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
Condition: Lungcancer
MeSH terms: Carcinoma; Lung Neoplasms
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Intervention name(s): Binimetinib; Pemetrexed; Carboplatin
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Continuous MEK162 with dose escalation until the Recommended Phase 2 dose (RP2D) one dose level below the Maximum administered dose (MAD) or progression of disease.
MEK162 tablets 15 mg strength will be taken orally on a BID dose schedule.; 4-6 cycles given intravenously in combination with carboplatin as per standard therapy.; 4-6 cycles of intravenous Carboplatin in combination with Pemetrexed as per standard therapy.
Other intervention name(s): MEK162; Alimta; Paraplatin AG
Intervention MeSH terms: Carboplatin; Pemetrexed
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Lung cancer; Non small cell lung cancer; non squamous; pemetrexed; carboplatin; binimetinib; chemotherapy; combination chemotherapy; Phase 1; Princess Margaret Cancer Centre; carcinoma