A Study of Pemetrexed and Gefitinib Versus Gefitinib in Non-Small Cell Lung Cancer (NSCLC)

Study Overview
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Brief Summary
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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.

Official Title
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A Randomised Phase 2 Trial of Pemetrexed and Gefitinib Versus Gefitinib as First Line Treatment for Patients With Stage IV Non-Squamous Non-Small Cell Lung Cancer With Activating Epidermal Growth Factor Receptor Mutations

Conditions
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Carcinoma, Non Small Cell Lung

Intervention / Treatment
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* Drug: Gefitinib
* Drug: Pemetrexed


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 250 mg Gefitinib/500 mg Pemetrexed<br>250 milligrams (mg) Gefitinib taken orally once daily (QD) and 500 milligrams per square meter (mg/m²) Pemetrexed taken intravenously (IV) once every 3 weeks concurrently with Gefitinib taken orally QD. | Drug: Gefitinib<br>* 250 mg orally once per day. Number of cycles until disease progression or unacceptable toxicity develops.<br>* Other names: Iressa;Drug: Pemetrexed<br>* 500 mg/m² IV on day 1 of each 21 day cycle. Number of cycles until disease progression or unacceptable toxicity develops.<br>* Other names: Alimta;|
| Active Comparator: 250 mg Gefitinib<br>250 milligrams (mg) Gefitinib taken orally QD | Drug: Gefitinib<br>* 250 mg orally once per day. Number of cycles until disease progression or unacceptable toxicity develops.<br>* Other names: Iressa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS is defined as the time from randomization to the first date of objectively determined progressive disease or death from any cause,whichever is earlier.The censoring is taken in the following order: If a participant didn't have a complete baseline disease assessment,then the PFS time was censored at the enrollment date, regardless of whether or not objectively determined disease progression or death has been observed for the participant;otherwise,if a participant is not known to have died or have objective progression as of the data inclusion cutoff date for the analysis,the PFS time will be censored at the last complete objective progression-free disease assessment date.Progressive disease (PD) was defined as at least a 20% increase in the sum of the diameters of target lesions,taking as reference the smallest sum on study. Also,the sum must also demonstrate an absolute increase of at least 5 millimeter (mm).The appearance of one or more new lesions is also considered progression. | Randomization to Progressive Disease or Death Due to Any Cause (Up to 58.78 Months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time To Progressive Disease (TTPD) | TTPD is defined as time from the date of randomization to the first date of disease progression. For each participant who is not known to have had a progression of disease as of the data-inclusion cut-off date for a particular analysis, or who has died without progression of disease, TTPD will be censored for that analysis at the date of the participant's last tumor assessment prior to that cut-off date. TTPD was analyzed twice: (1) excluding clinical progressions of disease (that is,those not defined according to the RECIST version 1.1 criteria ), and (2) including clinical progressions. Progressive disease (PD) was defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. Also, the sum must also demonstrate an absolute increase of at least 5 millimeter (mm). The appearance of one or more new lesions is also considered progression. | Randomization to Progressive Disease (Up To 58.78 Months) | 
| Overall Survival (OS) | OS is defined as the time from randomization to the date of death from any cause. Survival time is censored at the date of last contact for participants who are still alive or lost to follow up. | Randomization to Date of Death Due to Any Cause (Up To 67.12 Months) | 
| Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate [ORR]) | ORR is the best response of complete response (CR) or partial response (PR) as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1). Complete Response (CR) is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Tumor marker results must have normalized. Partial Response (PR) is defined at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. | Randomization to Progressive Disease (Up to 57.36 Months) | 
| Percentage of Participants With CR, PR, and Stable Disease (SD) (Disease Control Rate [DCR]) | Disease control rate is the percentage of participants with a confirmed CR, PR or SD as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST version 1.1) criteria. CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Tumor marker results must have normalized. PR is defined at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. | Randomization to Progressive Disease (Up To 57.36 Months) | 
| Duration of Response (DoR) | DoR was defined as the time from the date of the first CR or PR to the first date of Progressive Disease (PD) ( RECIST 1.1 Criteria) or death from any cause.CR is the disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm.Tumor marker results must have normalized. PR is defined as at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. PD was defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. Also,the sum must also demonstrate an absolute increase of at least 5 mm.The appearance of one or more new lesions is also considered progression. Participants not known to have died or to have had progression of disease as of the data-inclusion cut-off date for a particular analysis,duration of tumor response was censored at the date of the participants last tumor assessment prior to that cut-off date. | First Observation of CR or PR to Progressive Disease or Death Due to Any Cause (Up To 57.36 Months) | 
| Time to Worsening of Symptom (TWS) as Per Lung Cancer Symptom Scale (LCSS) | TWS was the elapsed time from the date of randomization to the first date of worsening in any one of the 6 LCSS symptoms. The LCSS (patient and observer) were administered at baseline and at the end of each 21-day cycle, until disease progression, and at short-term follow-up. Content for the patient version -collected using a visual analog scale (VAS) anchored at 0 and 100, respectively representing the best and worst outcome- included 6 disease-specific measures: (appetite, fatigue, cough, dyspnea, hemoptysis and pain) and 3 summary consequences of lung cancer (overall symptom burden, diminished normal activities, and lowered quality-of-life).The observer version included only the 6 disease-specific measures and the responses were collected using a 5-point ordinal scale that was reverse coded with 0 and 100 respectively representing the worst and best outcome.TWS was censored at the date of the last LCSS assessment for participants who were not known to have LCSS worsening. | Baseline to Progressive Disease (Up To 50 Months ) |