Clinical trial NCT00280150: Combination Chemotherapy, Bev, RT, and Erlotinib in Treating Patients With Stage III Non-Small Cell Lung Cancer
Official title: Phase I/II Trial of Induction Carboplatin/Paclitaxel With Bevacizumab Followed by Concurrent Thoracic Conformal Radiation Therapy With Carboplatin/Paclitaxel, Bevacizumab and Erlotinib in Stage IIIA/B Non-Small Cell Lung Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Lung Cancer
Keywords: stage IIIA non-small cell lung cancer
stage IIIB non-small cell lung cancer
recurrent non-small cell lung cancer
squamous cell lung cancer
Lead sponsor: UNC Lineberger Comprehensive Cancer Center
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
name: Eli Lilly and Company
First posted: 2006-01-20
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: 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 or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of non-small cell lung cancer by blocking blood flow to the tumor. Radiation therapy uses high energy x-rays to kill tumor cells. Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving combination chemotherapy together with bevacizumab, radiation therapy, and erlotinib may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of bevacizumab and erlotinib when given together with combination chemotherapy and radiation therapy and to see how well they work in treating patients with stage III non-small cell lung cancer.

Detailed description: OBJECTIVES:

Primary

* Determine the maximum tolerated dose of bevacizumab and erlotinib hydrochloride when given together with carboplatin, paclitaxel, and thoracic conformal radiotherapy in patients with stage IIIA or IIIB non-small cell lung cancer. (Phase I \[closed to accrual as of 1/3/2008\])
* Determine the safety and toxicity profile of this regimen in these patients. (Phase I \[closed to accrual as of 1/3/2008\])
* Determine the progression-free survival of patients treated with induction therapy comprising carboplatin, paclitaxel, and bevacizumab followed by chemoradiotherapy comprising thoracic conformal radiotherapy, carboplatin, paclitaxel, bevacizumab, and erlotinib hydrochloride and consolidation therapy comprising bevacizumab and erlotinib hydrochloride. (Phase II)
* Determine the overall toxicity profile of this regimen in these patients. (Phase II)

Secondary

* Determine the response rate in patients treated with induction therapy comprising carboplatin, paclitaxel, and bevacizumab. (Phase I\[closed to accrual as of 1/3/2008\] and II)
* Determine the toxicity profile of induction therapy in these patients. (Phase I \[closed to accrual as of 1/3/2008\] and II)
* Determine the overall response rate and survival profile in patients treated with this regimen. (Phase I \[closed to accrual as of 1/3/2008\] and II)
* Determine the feasibility and tolerability of administering consolidation therapy comprising erlotinib hydrochloride and bevacizumab after treatment with combined modality therapy (induction therapy and chemoradiotherapy) in these patients. (Phase I \[closed to accrual as of 1/3/2008\] and II)
* Collect tumor and blood samples from these patients for future analysis of correlation between molecular markers and clinical benefit. (Phase I \[closed to accrual as of 1/3/2008\] and II)

OUTLINE: This is a nonrandomized, open-label, controlled, phase I (closed to accrual as of 1/3/2008), dose-escalation study of bevacizumab and erlotinib hydrochloride, followed by a phase II study.

* Phase I (closed to accrual as of 1/3/2008):

  * Induction therapy: Patients receive paclitaxel IV over 3 hours, carboplatin IV over 15-30 minutes, and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 2 courses. Patients with stable or responding disease proceed to chemoradiotherapy.
  * Chemoradiotherapy: Patients receive chemoradiotherapy according to their assigned dose cohort:

    * Cohort 1: Patients undergo thoracic conformal radiotherapy (TCRT) on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40, and 43-47. Patients also receive carboplatin IV and paclitaxel IV on days 1, 8, 15, 22, 29, 36, and 43 and bevacizumab IV over 30-90 minutes on days 1, 15, 29, and 43.
    * Cohort 2: Patients undergo TCRT and receive carboplatin, paclitaxel, and bevacizumab as in cohort 1. Patients also receive oral erlotinib hydrochloride on days 2-5, 9-12, 16-19, 23-26, 30-33, 37-40, and 44-47.
    * Cohort 3: Patients undergo TCRT and receive carboplatin, paclitaxel, and bevacizumab as in cohort 1. Patients also receive higher doses of oral erlotinib hydrochloride on days 2-5, 9-12, 16-19, 23-26, 30-33, 37-40, and 44-47.

Cohorts of 5 patients receive chemoradiotherapy as described above until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 (with grade 4 toxicity) or 3 (with grade 3 toxicity) of 5 patients experience dose-limiting toxicity.

Three to 6 weeks after completion of chemoradiotherapy, patients proceed to consolidation therapy.

* Consolidation therapy: Patients receive bevacizumab IV on day 1 and oral erlotinib hydrochloride on days 1-21. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

  * Phase II:
* Induction therapy: Patients receive induction therapy as in phase I (closed to accrual as of 1/3/2008).
* Chemoradiotherapy: Patients undergo TCRT and receive carboplatin and paclitaxel as in phase I (closed to accrual as of 1/3/2008). Patients also receive bevacizumab and erlotinib hydrochloride as in phase I (closed to accrual as of 1/3/2008) at the MTD/drug combination determined in phase I (closed to accrual as of 1/3/2008).
* Consolidation therapy: Patients receive consolidation therapy as in phase I (closed to accrual as of 1/3/2008).

Tumor tissue and peripheral blood is collected at baseline for future correlative and biomarker studies.

After completion of study therapy, patients are followed every 2 months for 2 years, every 4 months for 2 years, every 6 months for 2 years, and then annually thereafter.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Diagnosis of non-small cell lung cancer

  * Stage IIIA or IIIB disease
  * No malignant pleural or pericardial effusions
  * No palpable supraclavicular adenopathy
* Squamous cell histology allowed provided there is no hemoptysis and no central invasive lesions that abut or invade major blood vessels in the chest (with or without cavitation)
* Considered suitable and appropriate for combined modality therapy and thoracic conformal radiotherapy, as determined by the treating medical and radiation oncologist

PATIENT CHARACTERISTICS:

* Eastern Cooperative Oncology Group (ECOG) performance status 0-1
* Hemoglobin ≥ 9.0 mg/dL
* Platelet count ≥ 100,000/mm³
* Absolute neutrophil count (ANC) ≥ 1,500/mm³
* Forced expiratory volume 1 (FEV_1) ≥ 1 L
* Creatinine ≤ 1.5 times upper limit of normal (ULN)
* Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≤ 2.5 times ULN
* Bilirubin normal
* Partial thromboplastin time (PTT) and international normalized ratio (INR) normal
* Urine protein:creatinine ratio \< 1.0
* Blood pressure ≤ 150/100 mm Hg on 3 separate occasions
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* No significant recent hemoptysis (\> ½ teaspoon of bright red blood)
* No unstable angina
* No New York Heart Association (NYHA) congestive heart failure ≥ class II
* No myocardial infarction or stroke within the past 6 months
* No clinically significant peripheral vascular disease
* No evidence of bleeding diathesis or coagulopathy
* No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
* No serious, non-healing wound, ulcer, or bone fracture
* No thrombosis requiring therapeutic anticoagulation
* No significant traumatic injury within the last 28 days

PRIOR CONCURRENT THERAPY:

* Recovered from prior surgery
* At least 4 weeks since prior and no concurrent participation in another experimental drug study
* At least 4 weeks since prior and no concurrent major surgical procedure or open biopsy
* At least 2 weeks since prior mediastinoscopy or mediastinotomy
* At least 1 week since prior fine needle aspirations or core biopsies
* No other concurrent antineoplastic or antitumor agents, including chemotherapy, radiotherapy, immunotherapy, or hormonal anticancer therapy
* No other concurrent investigational agents

Primary outcomes:
measure: Maximum Dose of Erlotinib When Given Together With Carboplatin, Paclitaxel, and Thoracic Conformal Radiotherapy (Phase I [Closed to Accrual as of 1/3/2008])
timeFrame: 6 weeks after completion of therapy
measure: Safety and Toxicity Profile of Combining Both Bevacizumab and Erlotinib Hydrochloride With Carboplatin, Paclitaxel, and Thoracic Conformal Radiotherapy
timeFrame: 6 weeks after completion of therapy
Secondary outcomes:
measure: Progression-free Survival (PFS)
timeFrame: 5 years
measure: Response Rate to Induction Therapy (Phase I [Closed to Accrual as of 1/3/2008] and II)
timeFrame: 5 years
measure: Overall Response Rate and Survival Profile
timeFrame: 5 years
measure: Feasibility and Tolerability of Administering Consolidation Therapy
timeFrame: 6 cycles
Other outcomes:
Locations:
city: Chapel Hill
country: United States
facility: Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
state: North Carolina
city: Concord
country: United States
facility: Batte Cancer Center at Northeast Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Comprehensive Cancer Center
state: North Carolina
Study officials:
affiliation: UNC Lineberger Comprehensive Cancer Center
name: Thomas Stinchcombe, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of North Carolina, Chapel Hill
name: Thomas A. Stinchcombe, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Socinski MA, Stinchcombe TE, Moore DT, Gettinger SN, Decker RH, Petty WJ, Blackstock AW, Schwartz G, Lankford S, Khandani A, Morris DE. Incorporating bevacizumab and erlotinib in the combined-modality treatment of stage III non-small-cell lung cancer: results of a phase I/II trial. J Clin Oncol. 2012 Nov 10;30(32):3953-9. doi: 10.1200/JCO.2012.41.9820. Epub 2012 Oct 8.