A Study of Induction and Maintenance Treatment of Advanced Non-squamous Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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This study will compare progression-free survival in patients with advanced non-squamous non-small cell lung cancer. Patients who do not progress following 4 cycles of induction treatment with pemetrexed and cisplatin will be randomized 2:1 to receive either maintenance pemetrexed or placebo.

Official Title
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A Phase 3, Double-Blind, Placebo-Controlled Study of Maintenance Pemetrexed Plus Best Supportive Care Versus Best Supportive Care Immediately Following Induction Treatment With Pemetrexed + Cisplatin for Advanced Non-squamous Non-Small Cell Lung Cancer.

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Pemetrexed
* Drug: Cisplatin
* Drug: Placebo
* Drug: Pemetrexed
* Other: Best Supportive Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for the Induction Phase: You must sign an informed consent document for clinical research. You must have Stage IIIB or IV nonsquamous Non-Small Cell Lung Cancer. You must at least be able to be physically mobile, take care of yourself, and must be up and about and able to perform light activities such as light housework or office work. You are allowed to have had prior radiation therapy as long as it was not to more than 25% of the bone marrow and did not include the whole pelvis. Thoracic radiation must be completed more than 30 days before the study. You must be recovered from the toxic effects (except hair loss). You must have at least 1 measurable tumor lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines or disease that can be evaluated by computed tomography (CT) Scan. Your test results assessing the function of your blood forming tissue, kidneys, and liver must be satisfactory. You must be 18 years of age or older. Women must be sterile, postmenopausal or on contraception and men must be on contraception or sterile (e.g. post-vasectomy). Exclusion Criteria for the Induction Phase: You cannot have squamous cell and/or mixed small cell, non-small cell lung cancer You cannot have received other investigational drugs within the last 30 days of entering the trial. You cannot have previously completed or withdrawn from this study or any other study investigating pemetrexed. You cannot have other serious on-going illnesses including active infections. You cannot have a serious cardiac condition, such as a heart attack, angina, or heart disease within 6 months of entering the trial. You cannot have had another form of cancer other than superficial basal cell and superficial squamous (skin) cell cancer, or carcinoma in situ of the cervix within the last 5 years. Patients with a history of low-grade (Gleason score less than or equal to 6) localized prostate cancer will be eligible even if diagnosed less than 5 years ago. You cannot have known central nervous system (CNS) metastases, other than treated, stable brain metastasis. You cannot be receiving nor have received any prior systemic anticancer therapy for lung cancer (including chemotherapy given after surgery in early-stage treatment). You cannot have clinically significant third-space fluid collections (e.g. ascites or pleural effusions that cannot be controlled by drainage or other procedures). You cannot have received a recent (within 30 days) or are receiving a yellow fever vaccination. You are unable to stop taking more than 1.3 grams of aspirin on a daily basis or other non-steroidal anti-inflammatory drugs (NSAIDs). You are unable or unwilling to take folic acid, injections of vitamin B12, or corticosteroids. You cannot be pregnant or breastfeeding. Inclusion criteria at Randomization for the Maintenance Phase: You must at least be able to be physically mobile, take care of yourself, and must be up and about and able to perform light activities such as light housework or office work. You must have documented radiographic evidence of a tumor response of complete response (CR), partial response (PR), or stable disease (SD) according to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. Tumor assessment must occur between Cycle 4 (Day 1) of induction therapy and the date of randomization. This response does not have to be confirmed in order for the patient to be randomized to the maintenance phase.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: pemetrexed + cisplatin followed by pemetrexed<br>pemetrexed plus cisplatin followed by pemetrexed plus best supportive care | Drug: Pemetrexed<br>* Induction therapy: 500 mg/m^2, intravenous (IV), on Day 1 of each 21-day cycle for 4 cycles<br>* Other names: LY231514;Drug: Cisplatin<br>* Induction therapy: Cisplatin: 75 mg/m^2, IV, on Day 1 of each 21-day cycle for 4 cycles<br>Drug: Pemetrexed<br>* Maintenance therapy: 500 mg/m^2, IV, on Day 1 of each 21-day cycle until progressive disease or treatment discontinuation.<br>* Other names: LY231514;Other: Best Supportive Care<br>* Best Supportive Care is treatment given with the intent to maximize quality of life. Best Supportive Care excludes any treatment in which the goal is to cure or slow the progression of the study disease. Patients will receive Best Supportive Care as judged by their treating physician. Those therapies considered acceptable include, but are not limited to, palliative radiation to extrathoracic structures, antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, and/or nutritional support (enteral or parenteral).<br>|
| Placebo Comparator: pemetrexed + cisplatin followed by placebo<br>pemetrexed plus cisplatin followed by placebo plus best supportive care | Drug: Pemetrexed<br>* Induction therapy: 500 mg/m^2, intravenous (IV), on Day 1 of each 21-day cycle for 4 cycles<br>* Other names: LY231514;Drug: Cisplatin<br>* Induction therapy: Cisplatin: 75 mg/m^2, IV, on Day 1 of each 21-day cycle for 4 cycles<br>Drug: Placebo<br>* Maintenance therapy: Normal saline (0.9% sodium chloride) administered IV on Day 1 every 21-day cycle until progressive disease or treatment discontinuation<br>Other: Best Supportive Care<br>* Best Supportive Care is treatment given with the intent to maximize quality of life. Best Supportive Care excludes any treatment in which the goal is to cure or slow the progression of the study disease. Patients will receive Best Supportive Care as judged by their treating physician. Those therapies considered acceptable include, but are not limited to, palliative radiation to extrathoracic structures, antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, and/or nutritional support (enteral or parenteral).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigator-assessed Objective Progression-free Survival (PFS) | Investigator-assessed objective PFS was measured from the date of randomization to the first date of objectively determined progressive disease (PD) or death from any cause. For patients not known to have died as of the data cutoff date and who did not have objective PD, PFS was censored at the date of last objective tumor assessment. PD was determined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria. PD = 20% increase in sum of longest diameter of target lesions. | Date of randomization to the date of measured PD or date of death from any cause (up to 19.3 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Independently-assessed Objective Progression-free Survival (PFS) | To further evaluate the robustness of the PFS analysis, Lilly established an independent review of PFS to assess the potential for investigator bias in the determination of objective PD. PFS was measured from the date of randomization to the first date of objectively determined PD or death. For patients alive as of the data cutoff date and who did not have PD, PFS was censored at the date of the last objective tumor assessment. PD was determined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria. PD = 20% increase in sum of longest diameter of target lesions. | Date of randomization to first date of measured PD or date of death from any cause (up to 19.3 months) | 
| Overall Survival (OS) | OS is the duration from enrollment to death. For patients who are alive, OS is censored at the last contact. | Date of randomization to the date of death from any cause up to 39.5 months | 
| Change From Baseline in the EuroQol Instrument (EQ-5D) Index Score | The EQ-5D is a generic instrument that describes health status in 5 attributes (mobility, self-care, pain/discomfort, anxiety/depression, usual activities) using a three level scale (no problem, some problems, and major problems). These combinations of attributes are converted into a weighted health-state Index Score according to the United Kingdom (UK) population-based algorithm. The possible values for the Index Score range from -0.59 (severe problems in all 5 dimensions) to 1.0 (no problem in any dimension). | Baseline randomization through 30-day post-discontinuation visit (up to 19.3 months) | 
| Change From Baseline in EuroQol Instrument (EQ-5D) Visual Analog Scale (VAS) | Patients indicate their present health state through completion of the VAS. Possible scores range from 0 (worst imaginable health state) to 100 (best imaginable health state). | Baseline randomization through 30-day post-discontinuation visit (up to 19.3 months) | 
| Percentage of Participants With Hospitalizations Due to Adverse Events or Requiring Transfusion (Resource Utilization) |  | Baseline randomization through 30-day post-discontinuation visit (up to 19.3 months) | 
| Percentage of Participants With a Non-Serious Adverse Event (AE) During Maintenance Phase | A summary of non-serious AEs is located in the Reported Adverse Event Module. | Baseline randomization through 30-day post-discontinuation visit (up to 49.7 months) | 
| Percentage of Participants With Serious Adverse Events During Maintenance Phase | A summary of serious adverse events is located in the Reported Adverse Event Module. | Baseline randomization through 30-day post-discontinuation visit (up to 49.7 months) | 
| Percentage of Participants With Objective Tumor Response (Response Rate) During Maintenance Phase of Study up to Primary Data Cut-Off | Analysis for combined phases was not performed since response was calculated separately for each phase of study. Response using Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Complete Response (CR)=disappearance of all target lesions; Partial Response(PR)is at least a 30% decrease in sum of longest diameter of target lesions; Progressive Disease(PD) is at least a 20% increase in sum of longest diameter of target lesions; Stable Disease(SD)=no change or small changes that do not meet the above criteria for CR, PR, or PD. | Baseline to date of measured progressive disease (up to 19.3 months) | 
| Percentage of Participants With Independently-Assessed Objective Tumor Response (Response Rate) During Maintenance Phase Up to Primary Data Cut-Off | Response using Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Complete Response (CR)=disappearance of all target lesions; Partial Response (PR) is at least a 30% decrease in sum of longest diameter of target lesions; Progressive Disease (PD) is at least a 20% increase in sum of longest diameter of target lesions; Stable Disease (SD)=no change or small changes that do not meet the above criteria for CR, PR, or PD. Response Rate = (CR+PR)/Participants in Arm*100. Disease Control Rate=(CR+PR+SD)/Number of Participants in Arm*100. | Date of randomization to date of measured PD (up to 19.3 months) |