A Study of Pemetrexed and Gefitinib Versus Gefitinib in Non-Small Cell Lung Cancer (NSCLC)
Condition: Carcinoma, Non Small Cell Lung
MeSH terms: Carcinoma, Non-Small-Cell Lung
Intervention: Gefitinib; Pemetrexed
Intervention description: 250 mg orally once per day. Number of cycles until disease progression or unacceptable toxicity develops.; 500 mg/m² IV on day 1 of each 21 day cycle. Number of cycles until disease progression or unacceptable toxicity develops.
Intervention MeSH terms: Pemetrexed; Gefitinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 195.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to compare the combination of pemetrexed and gefitinib versus
      gefitinib alone, in terms of progression-free survival. This study is in participants who
      have stage IV non squamous NSCLC with activating epidermal growth factor mutations and who
      have not had any previous chemotherapy for stage IV disease.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically or cytologically confirmed advanced (Stage IV) or recurrent
             non-squamous NSCLC

          -  Eligible participants of reproductive potential must agree to use adequate
             contraceptive methods during the study period and for at least 6 months after the last
             dose of study therapy

          -  Negative pregnancy test for women of childbearing potential

          -  Males or females, aged 18 years or above

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1

          -  The participant's primary NSCLC tumor has an activating Epidermal Growth Factor
             Receptor (EGFR) mutation, as determined by any validated method

          -  The participant consents to provide a tissue sample for prestudy EGFR mutation testing
             and the tumor tissue sample is available for detection of EGFR expression and other
             markers for centralized testing by Lilly

          -  The participant has measurable disease at the time of study entry, documented by
             computed tomography (CT) scan or magnetic resonance imaging (MRI), as defined by the
             Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

          -  The participant has not had any prior systemic chemotherapy, immunotherapy, or
             biological therapy (for example, targeted therapy, such as erlotinib or gefitinib) for
             Stage IV or recurrent non-squamous NSCLC

          -  The participant has adequate organ function, defined as:

               -  White blood cell count ≥3 x 10^9/liter (L); absolute neutrophil count (segmented
                  and bands) ≥1.5 x 10^9/L; platelet count ≥100 x 10^9/L; hemoglobin ≥9.0 gram per
                  deciliter (g/dL)

               -  Total bilirubin ≤1.5 times the upper limit of the normal (ULN) range; and
                  alkaline phosphatase (AP), aspartate transaminase (AST) and alanine transaminase
                  (ALT) ≤2.5 times ULN (or ≤5 times ULN if the liver has tumor involvement)

               -  Calculated creatinine clearance ≥45 milliliter per minute (mL/min)

          -  The participant is able to take folic acid, vitamin B12, and dexamethasone, according
             to the protocol's requirements

          -  Life expectancy of at least 3 months

          -  Provision of informed consent

          -  Prior radiation therapy is allowed to <25% of the bone marrow; however, prior
             radiation to the whole pelvis not allowed. Prior radiation therapy must be completed
             at least 2 weeks prior to first study-drug administration. Participants must have
             recovered from the acute toxic effects prior to first study-drug administration.

        Exclusion Criteria:

          -  The participant has received prior chemotherapy for advanced and/or metastatic
             disease, or adjuvant/neoadjuvant treatment with pemetrexed or an EGFR-tyrosine Kinase
             inhibitor (TKI)

          -  The participant's tumor contains predominantly small cell lung cancer or squamous
             NSCLC

          -  The participant is receiving concurrent treatment with any other anticancer therapy,
             including other chemotherapy, immunotherapy, hormonal therapy, chemoembolization,
             biological or targeted therapy, or radiotherapy (palliative irradiation of bone
             lesions is allowed)

          -  The participant has untreated central nervous system (CNS) metastases Participants
             with treated brain metastases are eligible if they are clinically stable with regard
             to neurologic function, off steroids after cranial irradiation (whole brain radiation
             therapy, focal radiation therapy, stereotactic radiosurgery) ending at least 2 weeks
             before enrollment, or after surgical resection performed at least 28 days before
             enrollment. No evidence of Grade ≥1 CNS hemorrhage based on pretreatment MRI or
             Intravenous (IV) contrast CT scan (performed within 21 days before randomization).

          -  The participant has undergone radiotherapy within 28 days before enrollment (localized
             radiotherapy for pain relief allowed, provided 25% or less of their total bone marrow
             had been irradiated)

          -  The participant has clinically relevant congestive heart failure (New York Heart
             Association [NYHA] II-IV) or symptomatic or poorly controlled cardiac arrhythmia

          -  The participant has a serious illness or medical condition that would compromise their
             safety or impair their ability to comply with the protocol's requirements, including,
             but not limited to, the following:

               -  Known human immunodeficiency virus (HIV) infection or acquired immunodeficiency
                  syndrome (AIDS)-related illness

               -  Active or uncontrolled clinically serious infection

               -  Previous or concurrent malignancy except for basal or squamous cell skin cancer
                  and/or in situ carcinoma of the cervix, or other solid tumors treated curatively
                  and without evidence of recurrence for at least 5 years prior to the study

               -  Uncontrolled metabolic disorders or other nonmalignant organ or systemic diseases
                  or secondary effects of cancer that induce a high medical risk and/or make
                  assessment of survival uncertain

               -  Other severe acute or chronic medical or psychiatric condition or laboratory
                  abnormality that may increase the risk associated with study participation or
                  study drug administration, or may interfere with the interpretation of study
                  results, and in the judgment of the Investigator would make the participant
                  ineligible for entry into this study

               -  The participant has significant third space fluid retention, and is not amenable
                  for required repeated drainage

               -  Known allergy or hypersensitivity reaction to any of the treatment components

          -  Are unable to interrupt aspirin or other non-steroidal anti-inflammatory drugs
             (NSAIDs), other than an aspirin dose ≤1.3 grams per day, for at least 2 days (5 days
             for long-acting agents [for example, piroxicam]) before, during, and for at least 2
             days after administration of pemetrexed

          -  Concomitant use of cytochrome P450 (CYP)3A4 inducers or CYP3A4 inhibitors

          -  Participants under therapy with warfarin or coumarin derivatives who are unable to
             switch to low molecular weight heparin, unless regular monitoring of changes in
             prothrombin time (PT) (PT/international normalized ratio [INR]) will be applicable

          -  Any known significant ophthalmologic abnormalities of the surface of the eye. The use
             of contact lenses is not recommended during the study

          -  Are currently enrolled in, or discontinued within the last 30 days from, a clinical
             trial involving an investigational product or non-approved use of a drug or device, or
             concurrently enrolled in any other type of medical research judged not to be
             scientifically or medically compatible with this study Participants participating in
             surveys or observational studies are eligible to participate in this study

          -  The participant has previously received treatment with gefitinib, erlotinib or
             pemetrexed

          -  Any evidence of clinically active interstitial lung disease. Asymptomatic participants
             with chronic, stable, radiographic changes are eligible.

          -  Have preexisting idiopathic pulmonary fibrosis as evidenced by computed tomography
             (CT) scan/x-ray at baseline; have or had any disease of acute lung injury, idiopathic
             pulmonary fibrosis, pulmonary pneumonia, or pneumoconiosis evident on an x-ray; have
             or had any disease of radiation pneumonia or drug-induced pneumonia, which requires
             treatment with corticosteroids.

          -  The participant is pregnant or breastfeeding