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S0819: Carboplatin and Paclitaxel With or Without Bevacizumab and/or Cetuximab in Treating Patients With Stage IV or Recurrent Non-Small Cell Lung Cancer

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ClinicalTrials.gov Identifier: NCT00946712
Recruitment Status : Active, not recruiting
First Posted : July 27, 2009
Results First Posted : March 7, 2019
Last Update Posted : May 19, 2021
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Southwest Oncology Group

Tracking Information
First Submitted Date  ICMJE July 24, 2009
First Posted Date  ICMJE July 27, 2009
Results First Submitted Date  ICMJE December 6, 2018
Results First Posted Date  ICMJE March 7, 2019
Last Update Posted Date May 19, 2021
Study Start Date  ICMJE July 15, 2009
Actual Primary Completion Date August 31, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 13, 2019)
  • Overall Survival (OS) in the Entire Study Population [ Time Frame: Patients will be followed every 3 weeks while on protocol treatment. Once off all protocol treatment, patients will be followed every 6 months until death or up to 3 years ]
    From date of randomization to date of death due to any cause. Patients last known to be alive are censored at date of last contact.
  • Progression-free Survival (PFS) of EGFR FISH-positive Patients by Institutional Review [ Time Frame: Disease assessment will be repeated every 6 weeks for the first 9 months and every 3 months thereafter, until disease progression. ]
    From date of randomization to date of first documentation of progression or symptomatic deterioration, or death due to any cause, whichever comes first by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as assessed by the treating investigator.Patients last known to be alive and progression-free are censored at date of last contact. Progression is defined using RECIST 1.1, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Original Primary Outcome Measures  ICMJE
 (submitted: July 24, 2009)
  • Overall survival (OS)
  • Progression-free Survival (PFS) of EGFR FISH-positive Patients by Institutional Review
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 13, 2019)
  • OS of EGFR FISH-positive Patients by Centralized Review [ Time Frame: Patients will be followed every 3 weeks while on protocol treatment. Once off all protocol treatment, patients will be followed every 6 months until death or up to 3 years ]
    From date of randomization to date of death due to any cause. Patients last known to be alive are censored at date of last contact.
  • PFS of EGFR FISH-positive Patients by Centralized Review [ Time Frame: Disease assessment will be repeated every 6 weeks until disease progression while on treatment. After off treatment, the frequency of disease assessment may be reduced to every 3 months until disease progression. ]
    From date of randomization to date of first documentation of progression or symptomatic deterioration, or death due to any cause, whichever comes first by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as assessed by the treating investigator.Patients last known to be alive and progression-free are censored at date of last contact. Progression is defined using RECIST 1.1, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
  • PFS of the Entire Study Population by Centralized Review and by Institutional Review [ Time Frame: Disease assessment will be repeated every 6 weeks until disease progression while on treatment. After off treatment, the frequency of disease assessment may be reduced to every 3 months until disease progression. ]
    From date of randomization to date of first documentation of progression or symptomatic deterioration, or death due to any cause, whichever comes first by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as assessed by the treating investigator.Patients last known to be alive and progression-free are censored at date of last contact. Progression is defined using RECIST 1.1, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
  • Response Rate (Confirmed Plus Unconfirmed, Complete and Partial Responses) in the Subset of Patients With Measurable Disease in EGFR FISH-positive Patients [ Time Frame: Disease assessment will be repeated every 6 weeks for the first 9 months and every 3 months thereafter, until disease progression. ]
    Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
  • Response Rate (Confirmed Plus Unconfirmed, Complete and Partial Responses) in the Subset of Patients With Measurable Disease in the Entire Study Population [ Time Frame: Disease assessment will be repeated every 6 weeks for the first 9 months and every 3 months thereafter, until disease progression. ]
    Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
  • Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs [ Time Frame: Toxicity assessment was evaluated every 3 weeks while one protocol treatment. Chemo and cetuximab is treated for 6 cycles (1 cycle =3 weeks) and Bevacizumab is treated until progression or unacceptable toxicity. ]
    Adverse Events (AEs) are reported by CTCAE Version 4.0. Only adverse events that are possibly, probably or definitely related to study drug are reported.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 24, 2009)
  • OS and PFS of EGFR FISH-positive patients by centralized review
  • PFS of the entire study population by centralized review and by institutional review
  • Response
  • Toxicity as assessed by NCI CTCAE version 3.0
  • Comparison of other purported EGFR-related biomarkers with EGFR IHC, EGFR FISH, and patient outcomes
  • Correlation of KRAS mutations with response and outcome
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE S0819: Carboplatin and Paclitaxel With or Without Bevacizumab and/or Cetuximab in Treating Patients With Stage IV or Recurrent Non-Small Cell Lung Cancer
Official Title  ICMJE A Randomized, Phase III Study Comparing Carboplatin/Paclitaxel or Carboplatin/Paclitaxel/Bevacizumab With or Without Concurrent Cetuximab in Patients With Advanced Non-small Cell Lung Cancer (NSCLC)
Brief Summary This randomized phase III trial studies carboplatin and paclitaxel to compare how well they work with or without bevacizumab and/or cetuximab in treating patients with stage IV or non-small cell lung cancer that has returned after a period of improvement (recurrent). Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Bevacizumab may prevent the growth of new blood vessels that tumor needs to grow. Cetuximab may also stop cancer cells from growing by binding and interfering with a protein on the surface of the tumor cell that is needed for tumor growth. It is not yet known whether giving carboplatin and paclitaxel are more effective with or without bevacizumab and/or cetuximab in treating patients with non-small cell lung cancer.
Detailed Description

PRIMARY OBJECTIVES:

I. To compare overall survival (OS) in the entire study population. II. To compare progression-free survival (PFS) by institutional review of epidermal growth factor receptor (EGFR) fluorescent in situ hybridization (FISH)-positive patients.

SECONDARY OBJECTIVES:

I. To compare OS and PFS by centralized review in EGFR FISH-positive patients. II. To compare PFS by centralized image review and by institutional review in the entire study population.

III. To compare the response rate (confirmed plus unconfirmed, complete and partial responses) in a subset of patients with measurable disease in EGFR FISH-positive patient and the entire study population.

IV. To assess the toxicities of these treatment regimens. V. To prospectively test EGFR FISH as a predictive marker for the selection of patients for cetuximab plus chemotherapy.

III. To evaluate the role of V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in terms of cetuximab efficacy.

IV. To compare the results of EGFR FISH with KRAS mutations, EGFR mutations, EGFR immunohistochemistry (IHC), and other purported EGFR-related biomarkers.

TERTIARY OBJECTIVES:

I. To compare PFS in patients with advanced non-small cell lung cancer (NSCLC) with an IHC score > 200 treated with carboplatin, paclitaxel, and bevacizumab (if appropriate) with or without cetuximab.

II. To compare OS in patients with advanced NSCLC with an IHC score > 200 treated with carboplatin, paclitaxel, and bevacizumab (if appropriate) with or without cetuximab.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive paclitaxel intravenously (IV) over 3 hours and carboplatin IV over 30 minutes with or without bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients receiving bevacizumab may continue to receive bevacizumab (as above) in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive paclitaxel and carboplatin with or without bevacizumab as in Arm I. Patients also receive cetuximab IV over 1-2 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients may continue to receive cetuximab with or without bevacizumab (as above) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year and then every 6 months for 2 years.

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
  • Recurrent Large Cell Lung Carcinoma
  • Recurrent Lung Adenocarcinoma
  • Recurrent Squamous Cell Lung Carcinoma
  • Stage IV Large Cell Lung Carcinoma
  • Stage IV Lung Adenocarcinoma
  • Stage IV Squamous Cell Lung Carcinoma
Intervention  ICMJE
  • Biological: Bevacizumab
    Given IV
    Other Names:
    • Anti-VEGF
    • Anti-VEGF Humanized Monoclonal Antibody
    • Anti-VEGF rhuMAb
    • Avastin
    • Bevacizumab Biosimilar BEVZ92
    • Bevacizumab Biosimilar BI 695502
    • Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer
    • Recombinant Humanized Anti-VEGF Monoclonal Antibody
    • rhuMab-VEGF
  • Drug: Carboplatin
    Given IV
    Other Names:
    • Blastocarb
    • Carboplat
    • Carboplatin Hexal
    • Carboplatino
    • Carbosin
    • Carbosol
    • Carbotec
    • CBDCA
    • Displata
    • Ercar
    • JM-8
    • Nealorin
    • Novoplatinum
    • Paraplat
    • Paraplatin
    • Paraplatin AQ
    • Paraplatine
    • Platinwas
    • Ribocarbo
  • Biological: Cetuximab
    Given IV
    Other Names:
    • Chimeric Anti-EGFR Monoclonal Antibody
    • Chimeric MoAb C225
    • Chimeric Monoclonal Antibody C225
    • Erbitux
    • IMC-C225
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Paclitaxel
    Given IV
    Other Names:
    • Anzatax
    • Asotax
    • Bristaxol
    • Praxel
    • Taxol
    • Taxol Konzentrat
Study Arms  ICMJE
  • Experimental: Arm I (chemo +/- bevacizumab)
    Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes with or without bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients receiving bevacizumab may continue to receive bevacizumab (as above) in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Biological: Bevacizumab
    • Drug: Carboplatin
    • Other: Laboratory Biomarker Analysis
    • Drug: Paclitaxel
  • Experimental: Arm II (chemo, cetuximab, +/- bevacizumab)
    Patients receive paclitaxel and carboplatin with or without bevacizumab as in Arm I. Patients also receive cetuximab IV over 1-2 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients may continue to receive cetuximab with or without bevacizumab (as above) in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Biological: Bevacizumab
    • Drug: Carboplatin
    • Biological: Cetuximab
    • Other: Laboratory Biomarker Analysis
    • Drug: Paclitaxel
Publications * Herbst RS, Redman MW, Kim ES, Semrad TJ, Bazhenova L, Masters G, Oettel K, Guaglianone P, Reynolds C, Karnad A, Arnold SM, Varella-Garcia M, Moon J, Mack PC, Blanke CD, Hirsch FR, Kelly K, Gandara DR. Cetuximab plus carboplatin and paclitaxel with or without bevacizumab versus carboplatin and paclitaxel with or without bevacizumab in advanced NSCLC (SWOG S0819): a randomised, phase 3 study. Lancet Oncol. 2018 Jan;19(1):101-114. doi: 10.1016/S1470-2045(17)30694-0. Epub 2017 Nov 20.

*   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 Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: February 13, 2019)
1333
Original Estimated Enrollment  ICMJE
 (submitted: July 24, 2009)
1546
Estimated Study Completion Date  ICMJE December 31, 2022
Actual Primary Completion Date August 31, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients must have histologically or cytologically proven primary non-small cell lung cancer (adenocarcinoma, large cell carcinoma, squamous or unspecified); disease must be stage IV; disease may be either newly diagnosed or recurrent after previous surgery and/or irradiation; patients with additional lesions in an ipsilateral non-primary lobe without M1a or M1b disease will not be considered to have stage IV disease and are not eligible
  • Patients must have a computed tomography (CT) or magnetic resonance imaging (MRI) scan of the brain to evaluate for central nervous system (CNS) disease within 42 days prior to registration; patient must not have brain metastases unless: (1) metastases have been treated and have remained controlled for at least two weeks following treatment, AND (2) patient has no residual neurological dysfunction off corticosteroids for at least 1 day
  • Patients may have measurable or non-measurable disease documented by CT or MRI; the CT from a combined positron emission tomography (PET)/CT may be used to document only non-measurable disease unless it is of diagnostic quality; measurable disease must be assessed within 28 days prior to registration; pleural effusions, ascites and laboratory parameters are not acceptable as the only evidence of disease; non-measurable disease must be assessed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form
  • Patients must have tumor tissue available for submission that is sufficient for EGFR FISH testing and must agree to submission of these specimens; patients must also agree to submission of specimens for other translational medicine studies; patient must be offered participation in banking for future research
  • Patients must not have received prior chemotherapy for any stage non-small cell lung cancer; patients must not have received prior platinum-based chemotherapy for any purpose; patient must not have received any cetuximab, gefitinib, erlotinib, or other investigational agents that target the EGFR pathway; patients must not have received for any purpose prior bevacizumab or other vascular endothelial growth factor (VEGF)-related agents; patients must not have received for any purpose prior chimerized or murine monoclonal antibody therapy or have documented presence of human anti-mouse antibodies (HAMA)
  • Prior radiation is permitted; however, patients must have recovered from all associated toxicities at time of registration; in order to qualify as measurable, measurable disease must be outside the previous radiation field or must have progressed
  • Time from surgical or biopsy procedures is dependent on whether it is planned for the patient to receive bevacizumab

    • For patients who are bevacizumab-appropriate AND bevacizumab is planned: at least 28 days must have elapsed since major surgery (i.e. thoracotomy or video-assisted thoracoscopic surgery [VATS] resection of lung cancer, open pleural biopsy or another major surgical procedure such as abdominal surgery) or significant traumatic injury; patients must have recovered from all associated toxicities at the time of registration; there must be no anticipation of need for major surgical procedures during protocol treatment; patients must not have had a core biopsy, mediastinoscopy, pleurodesis, VATS pleural biopsy or VATS pericardial window within 14 days prior to registration; patients must not have had a percutaneous fine needle aspiration (FNA), thoracentesis or central venous access device implanted within 7 days prior to registration; for other surgical procedures not listed here, please contact the study coordinators
    • For patients who are bevacizumab-inappropriate or bevacizumab is not planned: at least 28 days must have elapsed since major surgery (i.e. thoracotomy or VATS resection of lung cancer, open pleural biopsy or another major surgical procedure such as abdominal surgery) or significant traumatic injury; patients must have recovered from all associated toxicities at the time of registration; there must be no anticipation of need for major surgical procedures during protocol treatment; patients must not have had a core biopsy, mediastinoscopy, pleurodesis, VATS pleural biopsy or VATS pericardial window within 7 days prior to registration; patients must not have had a percutaneous fine needle aspiration (FNA), or thoracentesis within 1 day prior to registration; patients may have had a central venous access device placed at any time prior to registration; for other surgical procedures not listed here, please contact the study coordinators
  • Absolute neutrophil count (ANC) >= 1,500/mcl
  • Platelet count >= 100,000/mcl
  • Hemoglobin >= 9 g/dL
  • Serum creatinine =< institutional upper limit of normal (IULN) AND calculated or measured creatinine clearance >= 50 cc/min using the following Cockroft-Gault formula
  • For patients who will be receiving bevacizumab, urine protein must be screened by urine analysis for urine protein creatinine (UPC) ratio; for UPC ratio > 0.5, 24-hour urine protein must be obtained and the level must be < 1,000 mg for patient enrollment; the urine protein used to calculate the UPC ratio must be obtained within 14 days prior to registration; UPC or 24-hour protein is not required for patients who will not receive bevacizumab Note: UPC ratio of spot urine is an estimation of the 24-hour urine protein excretion - a UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm
  • Serum bilirubin =< 2 times IULN (for patients with liver metastases, bilirubin must be =< 5 X IULN)
  • Serum glutamic oxaloacetic transaminase (SGOT) OR serum glutamate pyruvate transaminase (SGPT) =< 2 times IULN (for patients with liver metastases, either SGOT or SGPT must be =< 5 X IULN)
  • Zubrod performance status 0-1
  • Patients must not have >= grade 2 symptomatic neuropathy-sensory (National Cancer Institute [NCI] Common Terminology Criteria version 3.0)
  • Patients must not have documented evidence of acute hepatitis or have an active or uncontrolled infection
  • Patients must not have the following: history (within past 6 months) of cerebrovascular accident (CVA), myocardial infarction or unstable angina; or at the time of registration, uncontrolled hypertension, New York Heart Association grade 2 or greater congestive heart failure, serious cardiac arrhythmia requiring medication, or clinically significant peripheral vascular disease
  • Patients must have no known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies (examples include trastuzumab [Herceptin] and epoetin alpha)
  • Patients must be willing to provide prior smoking history
  • No other prior malignancy is allowed except for any of the following:

    • Adequately treated basal cell or squamous cell skin cancer
    • In situ cervical cancer
    • Adequately treated stage I or II cancer from which the patient is currently in complete remission
    • Any other cancer from which the patient has been disease-free for 5 years
  • Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures
  • Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines
  • As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
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 Mexico,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00946712
Other Study ID Numbers  ICMJE S0819
NCI-2009-01664 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CDR0000649817
S0819 ( Other Identifier: SWOG )
S0819 ( Other Identifier: CTEP )
U10CA180888 ( U.S. NIH Grant/Contract )
U10CA032102 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Southwest Oncology Group
Study Sponsor  ICMJE Southwest Oncology Group
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Roy Herbst Southwest Oncology Group
PRS Account Southwest Oncology Group
Verification Date April 2021

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