Study to Assess the Effect of Rifampicin on Blood Levels and Safety of AZD9291, in Patients With EGFRm+ NSCLC
Condition: Non Small Cell Lung Cancer
MeSH terms: Carcinoma, Non-Small-Cell Lung
Intervention: Pharmacokinetic sampling - AZD9291; Rifampicin; AZD9291 tablet dosing; Pharmacokinetic sampling - rifampicin; Pharmacokinetic sampling - AZ5140 and AZ7550
Intervention description: Blood sampling to measure AZD9291; Rifampicin (CYP inducer) 600mg taken once daily from Day 29 to Day 49 (Part A); Part A: AZD9291 80mg tablet taken daily from Days 1 to 77. Part B: AZD9291 80mg tablet taken daily for 12 months.; Blood sampling to measure rifampicin levels; Blood samples to measure levels of AZ5140 and AZ7550
Intervention MeSH terms: Rifampin; Osimertinib
Phase: Phase 1
Study type: Interventional
Primary purpose: Other
Masking: None (Open Label)
Enrollment: 41.0
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, rifampicin, CYP P450 inducer, 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 rifampicin on the pharmacokinetic (PK) parameters of AZD9291
      and metabolites AZ5104 and AZ7550 following multiple oral dosing of both rifampicin and
      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 who complete Part A will be able
      to enter part B, and 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, erlotinib or afatinib. 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.

        9. Contact lens wearers must be prepared to not wear contact lenses and wear glasses for
        the duration of the rifampicin dosing.

          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 (eg, erlotinib or
             gefitinib) w/in 8 days or approx. 5 x half-life, whichever is the longer, of the first
             dose of study treatment; any cytotoxic chemo, investigational agents or other
             anticancer drugs from a previous treatment regimen w/in 14 days of the first dose of
             study treatment; major surgery (excluding placement of vascular access) w/in 4 weeks
             of the first dose of study treatment; radiotherapy with a limited field of radiation
             for palliation w/in 1 week of the first dose of study treatment, with the exception of
             patients receiving radiation to more than 30% of bone marrow or with a wide field of
             radiation which must be completed w/in 4 weeks of the first; patients currently
             receiving (or unable to stop use prior to receiving the first dose) 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 78 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 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 times the ULN if no demonstrable liver metastases or >5
             times ULN in the presence of liver metastases; 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
             electrocardiograms (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 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 rifampicin or any of the
             excipients of the products.

         13. Concomitant medication contraindicated for use with rifampicin (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 metabolised by CYP3A4, such as lovastatin and
             simvastatin, ergot alkaloids metabolised by CYP3A4, such as dihydroergotamine,
             ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine).

         14. 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.