Clinical trial NCT00334815: Combination Chemotherapy, Radiation Therapy, and Bevacizumab in Treating Patients With Newly Diagnosed Stage III Non-small Cell Lung Cancer That Cannot Be Removed by Surgery
Official title: A Pilot Trial of Cisplatin/Etoposide/Radiotherapy Followed by Consolidation Docetaxel and the Addition of Bevacizumab (NSC-704865) in Three Cohorts of Patients With Inoperable Locally Advanced Stage III Non-small Cell Lung Cancer
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Lung Adenocarcinoma
Lung Adenosquamous Carcinoma
Lung Large Cell Carcinoma
Lung Squamous Cell Carcinoma
Minimally Invasive Lung Adenocarcinoma
Stage IIIA Lung Non-Small Cell Cancer AJCC v7
Stage IIIB Lung Non-Small Cell Cancer AJCC v7
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2006-06-08
Enrollment: 29
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This clinical trial studies combination chemotherapy, radiation therapy, and bevacizumab in treating patients with newly diagnosed stage III non-small cell lung cancer that cannot be removed by surgery. Drugs used in chemotherapy, such as cisplatin, etoposide, and docetaxel, work in different ways to stop the growth of \[cancer/tumor\] cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving more than one drug (combination chemotherapy) together with radiation therapy and bevacizumab may kill more tumor cells.

Detailed description: PRIMARY OBJECTIVES:

I. Determine the frequency and severity of toxic effects of induction therapy comprising cisplatin, etoposide, and radiotherapy with or without bevacizumab followed by consolidation therapy comprising docetaxel and bevacizumab, in terms of grade 4 or 5 hemorrhage, in patients with newly diagnosed, unresectable, stage III non-small cell lung cancer.

SECONDARY OBJECTIVES:

I. Determine progression-free and overall survival of patients treated with these regimens.

II. Determine response (confirmed, unconfirmed, partial, and complete) in patients with measurable disease treated with these regimens.

OUTLINE: This is a pilot, multicenter study. Patients are stratified according to risk (high\* vs low).

NOTE: \*High-risk stratum closed to accrual as of 2/20/09.

INDUCTION THERAPY: Patients in each stratum are assigned to 1 of 3 sequential treatment groups.

GROUP 1: Patients receive cisplatin intravenously (IV) over 1 hour on days 1, 8, 29, and 36 and etoposide IV over 1 hour on days 1-5 and 29-33. Patients undergo concurrent thoracic radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40, and 43-47.

GROUP 2: Patients receive cisplatin, etoposide, and thoracic radiotherapy as in group 1. Patients also receive bevacizumab IV over 30-90 minutes on days 15, 36, and 57.

GROUP 3: Patients receive cisplatin, etoposide, and thoracic radiotherapy as in group 1. Patients also receive bevacizumab IV over 30-90 minutes on days 1, 22, and 43.

CONSOLIDATION CHEMOTHERAPY: Beginning 3-6 weeks after completion of induction therapy, all patients receive consolidation chemotherapy comprising docetaxel IV over 1 hour and bevacizumab IV over 30-90 minutes on day 1. Patients also receive filgrastim (G-CSF) subcutaneously (SC) beginning on day 2 and continuing until blood counts recover OR pegfilgrastim SC once on day 2.

Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically for up to 4 years.

Eligibility criteria: Inclusion Criteria:

* Histologically or cytologically confirmed single, primary, bronchogenic, non-small cell lung cancer (NSCLC)

  * Newly diagnosed disease
  * Unresectable disease
  * No more than 1 parenchymal lesions on same or opposite sides of the lungs
* Meets 1 of the following stage criteria:

  * Stage IIIA (N2) disease meeting the following criteria:

    * N2 mediastinal lymph nodes must be multiple and/or bulky on CT scan or x-ray so that the patient is not a candidate for induction chemotherapy or chemoradiotherapy followed by surgical resection
    * N2 status must be documented by ≥ 1 of the following methods:

      * Histologically or cytologically confirmed N2 disease by exploratory thoracotomy, thoracoscopy, mediastinoscopy, mediastinotomy, Chamberlain procedure, Wang needle biopsy (WNB), fine needle aspiration (FNA) under bronchoscopic or CT guidance, or any other method
      * Node positive by fludeoxyglucose-positron emission tomography (FDG-PET) scan
      * Nodes \> 3 cm on CT scan
      * Paralyzed left true vocal cord with separate left lung primary distinct from anterior-posterior window nodes on CT scan
  * Stage IIIB disease meeting ≥ 1 of the following criteria:

    * Histologically or radiographically confirmed positive N3 nodes\*, documented by ≥ 1 of the following methods:

      * FNA, core needle biopsy (CNB), or excisional biopsy of supraclavicular N3 nodes
      * Biopsy of contralateral mediastinal N3 nodes by mediastinoscopy, mediastinotomy, or thoracotomy
      * FNA, CNB, or WNB under CT or bronchoscopic fluoroscopic guidance of enlarged contralateral N3 mediastinal nodes
      * Contralateral mediastinal nodes \> 3 cm on CT scan
      * Node positivity by FDG-PET scan
      * Right-sided primary with paralyzed left true vocal cord
    * T4 lesions of any size that invade the mediastinum, heart, great vessels, trachea, esophagus, vertebral body, or carina, documented by ≥ 1 of the following methods:

      * Written documentation of type of T4 extent if patient had a prior exploratory thoracotomy or thoracoscopy
      * T4 involvement of the trachea or carina by direct bronchoscopic visualization
      * T4 involvement of the heart, esophagus, aorta, or vertebral body by CT scan, MRI, or transesophageal ultrasound
      * T4 involvement of the mediastinum by CT scan or MRI if, in the absence of the above organ involvement, there is soft tissue extension directly into the mediastinal space\*\*
* Meets 1 of the following risk criteria:

  * Low risk disease, meeting the following criteria:

    * Non-squamous cell NSCLC, including adenocarcinoma, bronchoalveolar cell carcinoma, or large cell carcinoma

      * If mixed histology, the squamous cell carcinoma component must be \< 50%
      * Histology or cytology from involved mediastinal or supraclavicular lymph nodes allowed if a separate distal primary lesion is clearly evident on radiographs (i.e., second biopsy not required)
    * No primary tumor with cavitation and/or tumor within 1 cm of a major vessel
    * No hemoptysis (i.e., bright red blood ≥ ½ teaspoon) in the past 28 days
  * High-risk\* disease, meeting ≥ 1 of the following criteria:

    * Squamous cell NSCLC

      * If mixed histology, the squamous cell component must be ≥ 50%
    * Tumor with any histology that has cavitation or is located within 1 cm of a major vessel

      * No aortic involvement
    * Any histology and hemoptysis (i.e., bright red blood ≥ ½ teaspoon) within past 28 days
* Measurable or nonmeasurable disease by CT scan or MRI

  * Pleural effusions, ascites, and laboratory parameters are not acceptable as the only evidence of disease
* No pleural effusion except for small pleural effusion visible on CT scan or MRI alone
* No pericardial effusions
* No metastatic disease involving the contralateral chest, liver, or adrenals confirmed by CT scan of the upper abdomen or by chest CT scan with complete liver and adrenals in the report
* Patients must be offered participation in SWOG-S9925 (Lung Cancer Specimen Repository Protocol)
* No brain metastases by CT scan or MRI
* No evidence of cavitation
* Creatinine normal
* Creatinine clearance ≥ 50 mL/min
* FEV_1 ≥ 2.0 liters OR predicted FEV_1 of the contralateral lung \> 800 mL
* Absolute neutrophil count ≥ 1,500/mm\^3
* Platelet count ≥ 100,000/mm\^3
* Urine protein: creatinine ratio ≤ 0.5 by urinalysis OR urine protein \< 1,000 mg by 24-hour urine collection
* INR \< 1.5
* Zubrod performance status 0-1
* No sensory neuropathy \> grade 1
* No cerebrovascular accident within the past 6 months
* No myocardial infarction or unstable angina within the past 6 months
* No uncontrolled hypertension
* No New York Heart Association class II-IV congestive heart failure
* No serious cardiac arrhythmia requiring medication
* No clinically significant peripheral vascular disease
* No evidence of bleeding diathesis or coagulopathy
* No pathologic condition other than lung cancer that carries a high risk of bleeding
* No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
* No serious, nonhealing wound, ulcer, or bone fracture
* No other prior malignancy except adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer for which the patient is currently in complete remission, or other cancer for which the patient has been disease-free for 5 years
* Not pregnant or nursing

  * No nursing during and for ≥ 6 months after the last dose of bevacizumab
* Negative pregnancy test
* Fertile patients must use effective contraception during and for ≥ 6 months after the last dose of bevacizumab
* Must have pre-treatment simulation demonstrating a V20 ≤ 35% with planned radiation dose of 6,480 cGy
* No prior surgical resection

  * Prior exploratory thoracotomy, mediastinoscopy, excisional biopsy, or similar surgery allowed for diagnosing, staging, or determining potential resectability of lung tumor
* No prior chemotherapy or radiotherapy for lung cancer
* No prior radiotherapy to the neck or thorax
* At least 4 weeks since prior thoracic or other major surgery (excluding mediastinoscopy) and recovered
* More than 7 days since prior FNA, CNB, or mediastinoscopy
* No other concurrent anticancer therapy, including chemotherapy, radiotherapy, or biologic agents
* No other concurrent investigational drugs
* No concurrent major surgical procedures
* No concurrent full-dose anticoagulants (e.g., low-molecular weight and unfractionated heparin or warfarin)

  * Low-dose warfarin (i.e., 1 mg) is allowed to prevent clotting of an infusaport or central line
* No concurrent brachytherapy, radiopharmaceuticals, high linear energy transfer radiation (i.e., fast neutrons), particle therapy (i.e., protons, carbon, or helium), and/or altered fractionation schemes
* No concurrent intensity-modulated radiotherapy
* No concurrent prophylactic contralateral hilar or supraclavicular lymph node radiotherapy

Primary outcomes:
measure: Adverse Events
timeFrame: Up to one year
Secondary outcomes:
measure: Progression-free Survival
timeFrame: Disease assessments were performed every 10 weeks as long as the patient remained on protocol treatment, up to 4 years.
measure: Overall Survival
timeFrame: Every week, up to 4 years
measure: Response Rate (Confirmed or Unconfirmed Partial Response)
timeFrame: Response assessment occured at the end of CRT and docetaxel/bevacizumab and then every 2-3 months for 2 years and then every 6 months until 4 years after the initial registration
Other outcomes:
Locations:
city: Mobile
country: United States
facility: Providence Hospital
state: Alabama
city: Jonesboro
country: United States
facility: Saint Bernards Regional Medical Center
state: Arkansas
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Rogers
country: United States
facility: Highlands Oncology Group - Rogers
state: Arkansas
city: Los Angeles
country: United States
facility: USC / Norris Comprehensive Cancer Center
state: California
city: Marysville
country: United States
facility: Fremont - Rideout Cancer Center
state: California
city: Orange
country: United States
facility: UC Irvine Health/Chao Family Comprehensive Cancer Center
state: California
city: Sacramento
country: United States
facility: University of California Davis Comprehensive Cancer Center
state: California
city: Santa Rosa
country: United States
facility: Providence Santa Rosa Memorial Hospital
state: California
city: Truckee
country: United States
facility: Gene Upshaw Memorial Tahoe Forest Cancer Center
state: California
city: Vacaville
country: United States
facility: Northbay Cancer Center
state: California
city: Aurora
country: United States
facility: Rocky Mountain Regional VA Medical Center
state: Colorado
city: Aurora
country: United States
facility: UCHealth University of Colorado Hospital
state: Colorado
city: Denver
country: United States
facility: Denver Health Medical Center
state: Colorado
city: Denver
country: United States
facility: University of Colorado
state: Colorado
city: Edwards
country: United States
facility: Shaw Cancer Center
state: Colorado
city: Glenwood Springs
country: United States
facility: Valley View Hospital Cancer Center
state: Colorado
city: Montrose
country: United States
facility: Montrose Memorial Hospital
state: Colorado
city: Leesburg
country: United States
facility: Cancer Centers of Central Florida PA
state: Florida
city: Savannah
country: United States
facility: Lewis Cancer and Research Pavilion at Saint Joseph's/Candler
state: Georgia
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Naperville
country: United States
facility: Edward Hospital/Cancer Center
state: Illinois
city: Hays
country: United States
facility: HaysMed
state: Kansas
city: Hutchinson
country: United States
facility: Hutchinson Regional Medical Center
state: Kansas
city: Kansas City
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Olathe
country: United States
facility: Olathe Cancer Center
state: Kansas
city: Salina
country: United States
facility: Salina Regional Health Center
state: Kansas
city: Topeka
country: United States
facility: University of Kansas Health System Saint Francis Campus
state: Kansas
city: Shreveport
country: United States
facility: LSU Health Sciences Center at Shreveport
state: Louisiana
city: Shreveport
country: United States
facility: Highland Clinic
state: Louisiana
city: Brighton
country: United States
facility: Steward Saint Elizabeth's Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State University/Karmanos Cancer Institute
state: Michigan
city: Mount Clemens
country: United States
facility: McLaren Cancer Institute-Macomb
state: Michigan
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Kansas City
country: United States
facility: Kansas City Veterans Affairs Medical Center
state: Missouri
city: Billings
country: United States
facility: Montana Cancer Consortium NCORP
state: Montana
city: Great Falls
country: United States
facility: Benefis Sletten Cancer Institute
state: Montana
city: Elmira
country: United States
facility: Arnot Ogden Medical Center/Falck Cancer Center
state: New York
city: Rochester
country: United States
facility: Highland Hospital
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Charlotte
country: United States
facility: Novant Health Presbyterian Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Southeast Clinical Oncology Research Consortium NCORP
state: North Carolina
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Portland
country: United States
facility: Portland VA Medical Center
state: Oregon
city: Charleston
country: United States
facility: Roper Hospital
state: South Carolina
city: Kingsport
country: United States
facility: Wellmont Holston Valley Hospital and Medical Center
state: Tennessee
city: Memphis
country: United States
facility: University of Tennessee Health Science Center
state: Tennessee
city: Amarillo
country: United States
facility: The Don and Sybil Harrington Cancer Center
state: Texas
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Audie L Murphy VA Hospital
state: Texas
city: San Antonio
country: United States
facility: Cancer Therapy and Research Center at The UT Health Science Center at San Antonio
state: Texas
city: San Antonio
country: United States
facility: University Hospital
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Danville
country: United States
facility: Danville Regional Medical Center
state: Virginia
city: Norton
country: United States
facility: Ballad Health Cancer Care - Norton
state: Virginia
city: Auburn
country: United States
facility: MultiCare Auburn Medical Center
state: Washington
city: Centralia
country: United States
facility: Providence Regional Cancer System-Centralia
state: Washington
city: Federal Way
country: United States
facility: Saint Francis Hospital
state: Washington
city: Lakewood
country: United States
facility: Saint Clare Hospital
state: Washington
city: Olympia
country: United States
facility: Providence - Saint Peter Hospital
state: Washington
city: Puyallup
country: United States
facility: MultiCare Good Samaritan Hospital
state: Washington
city: Tacoma
country: United States
facility: MultiCare Allenmore Hospital
state: Washington
city: Tacoma
country: United States
facility: Saint Joseph Medical Center
state: Washington
Study officials:
affiliation: SWOG Cancer Research Network
name: Antoinette J Wozniak
role: PRINCIPAL_INVESTIGATOR
References: