Clinical Trials /

A Phase I/Ib Study of MEK162, a MEK Inhibitor, in Combination With Carboplatin and Pemetrexed in Patients With Non-squamous Carcinoma of the Lung

NCT02185690

Description:

MEK162 has shown significant inhibition of tumor growth as a single agent in NSCLC xenograft models in mice and human cancer cells in vitro, which have KRAS and/or other mutations. These data suggest that MEK162 may provide a potential benefit in cancer indications harboring these mutations. MEK162 is currently being investigated in phase I clinical testing and has been well tolerated up to an MTD of 45mg BID in cancer patients. There has been little change in survival benefit for patients with non-small cell lung cancer in recent years. Emerging new treatment options relying on molecular and genetic markers are being studied extensively. Thus, there has been a shift to manage non-small cell lung cancer with molecular targeted therapies in combination with standard chemotherapy. This study will be targeting patients with KRAS mutations.

Related Conditions:
  • Lung Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Phase I/Ib Study of MEK162, a MEK Inhibitor, in Combination With Carboplatin and Pemetrexed in Patients With Non-squamous Carcinoma of the Lung
  • Official Title: A Phase I/Ib Study of MEK162, a MEK Inhibitor, in Combination With Carboplatin and Pemetrexed in Patients With Non-squamous Carcinoma of the Lung

Clinical Trial IDs

  • ORG STUDY ID: CMEK162BCA01T
  • SECONDARY ID: CMEK162BCA01T
  • NCT ID: NCT02185690

Conditions

  • Lungcancer

Interventions

DrugSynonymsArms
BinimetinibMEK162Binimetinib efficacy/safety
PemetrexedAlimtaBinimetinib efficacy/safety
CarboplatinParaplatin AGBinimetinib efficacy/safety

Purpose

MEK162 has shown significant inhibition of tumor growth as a single agent in NSCLC xenograft models in mice and human cancer cells in vitro, which have KRAS and/or other mutations. These data suggest that MEK162 may provide a potential benefit in cancer indications harboring these mutations. MEK162 is currently being investigated in phase I clinical testing and has been well tolerated up to an MTD of 45mg BID in cancer patients. There has been little change in survival benefit for patients with non-small cell lung cancer in recent years. Emerging new treatment options relying on molecular and genetic markers are being studied extensively. Thus, there has been a shift to manage non-small cell lung cancer with molecular targeted therapies in combination with standard chemotherapy. This study will be targeting patients with KRAS mutations.

Detailed Description

      OBJECTIVES

      1.1 Primary Objectives

        -  To assess the safety of MEK162 administered in combination with carboplatin and
           pemetrexed as first line treatment in advanced non-small cell lung cancer (NSCLC).

        -  To determine the recommended phase II dose (RP2D) of MEK162 to be used when given in a
           continuous dosing schedule together with pemetrexed and carboplatin administered on a
           3-weekly schedule as first line treatment in advanced NSCLC.

        -  To explore the efficacy (as measured by tumor response in the Phase Ib portion) of the
           combination of MEK162 in addition to pemetrexed and carboplatin in treatment-naïve
           patients with EGFR wild-type, ALK-rearrangement negative NSCLC of the lung.

      1.2 Secondary Objectives

        -  To characterize the population pharmacokinetics of MEK162 administered in combination
           with carboplatin and pemetrexed (Phase I).

        -  To explore relationships between KRAS mutation (and sub-types) and additional genomic
           mutations and objective clinical response.

      1.3 Trial End-points Primary Phase I • Development of dose-limiting toxicity (DLT), (defined
      in section 4.3) as measured with NCI CTC AE v4.

      Phase Ib

      • Objective response rate (ORR) as per RECIST v1.1.

      Secondary Phase I • Adverse events, serious adverse events, changes in hematology and
      chemistry values, vital signs, ECGs.

      Phase Ib

        -  Evaluation of response rate (RR), progression-free survival (PFS) and disease control
           rate (DCR) for patients with and without KRAS mutation in tumor tissue.

        -  Exploratory analysis of KRAS mutation sub-type.

      Exploratory end-points

      • A limited sampling strategy pharmacokinetic model will be used to ensure that the clearance
      of MEK162 is not influenced by the concurrent administration of pemetrexed-based
      chemotherapy.
    

Trial Arms

NameTypeDescriptionInterventions
Binimetinib efficacy/safetyOtherThis is a Phase I/Ib, open-label, dose-escalation, multi-center, non-randomized study designed to evaluate the safety and tolerability of oral Binimetinib in combination with carboplatin and pemetrexed. Phase I part A standard 3+3 dose-escalation will be used to determine the maximum administered dose (MAD) and the RP2D for the combination in subjects with advanced non-squamous lung carcinoma. Phase Ib part Once RP2D has been identified, an expansion cohort will be accrued; these patients will be stratified by KRAS genotype. The RP2D will be expanded by enrolling additional patients, stratified by KRAS genotype, to a total of 30 patients eligible for the safety set (including those treated at the same dose combination in the dose-escalation phase of the study who are eligible for the safety set) to be evaluated for safety, tolerability, pharmacokinetics and biologic activity of MEK162.
  • Binimetinib
  • Pemetrexed
  • Carboplatin

Eligibility Criteria

        Inclusion Criteria:

          -  Subjects eligible for enrolment on the study must meet all of the following criteria:

          -  Patients with histologically confirmed non-squamous EGFR wild-type, ALK-rearrangement
             negative carcinoma of lung. Patients with neuroendocrine carcinoma, mixed small and
             non-small cell carcinoma or squamous carcinoma are not eligible.

          -  Tissue available for KRAS mutation status analysis.

          -  Patients must have metastatic disease (Incurable stage IIIB/stage IV).

          -  Patients must have clinically and/or radiographically documented measurable disease.
             At least one site of disease must be unidimensionally measurable by RECIST v1.1 as
             follows (Eisenhauer et al.):

        CT-scan, physical exam ≥10 mm Chest X-ray ≥20 mm Lymph node short axis ≥15 mm

          -  All radiology studies must be performed within 28 days prior to registration (35 days
             if negative).

          -  Lesions in previously irradiated areas should not be selected unless there is clear
             evidence of progression in such lesions.

          -  Patients may not have received any prior systemic treatment for metastatic NSCLC.
             Patients who have received adjuvant treatment or chemoradiation for stage III disease
             should have completed this ≥12 months prior to study enrollment.

          -  Patients with stable CNS metastases are permitted if stability of disease is
             documented with imaging ≥28 days after treatment completion, are and off
             corticosteroids by day 1 of study treatment.

          -  Patients may have had prior malignancy if definitively treated and/or, in the opinion
             of the investigator, the only active malignancy is NSCLC. Patients with mixed small
             cell lung cancer histology are excluded. Patients who have received radiotherapy to
             >30% bone marrow are excluded. Consult PI if unsure whether second malignancies meet
             requirements specified above.

          -  In patients treated for other malignancy, all prior treatment-related toxicities must
             be CTCAE v4.0 ≤ Grade 1 (except alopecia) at the time of enrollment.

          -  Able to swallow and retain oral medication and does not have any clinically
             significant gastrointestinal abnormalities that may alter absorption such as
             malabsorption syndrome or major resection of the stomach or bowels.

          -  Patients receiving medications or substances that are inhibitors or inducers of
             CYP1A2, CYP2A19, CYP2B6, CYP3A4 and/or UGT1A1 and UGT1A9 are eligible but these drugs
             must be used with caution (Appendix C).

        Because the lists of these agents are constantly changing, it is important to regularly
        consult a frequently-updated list such as
        http://medicine.iupui.edu/clinpharm/ddis/table.aspx;

          -  Patients must be aged ≥18 years.

          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤1

          -  Adequate organ and laboratory parameters, defined below.

          -  Laboratory Requirements - within 7 days prior to enrollment:

        Haematology: absolute granulocytes ≥1.5 × 109/L platelets ≥100 × 109/L Biochemistry:
        bilirubin ≤1.25 × institutional upper limit of normal AST(SGOT) ≤2.5 × institutional upper
        limit of normal /ALT(SGPT) or ≤5 × institutional upper limit of normal in the presence of
        liver metastases

        creatinine clearance ≥45 mL/min/1.73 m2

        -Patients must be able to provide Informed Consent based on the details below:

          -  absence of any psychological, familial, sociological or geographical condition
             potentially hampering compliance with the study protocol and follow-up schedule; those
             conditions should be discussed with the patient before registration in the trial

          -  before patient registration/randomization, written informed consent must be given
             according to ICH/GCP, and national/local regulations.

        Exclusion Criteria:

          -  History or current evidence/risk of retinal vein occlusion (RVO) or central serous
             retinopathy (CSR):

               -  History of RVO or CSR, or predisposing factors to RVO or CSR (e.g., uncontrolled
                  glaucoma or ocular hypertension, uncontrolled systemic disease such as
                  hypertension, diabetes mellitus, or history of hyperviscosity or
                  hypercoagulability syndromes). Patients with prior deep venous thrombosis or
                  pulmonary embolism are permitted.

               -  Visible retinal pathology as assessed by ophthalmologic exam that is considered a
                  risk factor for RVO or CSR such as:

          -  Evidence of new optic disc cupping

          -  Evidence of new visual field defects on automated perimetry

          -  Intraocular pressure >21mmHg as measured by tonography

          -  Any serious and/or unstable pre-existing medical (aside from malignancy exception),
             psychiatric disorder, or other conditions that could interfere with subjects' safety,
             obtaining informed consent or compliance to the study procedures, in the opinion of
             the PI.

          -  History of interstitial lung disease or pneumonitis.

          -  Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated
             respiratory, hepatic, renal metabolic or cardiac disease).

          -  Any factors that increase the risk of QTc prolongation or risk of arrhythmic events
             (e.g. congenital long QT syndrome, family history of long QT syndrome, hypokalemia) or
             baseline QTcB interval ≥480 msec.

          -  History of acute coronary syndromes (including myocardial infarction and unstable
             angina), coronary angioplasty, or stenting within the past 6 months or cardiac
             metastases.

          -  History or evidence of current clinically significant uncontrolled arrhythmias.

          -  History or evidence of current ≥Class II congestive heart failure as defined by New
             York Heart Association (NYHA).

          -  Known positivity for Hepatitis B surface antigen or Hepatitis C antibody.

          -  Known Human Immunodeficiency Virus (HIV) infection.

          -  Treatment refractory hypertension defined as a blood pressure systolic >140 mmHg
             and/or diastolic >90 mmHg which cannot be controlled by anti-hypertensive therapy.

          -  Subjects with intra-cardiac defibrillators or permanent pacemakers.

          -  Pregnant or nursing (lactating) women are excluded.

          -  Female patient of child bearing potential must have a negative serum or urine
             pregnancy test.

          -  Women of child-bearing potential must agree to use of appropriate contraceptive
             methods throughout the study and for 120 days after, These methods include

          -  Total abstinence or 2 barrier methods or a barrier method plus hormonal method from
             visit 1 to 120 days after the last dose of treatment.

          -  Men must agree to use an appropriate method of contraception starting with first dose
             of study drug through 120 days after the last dose of treatment (see above).

          -  Whilst not excluded, patients with significant impaired hearing must be made aware of
             potential ototoxicity and may choose not to be included. If included, baseline
             audiograms are recommended and should be followed by repeat audiograms prior to cycle
             2.
      
Maximum Eligible Age:90 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Development of dose-limiting toxicity (DLT) in milligrams per day.
Time Frame:18 weeks of treatment
Safety Issue:
Description:To determine the recommended dose in milligrams per day of the combination of MEK162 with standard therapy pemetrexed and carboplatin as determined by toxicity.

Secondary Outcome Measures

Measure:Objective response rate (ORR) as per RECIST v1.1.
Time Frame:18 weeks of treatment & 30 days followup
Safety Issue:
Description:The size of tumours in centimetres before and after treatment. The measurements will be compared against the RECIST v1.1 criteria to ascertain response as defined in the protocol.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University Health Network, Toronto

Trial Keywords

  • Lung cancer
  • Non small cell lung cancer
  • non squamous
  • pemetrexed
  • carboplatin
  • binimetinib
  • chemotherapy
  • combination chemotherapy
  • Phase 1
  • Princess Margaret Cancer Centre
  • carcinoma

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