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Erlotinib Hydrochloride or Crizotinib and Chemoradiation Therapy in Treating Patients With Stage III Non-small Cell Lung Cancer

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ClinicalTrials.gov Identifier: NCT01822496
Recruitment Status : Terminated
First Posted : April 2, 2013
Results First Posted : August 5, 2019
Last Update Posted : August 5, 2019
Sponsor:
Collaborator:
NRG Oncology
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE April 1, 2013
First Posted Date  ICMJE April 2, 2013
Results First Submitted Date  ICMJE June 19, 2019
Results First Posted Date  ICMJE August 5, 2019
Last Update Posted Date August 5, 2019
Actual Study Start Date  ICMJE November 4, 2013
Actual Primary Completion Date June 4, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 2, 2019)
Progression-free Survival [ Time Frame: From randomization to study termination. Maximum follow-up was 39.0 months ]
Progression is defined using the Response Evaluation Criteria In Solid Tumors Criteria (RECIST) guideline v1.1 as a 20% increase in the sum of the longest diameter of target lesions, a measurable increase in a non-target lesion, or the appearance of new lesions at any location. Progression-free survival time is measured from the date of randomization to the date of first progression, death, or last known follow-up (censored). No statistical testing was done due to early study termination.
Original Primary Outcome Measures  ICMJE
 (submitted: April 1, 2013)
Progression-free survival (PFS) [ Time Frame: Occurrence of local or regional progression, distant metastases, or death from any cause from the time of randomization to the occurrence of one of the failure events, whichever occurs first, assessed up to 12 months ]
The product limit estimator developed by Kaplan and Meier will be used. Their 95% confidence intervals will be estimated. Comparisons between arms will be conducted using a log rank test.
Change History Complete list of historical versions of study NCT01822496 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 2, 2019)
  • Percentage of Patients With Complete or Partial Response [ Time Frame: From randomization to study termination. Maximum follow-up was 39.0 months ]
    Per the RECIST guideline v1.1 complete response is defined as the disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. No statistical testing was done due to early study termination.
  • Number of Patients With Grade 3-5 Adverse Events [ Time Frame: From randomization to study termination. Maximum follow-up was 39.0 months ]
    Adverse events (AE) are graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE.
  • Overall Survival [ Time Frame: From randomization to study termination. Maximum follow-up was 39.0 months ]
    Overall survival time is defined as time from randomization to the date of death from any cause. Overall survival rates are estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact.
  • Local-regional Progression-free Survival [ Time Frame: From randomization to study termination. Maximum follow-up was 39.0 months ]
    Progression is defined using the RECIST guideline v1.1 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 regional lesions. Local progression is defined as progression within the planning target volume (PTV). Regional progression is defined as progression outside of the PTV but within the same lobe of the lung as the primary tumor or in regional lymph nodes as defined by the American Joint Committee on Cancer (AJCC) 7th edition nodal stations. Local-regional progression-free survival time is measured from the date of randomization to the date of first local-regional progression, death, or last known follow-up (censored). Local-regional progression-free survival rates are estimated using the Kaplan-Meier method. No testing was done due to early study termination.
  • Distant Progression-free Survival [ Time Frame: From randomization to study termination. Maximum follow-up was 39.0 months ]
    Distant progression is defined as the first occurrence of distant metastasis. Distant progression-free survival time is measured from the date of randomization to the date of first distant progression, death, or last known follow-up (censored). Distant progression-free survival rates are estimated using the Kaplan-Meier method. No testing was done due to early study termination.
  • Correlation Between Clinical Outcomes and Tumor Molecular Aberrations [ Time Frame: Baseline ]
Original Secondary Outcome Measures  ICMJE
 (submitted: April 1, 2013)
  • Proportion of patients who respond (completely or partially) to each treatment, assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Up to 5 years ]
    Estimated as well as their 95% confidence intervals. Tested using Fisher's exact test and using a logistic regression model to incorporate other prognostic covariates.
  • Primary tumor control rate [ Time Frame: Up to 5 years ]
    Estimated as well as their 95% confidence intervals. Tested using Fisher's exact test and using a logistic regression model to incorporate other prognostic covariates.
  • Incidence of grade 3-5 adverse events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 [ Time Frame: Up to 5 years ]
    Summarized using frequency table methods.
  • Overall survival (OS) [ Time Frame: Time to death from any cause, assessed up to 12 months ]
    The product limit estimator developed by Kaplan and Meier will be used. Their 95% confidence intervals will be estimated. Comparisons between arms will be conducted using a log rank test.
  • Local-regional progression free survival [ Time Frame: Time from randomization to local-regional progression or death, whichever comes first, assessed up to 5 years ]
    Appropriate methods for competing risks will be applied, specifically cumulative incidence functions for estimation of cumulative cause specific event probabilities with associated testing for differences, and regression methods for cause-specific hazards and subdistribution hazards underlying cumulative incidence functions may be applied accordingly for exploratory purposes.
  • Distant progression free survival [ Time Frame: Time from randomization to distant progression or death, whichever occurs first, assessed up to 5 years ]
    Appropriate methods for competing risks will be applied, specifically cumulative incidence functions for estimation of cumulative cause specific event probabilities with associated testing for differences, and regression methods for cause-specific hazards and subdistribution hazards underlying cumulative incidence functions may be applied accordingly for exploratory purposes.
  • Deep sequencing of selected kinomes in patients from whom adequate baseline tissue is available [ Time Frame: Up to 5 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Erlotinib Hydrochloride or Crizotinib and Chemoradiation Therapy in Treating Patients With Stage III Non-small Cell Lung Cancer
Official Title  ICMJE A Randomized Phase II Study of Individualized Combined Modality Therapy for Stage III Non-small Cell Lung Cancer (NSCLC)
Brief Summary This randomized phase II trial studies how well erlotinib hydrochloride or crizotinib with chemoradiation therapy works in treating patients with stage III non-small cell lung cancer. Radiation therapy uses high energy x rays to kill tumor cells. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs used in chemotherapy, such as cisplatin, etoposide, paclitaxel, and carboplatin, 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. It is not yet known whether giving erlotinib hydrochloride is more effective than crizotinib with chemoradiation therapy in treating patients with non-small cell lung cancer.
Detailed Description

PRIMARY OBJECTIVES:

I. To assess whether patients with unresectable local-regionally advanced non-small cell lung cancer (NSCLC) treated with targeted agents based on molecular characteristics have a longer progression-free survival than those treated with standard care therapy alone.

SECONDARY OBJECTIVES:

I. To evaluate response rate. II. To assess toxicity. III. To assess overall survival. IV. To correlate clinical outcomes with tumor molecular aberrations identified from deep sequencing of selected kinomes in patients from whom adequate baseline tissue is available.

OUTLINE: Eligible patients are assigned to one of two cohorts based on pre-enrollment screening by the enrolling institution for two biomarkers: EGFR TK mutation and EML4-ALK fusion arrangement. Within each cohort, patients are randomized to either an experimental or control arm, resulting in a total of four treatment arms overall. Patients with both the EGFR mutation and ALK arrangement are placed in the ALK Cohort.

Planned Sample Size: 156 for the EGFR mutation cohort and 78 for the ALK translocation cohort

After completion of study treatment, patients are followed at 1 and 2 months, 4-6 weeks, every 3 months for 2 years, every 6 months for 3 years, and then annually for 5 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Stage III Non-Small Cell Lung Cancer AJCC v7
  • Stage IIIA Non-Small Cell Lung Cancer AJCC v7
  • Stage IIIB Non-Small Cell Lung Cancer AJCC v7
Intervention  ICMJE
  • Radiation: Radiation Therapy
    30 once-daily 2 Gy fractions over 6 weeks totaling 60 Gy of intensity-modulated radiation therapy (IMRT) or 3-dimensional conformal radiation therapy (3D-CRT).
    Other Names:
    • 3-dimensional conformal radiation therapy
    • 3-dimensional radiation therapy
    • 3D CONFORMAL RADIATION THERAPY
    • 3D CRT
    • 3D-CRT
    • Conformal Therapy
    • Radiation Conformal Therapy
    • IMRT
    • Intensity-modulated radiation therapy
  • Drug: Carboplatin

    Concurrent: AUC=2, IV, days 1, 8, 14, 22, 29, and 36 of radiation therapy. For patients receiving either erlotinib or crizotinib, carboplatin will begin 2 weeks after erlotinib or crizotinib, as applicable.

    Consolidation: 4-6 weeks after completion of RT, AUC=6, IV, days 1 and 22.

    Other Names:
    • Blastocarb
    • Carboplat
    • Carboplatin Hexal
    • Carboplatino
    • Carbosin
    • Carbosol
    • Carbotec
    • CBDCA
    • Displata
    • Ercar
    • JM-8
    • Nealorin
    • Novoplatinum
    • Paraplatin
    • Paraplatin AQ
    • Paraplatine
    • Platinwas
    • Ribocarbo
  • Drug: Cisplatin
    50 mg/m2, IV (intravenous), on days 1 and 8 of two 4-week cycles concurrent with radiation therapy. For patients receiving either erlotinib or crizotinib, cisplatin will begin 2 weeks after the completion of erlotinib or crizotinib, as applicable.
    Other Names:
    • Abiplatin
    • Blastolem
    • Briplatin
    • CDDP
    • Cis-diammine-dichloroplatinum
    • Cis-diamminedichloridoplatinum
    • Cis-diamminedichloro Platinum (II)
    • Cis-diamminedichloroplatinum
    • Cis-dichloroammine Platinum (II)
    • Cis-platinous Diamine Dichloride
    • Cis-platinum
    • Cis-platinum II
    • Cis-platinum II Diamine Dichloride
    • Cismaplat
    • Cisplatina
    • Cisplatinum
    • Cisplatyl
    • Citoplatino
    • Citosin
    • Cysplatyna
    • DDP
    • Lederplatin
    • Metaplatin
    • Neoplatin
    • Peyrone's Chloride
    • Peyrone's Salt
    • Placis
    • Plastistil
    • Platamine
    • Platiblastin
    • Platiblastin-S
    • Platinex
    • Platinol
    • Platinol- AQ
    • Platinol-AQ
    • Platinol-AQ VHA Plus
    • Platinoxan
    • Platinum
    • Platinum Diamminodichloride
    • Platiran
    • Platistin
    • Platosin
  • Drug: Crizotinib
    250 mg, orally, twice daily for four 3-week cycles (12 weeks in total)
    Other Names:
    • MET Tyrosine Kinase Inhibitor PF-02341066
    • PF-02341066
    • PF-2341066
    • Xalkori
  • Drug: Erlotinib
    150 mg, orally, once daily for four 3-week cycles (12 weeks in total)
    Other Names:
    • Cp-358,774
    • Erlotinib Hydrochloride
    • OSI-774
    • Tarceva
  • Drug: Etoposide
    50 mg/m2, IV, on days 1 and 8 of two 4-week cycles concurrent with radiation therapy. For patients receiving either erlotinib or crizotinib, etoposide will begin 2 weeks after the completion of erlotinib or crizotinib, as applicable.
    Other Names:
    • Demethyl Epipodophyllotoxin Ethylidine Glucoside
    • EPEG
    • Lastet
    • Toposar
    • Vepesid
    • VP 16-213
    • VP-16
    • VP-16-213
  • Drug: Paclitaxel

    Concurrent: 45 mg/m2, IV, days 1, 8, 14, 22, 29, and 36 of radiation therapy. For patients receiving either erlotinib or crizotinib, carboplatin will begin 2 weeks after erlotinib or crizotinib, as applicable.

    Consolidation: 4-6 weeks after completion of RT, 200 mg/m2, IV, days 1 and 22.

    Other Names:
    • Anzatax
    • Asotax
    • Bristaxol
    • Praxel
    • Taxol
    • Taxol Konzentrat
Study Arms  ICMJE
  • Experimental: EGFR: Erlotinib
    Induction erlotinib for 12 weeks followed by chemotherapy (either cisplatin/etoposide or paclitaxel/carboplatin) and radiation therapy. Patients who have had no response (partial or complete) after 6 weeks of induction therapy start chemoradiation therapy immediately.
    Interventions:
    • Radiation: Radiation Therapy
    • Drug: Carboplatin
    • Drug: Cisplatin
    • Drug: Erlotinib
    • Drug: Etoposide
    • Drug: Paclitaxel
  • Active Comparator: EGFR: No Erlotinib
    Chemotherapy (either cisplatin/etoposide or paclitaxel/carboplatin) and radiation therapy.
    Interventions:
    • Radiation: Radiation Therapy
    • Drug: Carboplatin
    • Drug: Cisplatin
    • Drug: Etoposide
    • Drug: Paclitaxel
  • Experimental: ALK: Crizotinib
    Induction crizotinib for 12 weeks followed by chemotherapy (either cisplatin/etoposide or paclitaxel/carboplatin) and radiation therapy. Patients who have had no response (partial or complete) after 6 weeks of induction therapy start chemoradiation therapy immediately.
    Interventions:
    • Radiation: Radiation Therapy
    • Drug: Carboplatin
    • Drug: Cisplatin
    • Drug: Crizotinib
    • Drug: Etoposide
    • Drug: Paclitaxel
  • Active Comparator: ALK: No Crizotinib
    Chemotherapy (either cisplatin/etoposide or paclitaxel/carboplatin) and radiation therapy.
    Interventions:
    • Radiation: Radiation Therapy
    • Drug: Carboplatin
    • Drug: Cisplatin
    • Drug: Etoposide
    • Drug: Paclitaxel
Publications * Not Provided

*   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 Terminated
Actual Enrollment  ICMJE
 (submitted: August 2, 2019)
59
Original Estimated Enrollment  ICMJE
 (submitted: April 1, 2013)
234
Actual Study Completion Date  ICMJE June 4, 2018
Actual Primary Completion Date June 4, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histologically or cytologically confirmed, newly diagnosed non-squamous NSCLC
  • Unresectable stage IIIA or IIIB disease; patients must be surgically staged to confirm N2 or N3 disease; patients may have invasive mediastinal staging by mediastinoscopy, mediastinotomy, endobronchial ultrasound transbronchial aspiration (EBUS-TBNA), endoscopic ultrasound (EUS), or video-assisted thoracoscopic surgery (VATS)
  • Patients with any tumor (T) with node (N)2 or N3 are eligible; patients with T3, N1-N3 disease are eligible if deemed unresectable; patients with T4, any N are eligible
  • Patients must have measurable disease, i.e., lesions that can be accurately measured in at least 1 dimension (longest dimension in the plane of measurement is to be recorded) with a minimum size of 10 mm by computed tomography (CT) scan (CT scan slice thickness no greater than 5 mm)
  • Patients with a pleural effusion, which is a transudate, cytologically negative and non-bloody, are eligible if the radiation oncologist feels the tumor can be encompassed within a reasonable field of radiotherapy
  • If a pleural effusion can be seen on the chest CT but not on chest x-ray and is too small to tap, the patient will be eligible; patients who develop a new pleural effusion after thoracotomy or other invasive thoracic procedure will be eligible
  • The institution's pre-enrollment biomarker screening at a Clinical Laboratory Improvement Amendments (CLIA) certified lab documents presence of known "sensitive" mutations in epidermal growth factor receptor tyrosine kinase (EGFR TK) domain (exon 19 deletion, L858) and/or EML4-anaplastic lymphoma kinase (ALK) fusion arrangement; either the primary tumor or the metastatic lymph node tissue may be used for testing of mutations
  • The institution's pre-enrollment biomarker screening at a CLIA certified lab documents absence of T790M mutation in the EGFR TK domain
  • Appropriate stage for protocol entry, including no distant metastases, based upon the following minimum diagnostic workup:

    • History/physical examination, including recording of pulse, blood pressure (BP), weight, and body surface area, within 45 days prior to registration
    • Whole body fludeoxyglucose-positron emission tomography (FDG-PET)/CT (orbits to mid-thighs) within 30 days prior to registration; PET/CT must be negative for distant metastasis
    • CT scan with contrast of the chest and upper abdomen to include liver and adrenals (unless medically contraindicated) within 30 days prior to registration
    • Magnetic resonance imaging (MRI) of the brain with contrast (or CT scan with contrast, if MRI medically contraindicated) within 30 days prior to registration
  • Zubrod performance status 0-1 within 14 days prior to registration
  • Absolute neutrophil count (ANC) >= 1,000 cells/mm^3
  • Platelets >= 100,000 cells/mm^3
  • Hemoglobin >= 8.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 8.0 g/dl is acceptable)
  • Serum creatinine < 1.5 mg/dL or calculated creatinine clearance >= 50 ml/min (by Cockcroft-Gault formula) within 14 days prior to registration
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN) within 14 days prior to registration
  • Bilirubin within normal institutional limits within 14 days prior to registration
  • Negative serum pregnancy test within 14 days prior to registration for women of childbearing potential
  • Patient must provide study specific informed consent prior to study entry, including consent for mandatory screening of tissue

Exclusion Criteria:

  • Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 730 days (2 years) (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible)
  • Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable
  • Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
  • Atelectasis of the entire lung
  • Contralateral hilar node involvement
  • Exudative, bloody, or cytologically malignant effusions
  • Severe, active co-morbidity, defined as follows:

    • Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
    • Transmural myocardial infarction within the last 6 months
    • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
    • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration; hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
    • Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol; protocol-specific requirements may also exclude immuno-compromised patients
  • Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception
  • Prior allergic reaction to the study drug(s) involved in this protocol
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 NCT01822496
Other Study ID Numbers  ICMJE NCI-2013-00737
NCI-2013-00737 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
RTOG-1306 ( Other Identifier: NRG Oncology )
RTOG-1306 ( Other Identifier: CTEP )
U10CA180868 ( U.S. NIH Grant/Contract )
U10CA021661 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE NRG Oncology
Investigators  ICMJE
Principal Investigator: Ramaswamy Govindan NRG Oncology
PRS Account National Cancer Institute (NCI)
Verification Date June 2019

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