A Study of Pemetrexed, Carboplatin and Bevacizumab in Participants With Nonsquamous Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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This study will compare overall survival in participants with Stage IIIB or IV nonsquamous non-small cell lung cancer.

Official Title
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Randomized, Open-Label, Phase 3 Study of Pemetrexed Plus Carboplatin and Bevacizumab Followed by Maintenance Pemetrexed and Bevacizumab Versus Paclitaxel Plus Carboplatin and Bevacizumab Followed by Maintenance Bevacizumab in Patients With Stage IIIB or IV Nonsquamous Non-Small Cell Lung Cancer

Conditions
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Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: Pemetrexed
* Drug: Pemetrexed
* Drug: Paclitaxel
* Drug: Carboplatin
* Biological: Bevacizumab
* Biological: Bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: You must sign an informed consent document for clinical research. You must have Stage IIIB or Stage IV nonsquamous non-small cell lung cancer. You must not have received any prior treatment for your disease. Prior radiation therapy is allowed to < 25% of the bone marrow; however, prior radiation to the whole pelvis is not allowed. If you have had radiation therapy to the chest, you are not eligible to participate. You must be at least 18 years of age or older. You must have measureable tumor lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST) or disease can be evaluated on computed tomography (CT) scan. Your test results assessing the function of blood forming tissue, kidneys and liver must be satisfactory. Women must be sterile, postmenopausal or on contraception and men must be sterile (for example post-vasectomy) or on contraception. Exclusion Criteria: 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 Non-small Cell Lung Carcinoma (NSCLC) of predominantly squamous cell histology. You cannot have known central nervous system (CNS) disease, other than stable, treated brain metastasis. You cannot have undergone a surgical procedure, open biopsy, open pleurodesis, or significant traumatic injury within 28 days of starting the study treatment, or have an anticipated need for major surgery during the study. You cannot have a history of gastrointestinal fistula, perforation, or abscess, inflammatory bowel disease, or diverticulitis. You are currently receiving ongoing treatment with full-dose warfarin or equivalent. You cannot have significant vascular disease, serious cardiac conditions (such as heart attack), stroke or transient ischemic attack within 6 months of the trial. You cannot have evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation). You cannot have inadequately controlled hypertension, or a history of hypertensive crisis or hypertensive encephalopathy. You cannot have a serious, nonhealing wound, active ulcer, or untreated bone fracture. You cannot have another form of cancer, other than superficial basal cell and superficial squamous (skin) cell, or carcinoma in situ of the cervix within the last 5 years. You cannot have received an investigational treatment within 30 days prior to the trial. You cannot have previously received treatment with paclitaxel, carboplatin, pemetrexed, or bevacizumab. You cannot be pregnant or breast-feeding. You cannot have a known sensitivity to any component of paclitaxel, carboplatin, pemetrexed, or bevacizumab. You cannot have a history of hemoptysis (coughing blood) within 3 months prior to the trial. You are unable to stop taking aspirin more than 1.3 grams per day or other nonsteroidal anti-inflammatory drugs (NSAIDs). You are unable or unwilling to take folic acid or vitamin B12 supplementation. You are unable to take corticosteroids. You have any other on-going illnesses including active infections that may not allow you to adhere to the requirements of the trial.

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: Pem/Carbo/Bev<br>Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab | Drug: Pemetrexed<br>* Induction therapy 500 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days<br>* Other names: LY231514;Drug: Pemetrexed<br>* Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation<br>* Other names: LY231514;Drug: Carboplatin<br>* Induction therapy area under the concentration curve (AUC) 6 IV every 21 days for up to 4 cycles of 21 days<br>Biological: Bevacizumab<br>* Induction therapy 15 milligrams per kilogram (mg/kg) IV every 21 days for up to 4 cycles of 21 days<br>Biological: Bevacizumab<br>* Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.<br>|
| Active Comparator: Pac/Carbo/Bev<br>Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab | Drug: Paclitaxel<br>* Induction therapy 200 mg/m^2 IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days<br>Drug: Carboplatin<br>* Induction therapy area under the concentration curve (AUC) 6 IV every 21 days for up to 4 cycles of 21 days<br>Biological: Bevacizumab<br>* Induction therapy 15 milligrams per kilogram (mg/kg) IV every 21 days for up to 4 cycles of 21 days<br>Biological: Bevacizumab<br>* Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival (OS) is the duration from date of randomization to date of death from any cause. Participants were censored at the date they were last known to be alive. | Baseline to date of death from any cause (up to 37.06 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Complete Response (CR) and Partial Response (PR) (Overall Response Rate) | Overall Response Rate (ORR) is the number of participants with a Complete Response (CR) and Partial Response (PR) divided by the total number of randomized participants per arm, then multiplied by 100. Response is based on the Response Evaluation Criteria In Solid Tumors (RECIST 1.0) criteria. Complete Response (CR) was defined as the disappearance of all target lesions. Partial Response (PR) was defined as at least a 30% decrease in sum of longest diameter of target lesions compared to baseline or the complete disappearance of target lesions, with persistence of 1 or more nontarget lesion(s) and no new lesions. | Baseline to measured progressive disease (up to 37.06 months) | 
| Percentage of Participants With a Complete Response (CR), Partial Response (PR), and Stable Disease (SD) (Disease Control Rate) | Disease Control Rate (DCR) is the number of participants with a Complete Response (CR), Partial Response (PR), and Stable Disease (SD) divided by the total number of randomized participants per arm, then multiplied by 100. Response is based on the Response Evaluation Criteria In Solid Tumors (RECIST 1.0) criteria. Complete Response (CR) was defined as the disappearance of all target lesions. Partial Response (PR) was defined as at least a 30% decrease in sum of longest diameter of target lesions compared with baseline or the complete disappearance of target lesions, with persistence of 1 or more nontarget lesion(s) and no new lesions. Progressive Disease (PD) was defined as at least 20% increase in sum of longest diameter of target lesions compared with the smallest sum of the longest diameter recorded since the start of treatment or the appearance of 1 or more new lesion(s). Stable Disease (SD) was defined as small changes that did not meet above criteria. | Baseline to measured progressive disease (up to 37.06 months) | 
| Progression Free Survival Time | Progression free survival (PFS) is defined as the time from date of randomization to the date of objective disease progression or death due to any cause. Participants were censored at date of last PFS assessment prior to the cutoff date or the date of initiation of subsequent systemic anticancer therapy, whichever was earlier. | Baseline to measured progressive disease or date of death from any cause (up to 33.54 months) | 
| Time to Progressive Disease | Time to progressive disease was defined as the time from randomization to the first date of objective disease progression. Participants were censored at date of last PFS assessment prior to the cutoff date or the date of initiation of subsequent systemic anticancer therapy, whichever was earlier. | Baseline to measured progressive disease (up to 37.06 months) | 
| Safety and Toxicity Profile of Study Treatments | Safety and toxicity profile was defined as serious and other non-serious adverse events. A summary of serious and all other non-serious adverse events is located in the Reported Adverse Event module. | Baseline to study endpoint (up to 37.06 months) | 
| Duration of Hospitalizations Per Participant | Length of hospitalization in participants hospitalized during the study or within 30 days of discontinuation regardless of whether the hospitalization was or was not due to study drug. | Baseline to study endpoint (up to 37.06 months) | 
| Number of Participants Who Received a Transfusion |  | Baseline to study endpoint (up to 37.06 months) | 
| Number of Participants Receiving Concomitant Medication |  | Baseline to study endpoint (up to 37.06 months) | 
| Change From Baseline in Participant Reported Outcomes as Assessed by the Functional Assessment of Cancer Therapy - General (FACT-G) | The FACT-G is a validated instrument used to measure quality of life (QOL) in participants with cancer consisting of the 27-item questionnaire and is organized into subscales, each designed to assess a QOL domain: physical well-being (PWB)-7 items; social/family well-being (SWB)-7 items; emotional well-being (EWB)-6 items; functional well-being (FWB)-7 items. Each item uses a 5 point rating scale (0=not at all and 4=equals very much). FACT-G Total is the sum of the scores of all 4 subscales and ranges from 0 to 108. Higher scores indicate better QOL. Least squares mean (LSmean) change is calculated using the linear-mixed model (LMM) analysis controlled for treatment, baseline value, time point and treatment by time point interaction. | Baseline, up to first 10 cycles (4 induction and 6 maintenance cycles, cycle=21 days) | 
| Change From Baseline in Participant Reported Outcomes as Assessed by the Functional Assessment of Cancer Therapy - Lung (FACT-L) | FACT-L is a valid instrument used to measure quality of life (QOL) in participants with cancer consisting of the 27-item FACT-General (G) and 9-item lung cancer subscale (LCS). FACT-G is organized into subscales: physical well-being (PWB)-7 items; social/family well-being (SWB)-7 items; emotional well-being (EWB)-6 items; functional well-being (FWB)-7 items. Each item uses a 5 point rating scale (0=not at all and 4=equals very much). FACT-L Total Score=4 subscales + LCS and ranges from 0 to 144. Trial Outcome Index-Lung (TOI-L)=PWB+FWB+LCS and ranges from 0 to 92. Higher scores indicate better QOL. Least squares mean (LSmean) change is calculated using the linear-mixed model (LMM) analysis controlled for treatment, baseline value, time point and treatment by time point interaction. | Baseline, up to first 10 cycles (4 induction and 6 maintenance cycles, cycle=21 days) | 
| Change From Baseline in Participant Reported Outcomes as Assessed by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group- Neurotoxicity (FACT/GOG-Ntx) | FACT/GOG-Ntx is a validated instrument used to measure quality of life (QOL) in participants with cancer and neurotoxicity (Ntx) consisting of 27-item FACT-General (G) and 11-item Ntx subscale. FACT-G is organized into domain subscales: physical well-being (PWB)-7 items; social/family well-being (SWB)-7 items; emotional well-being (EWB)-6 items; functional well-being (FWB)-7 items; each uses a 5 point rating scale (0=not at all and 4=equals very much). FACT/GOG-Ntx Total Score=sum 5 subscales and ranges from 0-152. Ntx Trial Outcome Index (TOI-Ntx)=PWB+FWB+NTX and range from 0-100. For all FACT scales, higher scores indicate better QOL. Least squares mean (LSmean) change is calculated using the linear-mixed model (LMM) analysis controlled for treatment, baseline value, time point and treatment by time point interaction. | Baseline, up to first 10 cycles (4 induction and 6 maintenance cycles, cycle=21 days) | 
| Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) for Pemetrexed |  | Cycle 1 (pre-dose, 0.17, 0.33, 0.58, 0.83, 1, 1.75, 2.5, 4. 6. 8, and 24 hours post-dose) | 
| Pharmacokinetics (PK): Elimination Half-life (t1/2) for Pemetrexed |  | Cycle 1 (pre-dose, 0.17, 0.33, 0.58, 0.83, 1, 1.75, 2.5, 4. 6. 8, and 24 hours post-dose) | 
| Pharmacokinetics (PK): Area Under the Concentration Time Curve From Zero to Infinity (AUC(0-∞)) for Pemetrexed |  | Cycle 1 (pre-dose, 0.17, 0.33, 0.58, 0.83, 1, 1.75, 2.5, 4. 6. 8, and 24 hours post-dose) | 
| Pharmacokinetics (PK): Pemetrexed Clearance (CL) |  | Cycle 1 (pre-dose, 0.17, 0.33, 0.58, 0.83, 1, 1.75, 2.5, 4. 6. 8, and 24 hours post-dose) | 
| Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) for Total (Bound and Unbound) Platinum and Unbound Platinum | Platinum is a metabolite of Carboplatin (Carbo) and is found in the blood as both a bound and unbound form. | Cycle 1 (pre-dose, 0.25, 0.5, 0.67, 1.42, 2.17, 4, 6, 8, 24, 48, and 72 hours post-dose) | 
| Pharmacokinetics (PK): Elimination Half-life (t1/2) for Total (Bound and Unbound) Platinum and Unbound Platinum | Platinum is a metabolite of Carboplatin (Carbo) and is found in the blood as both a bound and unbound form. | Cycle 1 (pre-dose, 0.25, 0.5, 0.67, 1.42, 2.17, 4, 6, 8, 24, 48, and 72 hours post-dose) | 
| Pharmacokinetics (PK): Area Under the Concentration Time Curve From Zero to Infinity (AUC(0-∞)) for Total (Bound and Unbound) Platinum and Unbound Platinum | Platinum is a metabolite of Carboplatin (Carbo) and is found in the blood as both a bound and unbound form. | Cycle 1 (pre-dose, 0.25, 0.5, 0.67, 1.42, 2.17, 4, 6, 8, 24, 48, and 72 hours post-dose) | 
| Pharmacokinetics (PK): Platinum Clearance (CL) for Total (Bound and Unbound) and Unbound Forms | Platinum is a metabolite of Carboplatin (Carbo) and is found in the blood as both a bound and unbound form. | Cycle 1 (pre-dose, 0.25, 0.5, 0.67, 1.42, 2.17, 4, 6, 8, 24, 48, and 72 hours post-dose) | 
| Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) for Bevacizumab |  | Cycle 1 (pre-dose, 0.75, 1.5, 3, 5, 7, 24, 48, 72, 168, 336, and 503 hours post-dose) | 
| Pharmacokinetics (PK): Elimination Half-life (t1/2) for Bevacizumab |  | Cycle 1 (pre-dose, 0.75, 1.5, 3, 5, 7, 24, 48, 72, 168, 336, and 503 hours post-dose) | 
| Pharmacokinetics (PK): Area Under the Concentration Time Curve From Zero to Infinity (AUC(0-∞)) Bevacizumab |  | Cycle 1 (pre-dose, 0.75, 1.5, 3, 5, 7, 24, 48, 72, 168, 336, and 503 hours post-dose) | 
| Pharmacokinetics (PK): Bevacizumab Clearance (CL) |  | Cycle 1 (pre-dose, 0.75, 1.5, 3, 5, 7, 24, 48, 72, 168, 336, and 503 hours post-dose) | 
| Translational Research: Number of Participants With Epidermal Growth Factor Receptor (EGFR) Mutations | Epidermal Growth Factor Receptor (EGFR) mutations were measured by polymerase chain reaction (PCR). | Baseline | 
| Translational Research: Overall Survival (OS) Based on Nuclear Thyroid Transcription Factor-1 (TTF-1) Expression Regardless of Study Treatment | Nuclear Thyroid Transcription Factor-1 (TTF-1) expression was measured using an Immunohistochemistry (IHC) assay which were scored using a 0 (negative, no staining) to 3+ (brightest staining) scoring system, and H score is a calculated using formula: 1x(percentage of cells stained 1+) + 2x(percentage of cells stained 2+) + 3x(percentage of cells stained 3+). TTF-1 Positive have an H score >0 and TTF-1 Negative have an H score=0. Overall survival (OS) is the duration from date of randomization to date of death from any cause. Participants were censored at the date they were last known to be alive. | Baseline to date of death from any cause (up to 37.06 months) | 
| Translational Research: Overall Survival (OS) Based on Cytoplasmic and Nuclear Thymidylate Synthase (TS) Expression | Cytoplasmic and nuclear Thymidylate Synthase (TS) expression was measured using an Immunohistochemistry (IHC) assay which were scored using a 0 (negative, no staining) to 3+ (brightest staining) scoring system for cytoplasmic and nuclear staining, and H score was calculated using formula: 1x(percentage of cells stained 1+) + 2x(percentage of cells stained 2+) + 3x(percentage of cells stained 3+). TS Positive have an H score >0 and TS Negative have an H score=0. Overall survival (OS) is the duration from date of randomization to date of death from any cause. Participants were censored at the date they were last known to be alive. | Baseline to date of death from any cause (up to 37.06 months) | 
| Translational Research: Overall Survival (OS) Based on Cytoplasmic and Membrane Folate Receptor Alpha (FR-α) Expression | Cytoplasmic and membrane Folate Receptor Alpha (FR-α) expression was measured using an Immunohistochemistry (IHC) assay which were scored using a 0 (negative, no staining) to 3+ (brightest staining) scoring system for cytoplasmic or membrane staining, and H score is a calculated using formula: 1x(percentage of cells stained 1+) + 2x(percentage of cells stained 2+) + 3x(percentage of cells stained 3+). FR-α Positive have an H score >0 and FR-α Negative have an H score=0. Overall survival (OS) is the duration from date of randomization to date of death from any cause. Participants were censored at the date they were last known to be alive. | Baseline to date of death from any cause (up to 37.06 months) |