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

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ClinicalTrials.gov Identifier: NCT00762034
Recruitment Status : Completed
First Posted : September 30, 2008
Results First Posted : November 28, 2013
Last Update Posted : December 21, 2015
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company

Tracking Information
First Submitted Date  ICMJE September 26, 2008
First Posted Date  ICMJE September 30, 2008
Results First Submitted Date  ICMJE March 28, 2013
Results First Posted Date  ICMJE November 28, 2013
Last Update Posted Date December 21, 2015
Study Start Date  ICMJE December 2008
Actual Primary Completion Date April 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 26, 2013)
Overall Survival [ Time Frame: Baseline to date of death from any cause (up to 37.06 months) ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: September 26, 2008)
Overall Survival [ Time Frame: Baseline to date of death from any cause ]
Change History Complete list of historical versions of study NCT00762034 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 26, 2013)
  • Percentage of Participants With a Complete Response (CR) and Partial Response (PR) (Overall Response Rate) [ Time Frame: Baseline to measured progressive disease (up to 37.06 months) ]
    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.
  • Percentage of Participants With a Complete Response (CR), Partial Response (PR), and Stable Disease (SD) (Disease Control Rate) [ Time Frame: Baseline to measured progressive disease (up to 37.06 months) ]
    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.
  • Progression Free Survival Time [ Time Frame: Baseline to measured progressive disease or date of death from any cause (up to 33.54 months) ]
    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 to Progressive Disease [ Time Frame: Baseline to measured progressive disease (up to 37.06 months) ]
    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.
  • Safety and Toxicity Profile of Study Treatments [ Time Frame: Baseline to study endpoint (up to 37.06 months) ]
    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.
  • Duration of Hospitalizations Per Participant [ Time Frame: Baseline to study endpoint (up to 37.06 months) ]
    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.
  • 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) [ Time Frame: Baseline, up to first 10 cycles (4 induction and 6 maintenance cycles, cycle=21 days) ]
    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.
  • Change From Baseline in Participant Reported Outcomes as Assessed by the Functional Assessment of Cancer Therapy - Lung (FACT-L) [ Time Frame: Baseline, up to first 10 cycles (4 induction and 6 maintenance cycles, cycle=21 days) ]
    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.
  • Change From Baseline in Participant Reported Outcomes as Assessed by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group- Neurotoxicity (FACT/GOG-Ntx) [ Time Frame: Baseline, up to first 10 cycles (4 induction and 6 maintenance cycles, cycle=21 days) ]
    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.
  • 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 [ 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) ]
    Platinum is a metabolite of Carboplatin (Carbo) and is found in the blood as both a bound and unbound form.
  • Pharmacokinetics (PK): Elimination Half-life (t1/2) for Total (Bound and Unbound) Platinum and Unbound Platinum [ 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) ]
    Platinum is a metabolite of Carboplatin (Carbo) and is found in the blood as both a bound and unbound form.
  • Pharmacokinetics (PK): Area Under the Concentration Time Curve From Zero to Infinity (AUC(0-∞)) for Total (Bound and Unbound) Platinum and Unbound Platinum [ 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) ]
    Platinum is a metabolite of Carboplatin (Carbo) and is found in the blood as both a bound and unbound form.
  • Pharmacokinetics (PK): Platinum Clearance (CL) for Total (Bound and Unbound) and Unbound Forms [ 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) ]
    Platinum is a metabolite of Carboplatin (Carbo) and is found in the blood as both a bound and unbound form.
  • 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 [ Time Frame: Baseline ]
    Epidermal Growth Factor Receptor (EGFR) mutations were measured by polymerase chain reaction (PCR).
  • Translational Research: Overall Survival (OS) Based on Nuclear Thyroid Transcription Factor-1 (TTF-1) Expression Regardless of Study Treatment [ Time Frame: Baseline to date of death from any cause (up to 37.06 months) ]
    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.
  • Translational Research: Overall Survival (OS) Based on Cytoplasmic and Nuclear Thymidylate Synthase (TS) Expression [ Time Frame: Baseline to date of death from any cause (up to 37.06 months) ]
    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.
  • Translational Research: Overall Survival (OS) Based on Cytoplasmic and Membrane Folate Receptor Alpha (FR-α) Expression [ Time Frame: Baseline to date of death from any cause (up to 37.06 months) ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 26, 2008)
  • Overall response rate [ Time Frame: Baseline to measured progressive disease ]
  • Disease control rate [ Time Frame: Baseline to measured progressive disease ]
  • Progression Free Survival Time [ Time Frame: Baseline to measured progressive disease or date of death from any cause ]
  • Time to Progressive Disease [ Time Frame: Baseline to measured progressive disease ]
  • Safety and Toxicity Profile of Study Treatments [ Time Frame: Every cycle ]
  • Compare hospitalizations between the treatment arms [ Time Frame: Every cycle ]
  • Compare transfusions between treatment arms. [ Time Frame: Every cycle ]
  • Compare concomitant medication use between treatment arms. [ Time Frame: Every cycle ]
  • Patient reported outcomes as assessed by the Functional Assessment of Cancer Therapy - Lung/Neurotoxicity. [ Time Frame: Baseline and every cycle ]
  • Pharmacokinetics (PK) of carboplatin and bevacizumab in the two treatment arms, and PK of pemetrexed in the experimental arm. [ Time Frame: Cycle 1 ]
  • Translational research to assess biomarkers relevant to study therapy and disease state. [ Time Frame: Baseline ]
  • Translational research to assess relation between biomarkers and clinical outcome. [ Time Frame: Baseline ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Pemetrexed, Carboplatin and Bevacizumab in Participants With Nonsquamous Non-Small Cell Lung Cancer
Official Title  ICMJE 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
Brief Summary This study will compare overall survival in participants with Stage IIIB or IV nonsquamous non-small cell lung cancer.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Non-small Cell Lung Cancer
Intervention  ICMJE
  • Drug: Pemetrexed
    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
    Other Names:
    • Alimta
    • LY231514
  • Drug: Pemetrexed
    Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation
    Other Names:
    • Alimta
    • LY231514
  • Drug: Paclitaxel
    Induction therapy 200 mg/m^2 IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days
  • Drug: Carboplatin
    Induction therapy area under the concentration curve (AUC) 6 IV every 21 days for up to 4 cycles of 21 days
  • Biological: Bevacizumab
    Induction therapy 15 milligrams per kilogram (mg/kg) IV every 21 days for up to 4 cycles of 21 days
  • Biological: Bevacizumab
    Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.
Study Arms  ICMJE
  • Experimental: Pem/Carbo/Bev
    Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab
    Interventions:
    • Drug: Pemetrexed
    • Drug: Pemetrexed
    • Drug: Carboplatin
    • Biological: Bevacizumab
    • Biological: Bevacizumab
  • Active Comparator: Pac/Carbo/Bev
    Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab
    Interventions:
    • Drug: Paclitaxel
    • Drug: Carboplatin
    • Biological: Bevacizumab
    • Biological: Bevacizumab
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 26, 2013)
939
Original Estimated Enrollment  ICMJE
 (submitted: September 26, 2008)
900
Actual Study Completion Date  ICMJE December 2014
Actual Primary Completion Date April 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00762034
Other Study ID Numbers  ICMJE 9707
H3E-MC-JMHD ( Other Identifier: Eli Lilly and Company )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Eli Lilly and Company
Study Sponsor  ICMJE Eli Lilly and Company
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMC - 5 hours, EST) Eli Lilly and Company
PRS Account Eli Lilly and Company
Verification Date November 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP