Selumetinib in Patients Receiving Pemetrexed and Platinum-based Chemotherapy in Advanced or Metastatic KRAS Wildtype or Unknown Non-Squamous NSCLC
Condition: Non-Small Cell Lung Cancer
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: Selumetinib; Pemetrexed; Cisplatin; Carboplatin
Intervention MeSH terms: Carboplatin; Pemetrexed
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 62.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to find out what effects a new drug, selumetinib, has on lung
      cancer when receiving standard chemotherapy with pemetrexed and platinum-based chemotherapy.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must have histologically and/or cytologically confirmed non-squamous, KRAS
             wildtype or unknown, non-small cell lung cancer that is stage IIIB or IV, metastatic
             or unresectable and for which standard curative measures do not exist.

          -  All patients must have a formalin fixed paraffin embedded tumour block (from primary
             or metastatic tumour) available for correlative studies and must have provided
             informed consent for the release of the block for correlative studies.

          -  Patients must have at least one site of disease which is unidimensionally measurable
             as follows:

          -  Measurable disease defined as at least one target lesion that has not been irradiated
             or has progressed after radiation and can be accurately measured in at least one
             dimension by RECIST 1.1 criteria.

          -  Chest X-ray ≥ 20 mm

          -  CT/MRI scan (with slice thickness of < 5 mm) ≥ 10 mm --> longest diameter

          -  Physical exam (using calipers) ≥ 10 mm

          -  Lymph nodes by CT scan ≥ 15 mm --> measured in short axis

          -  Presence of clinically and/or radiologically documented disease (marker positive only
             patients are not eligible). All radiology studies must be performed within 28 days
             prior to randomization (within 35 days if negative).

          -  Age ≥ 18 years.

          -  ECOG performance status 0 or 1

          -  Previous Therapy Surgery: Previous major surgery is permitted provided it has been at
             least 14 days prior to patient randomization and that wound healing has occurred.

        Radiation: Prior external beam radiation is permitted provided a minimum of 4 weeks has
        elapsed between the last dose and enrollment to the trial.

        Chemotherapy and systemic therapy: Prior therapy with ALK inhibitors is permissible.
        Patients may not have received prior MEK inhibitors or any other tyrosine kinase inhibitor
        (including EGFR inhibitors of any kind). Patients may have received vaccines, immunotherapy
        or other agents that are not MEK/tyrosine kinase inhibitors in the adjuvant setting or for
        advanced or metastatic disease.

        Prior adjuvant platinum-based chemotherapy or combined chemoradiotherapy with curative
        intent is permissible provided completed at least one year prior to enrollment. No prior
        cytotoxic chemotherapy for advanced / metastatic disease is permissible.

        - Laboratory Requirements (must be done within 7 days prior to randomization)

        Neutrophils ≥ 1.5 x 10^9/L Platelets ≥ 100 x 10^9/L

        Biochemistry:

        Creatinine Clearance* ≥ 50 ml/min Total bilirubin ≤ 1.5 x ULN AST and ALT ≤ 2.5 x ULN (if
        liver metastases ≤ 5x UNL permissible providing ALP also ≤ 6 x UNL)

        * Creatinine clearance to be measured directly by 24 hour urine sampling or as calculated
        by appropriate formula below: Females: GFR = 1.04 x (140-age) x weight in kg/serum
        creatinine in μmol/L Males: GFR = 1.23 x (140-age) x weight in kg/serum creatinine in
        μmol/L

          -  Patient consent must be appropriately obtained in accordance with applicable local and
             regulatory requirements. Each patient must sign a consent form prior to enrollment in
             the trial to document their willingness to participate

          -  Patients must be accessible for treatment and follow-up. Patients randomized on this
             trial must be treated and followed at the participating centre

          -  In accordance with CCTG policy, protocol treatment is to begin within 2 working days
             of patient randomization

        Exclusion Criteria:

          -  Patients with a history of other untreated malignancies or malignancies which required
             therapy within the past 2 years

          -  No symptomatic brain metastases or spinal cord compression. Patients with asymptomatic
             brain/spinal cord metastasis who are not planned for radiation, or who have been
             treated and are stable off steroids (or on a decreasing dose) and anticonvulsants are
             eligible.

          -  Patients with significant cardiac disease, including:

          -  any factors that increase the risk of QTc prolongation or risk of arrhythmic events
             (e.g. heart failure, hypokalaemia, congenital long QT syndrome, family history of long
             QT syndrome or unexplained sudden death under 40 years of age) or mean resting
             corrected QT interval (QTc) > 470 msec

          -  uncontrolled hypertension (BP ≥ 150/95 mmHg despite medical therapy)

          -  acute coronary syndrome within 6 months prior to starting treatment

          -  angina Canadian Cardiovascular Society Grade II-IV (despite medical therapy)

          -  symptomatic heart failure (NYHA II-IV)

          -  prior or current cardiomyopathy

          -  atrial fibrillation with a ventricular rate > 100 bpm at rest

          -  severe valvular heart disease Patients with cardiac disease, who do not meet the
             exclusion criteria above, must have a baseline LVEF ≥ 50%.

          -  Any evidence of severe or uncontrolled systemic disease, active infection, active
             bleeding diatheses or renal transplant, including any patient known to have hepatitis
             B, hepatitis C or human immunodeficiency virus (HIV).

          -  Patients who have neuropathy > grade 1 or other conditions precluding treatment with
             the standard chemotherapy regimen planned. Consult CCTG for patients with localised
             neuropathies as such patients may be eligible.

          -  Patients who have significant gastrointestinal disease and who are unable to swallow
             capsules.

          -  Patients on potent inhibitors or inducers of CYP3A4/5, CYP2C19 and CYP1A2 (must have
             discontinued within 2 weeks prior to randomization or 3 weeks for St. John's Wort).
             Patients who do not agree to avoid the ingestion of large amounts of grapefruit and
             Seville oranges (and other products containing these fruits, e.g. grapefruit juice or
             marmalade) and not take vitamin E supplements or multivitamin supplements.

        Patients who require oral anticoagulants (Coumadin) are eligible provided there is
        increased vigilance with respect to INR monitoring upon initiation of dosing with
        selumetinib. If medically appropriate and treatment available, the investigator should
        consider switching these patients to LMW heparin.

          -  Patients with current or past history of central serous retinopathy or retinal vein
             occlusion, high intraocular pressure (≥ 21mm) or uncontrolled glaucoma (irrespective
             of IOP). Patients with visual symptoms should undergo ophthalmologic examination prior
             to randomization.

          -  Pregnant or lactating women. Women of childbearing potential must have a urine
             pregnancy test proven negative within 7 days prior to randomization. Men and women of
             childbearing potential must agree to use adequate contraception

          -  Patients who do not agree to avoid excessive sun exposure and use adequate sunscreen
             protection.

          -  Selumetinib-specific precautions for patients of Asian ethnicity:

        Plasma exposure of selumetinib (Cmax and AUC) is higher, at a population level, in subjects
        of Asian descent by approximately 1.5- to 2-fold in non-Japanese Asians and Japanese
        subjects, compared with Western subjects. However, there is overlap in the range of
        exposure experienced by Asian and Western subjects and the higher average plasma exposure
        was not associated with a change in the tolerability profile of single dose selumetinib.

        Investigators should make a clinical judgment as to whether the potential risk of
        experiencing higher selumetinib plasma exposure and potential adverse events outweighs the
        potential benefit of treatment with selumetinib.