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

Phase 3CompletedNCT00762034

Eli Lilly and Company939 enrolled

Overview

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

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

939

Conditions

Non-small Cell Lung Cancer

Interventions

PemetrexedDRUG

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

PemetrexedDRUG

Maintenance therapy 500 mg/m\^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

PaclitaxelDRUG

Induction therapy 200 mg/m\^2 IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (67)

Outcomes

Primary Outcomes

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.

Time frame: Baseline to date of death from any cause (up to 37.06 months)

Secondary Outcomes

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.

Time frame: 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.

Data from ClinicalTrials.gov

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Induction therapy area under the concentration curve (AUC) 6 IV every 21 days for up to 4 cycles of 21 days

BevacizumabBIOLOGICAL

Induction therapy 15 milligrams per kilogram (mg/kg) IV every 21 days for up to 4 cycles of 21 days

BevacizumabBIOLOGICAL

Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Fayetteville, Arkansas, United States

Jonesboro, Arkansas, United States

Alhambra, California, United States

Bakersfield, California, United States

Duarte, California, United States

Fountain Valley, California, United States

Fullerton, California, United States

La Verne, California, United States

Long Beach, California, United States

Los Angeles, California, United States

...and 57 more locations

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline to study endpoint (up to 37.06 months)

Number of Participants Who Received a Transfusion

Time frame: Baseline to study endpoint (up to 37.06 months)

Number of Participants Receiving Concomitant Medication

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline, up to first 10 cycles (4 induction and 6 maintenance cycles, cycle=21 days)

Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) for Pemetrexed

Time frame: 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

Time frame: 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

Time frame: 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)

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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)

Time frame: 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).

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline to date of death from any cause (up to 37.06 months)