraceptive measures for female patients with child-bearing potential, OR

               -  Have evidence of non-child-bearing potential that meet 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 below 50 years old would be consider postmenopausal if they have been
                  amenorrheic for 12 months or more following cessation of exogenous hormonal
                  treatments and with luteinizing hormone (LH) and follicle-stimulating hormone
                  (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

          9. Male patients should be willing to use barrier contraception ie, condoms

        Exclusion Criteria:

          1. Treatment with any of the following (prior to first dose of study treatment)

               -  Treatment with an EGFR TKI within 8 days

               -  Any investigational agents or other anticancer drugs from a previous treatment
                  regimen or clinical study within 14 days

               -  Previous treatment with AZD9291, or a Thr790Met (T790M) directed EGFR TKIs

               -  Major surgery (excluding placement of vascular access) within 4 weeks

               -  Radiotherapy :

               -  Within 1 week if limited field of radiation for palliation of the first dose of
                  study treatment

               -  Within 4 weeks if receiving radiation to more than 30% of the bone marrow or with
                  a wide field of radiation

               -  Patients currently receiving (or unable to stop use at least 1 week) medications
                  or herbal supplements known to be potent inhibitors or inducers of cytochrome
                  P450 3A4 (CYP3A4)

               -  Treatment with an investigational drug within five half-lives of the compound

          2. 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

          3. Spinal cord compression or brain metastases unless asymptomatic, stable and not
             requiring steroids for at least 4 weeks prior to start of study treatment

          4. 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 trial 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

          5. Any of the following cardiac criteria:

               -  Mean resting corrected QT interval (QTc) >470 msec obtained from 3
                  electrocardiograms (ECGs), using the screening clinic ECG machine derivedQTc
                  value

               -  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, P wave to R wave (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 (Q-T interval) QT
                  syndrome, family history of long QT syndrome or unexplained sudden death under 40
                  years of age in first degree relatives or any concomitant medication known to
                  prolong the QT interval

          6. Past medical history of interstitial lung disease, drug-induced interstitial lung
             disease, radiation pneumonitis which required steroid treatment, or any evidence of
             clinically active interstitial lung disease 7, Inadequate bone marrow reserve or
             organs function as demonstrated by any of the following laboratory values:

               -  Absolute neutrophil count <1.5x109/L

               -  Platelet count <100x109/L

               -  Hemoglobin <90 g/L

               -  Alanine aminotransferase >2.5 times the upper limit of normal (ULN) if no
                  demonstrable liver metastases or >5 times ULN in the presence of liver metastases

               -  Aspartate aminotransferase >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

        8, 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
        Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the
        formulated product or previous significant bowel resection that would preclude adequate
        absorption of AZD9291 9, History of hypersensitivity to active or inactive excipients of
        AZD9291 or drugs with a similar chemical structure or class to AZD9291 10, Women who are
        breast feeding 11, Involvement in the planning and conduct of the study (applies to
        AstraZeneca staff or staff at the study site) 12, Judgement by the investigator that the
        patient should not participate in the study if the patient is unlikely to comply with study
        procedures, restrictions and requirements