Lung Cancer
Conditions
Keywords
recurrent non-small cell lung cancer, stage IIIB non-small cell lung cancer, stage IV non-small cell lung cancer, adenocarcinoma of the lung, bronchoalveolar cell lung cancer, large cell lung cancer
Brief summary
RATIONALE: Drugs used in chemotherapy, such as carboplatin and pemetrexed disodium, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Pemetrexed disodium may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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 tumor cells by blocking blood flow to the tumor. Giving carboplatin and pemetrexed disodium together with bevacizumab may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving carboplatin and pemetrexed disodium together with bevacizumab works in treating patients with stage IIIB, stage IV, or recurrent non-small cell lung cancer.
Detailed description
OBJECTIVES: Primary * Determine the median time to disease progression in patients with stage IIIB or IV or recurrent non-squamous cell non-small cell lung cancer treated with carboplatin, pemetrexed disodium, and bevacizumab. Secondary * Determine the response rate and duration of response in patients treated with this regimen. * Determine the toxic effects of this regimen in these patients. * Determine the overall survival of patients treated with this regimen. OUTLINE: This is a multicenter study. Patients receive pemetrexed disodium IV over 10 minutes, carboplatin IV over 30 minutes, and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients with complete response, partial response, or stable disease continue to receive pemetrexed disodium and bevacizumab in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 3 years. PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.
Interventions
BIOLOGICALbevacizumab
5 mg/kg administered intravenously over 90 minutes on day 1 of each cycle (cycle = 3 weeks)
DRUGcarboplatin
Administered intravenously at a dose of AUC=6 over 30 minutes on day 1 of each cycle (1 cycle = 3 weeks)
DRUGpemetrexed
Administered intravenously at a dose of 500 mg/m2 over 10 minutes on day 1 of each cycle (1 cycle = 3 weeks)
Sponsors
National Cancer Institute (NCI)
Northwestern University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically\* or cytologically\* confirmed non-small cell lung cancer * Any histology, except squamous cell carcinoma, allowed * Mixed tumors will be categorized by the predominant cell type unless small cell elements are present, in which case the patient is ineligible * No histology in close proximity to a major vessel or cavitation NOTE: \*Histologic or cytologic elements may be established on metastatic tumor aspirates or biopsy * Meets 1 of the following stage criteria: * Stage IIIB disease (with malignant pleural effusion) * Stage IV disease * Recurrent disease * Measurable or non-measurable disease * No known CNS metastases by CT scan or MRI PATIENT CHARACTERISTICS: Age * 18 and over Performance status * ECOG 0-1 Life expectancy * Not specified Hematopoietic * Absolute neutrophil count \> 1,500/mm\^3 * Platelet count \> 100,000/mm\^3 * No history of hemorrhagic disorders Hepatic * Bilirubin \< 1.5 mg/dL * AST and ALT \< 5 times upper limit of normal * INR \< 1.5 * PTT normal Renal * Creatinine clearance ≥ 45 mL/min * Urine protein:creatinine ≤ 1.0 by spot urinalysis Cardiovascular * No myocardial infarction within the past 6 months * No New York Heart Association class II-IV congestive heart failure * No unstable angina pectoris * No serious cardiac arrhythmia requiring medication * No stroke within the past 6 months * No peripheral vascular disease ≥ grade 2 * No uncontrolled hypertension (i.e., blood pressure ≥ 150/100 mm Hg) * Patients with a history of hypertension allowed provided blood pressure is well controlled on a stable regimen of anti-hypertensive therapy * No history of thrombotic disorders * No other clinically significant cardiovascular disease Pulmonary * No history of gross hemoptysis, defined as bright red blood of a ½ teaspoon or more Other * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * Must be willing and able to take daily oral folic acid, intermittent vitamin B\_12 injections, and corticosteroid premedication * No ongoing or active infection * No serious, non-healing wound, ulcer, or bone fracture * No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months * No psychiatric illness or social situation that would preclude study compliance PRIOR CONCURRENT THERAPY: Biologic therapy * More than 3 weeks since prior immunotherapy Chemotherapy * No prior systemic chemotherapy Endocrine therapy * More than 3 weeks since prior hormonal therapy Radiotherapy * See Disease Characteristics * More than 3 weeks since prior radiotherapy Surgery * More than 4 weeks since prior major surgery * More than 1 week since prior minor surgery, fine needle aspiration, or core biopsy * No concurrent major surgery Other * Recovered from all prior therapy * More than 4 weeks since prior and no concurrent participation in another experimental drug study * No aspirin or other nonsteroidal anti-inflammatory drug (NSAID) 2 days before and 2 days after each pemetrexed disodium infusion (5 days before and 2 days after each pemetrexed disodium infusion for NSAIDs with a long half-life \[e.g., naproxen, rofecoxib, or celecoxib\]) * No concurrent therapeutic anticoagulation * Concurrent prophylactic anticoagulation for venous access devices allowed provided requirements for INR and PTT are met * No concurrent administration of any of the following: * Chronic daily treatment with aspirin (\> 325 mg per day) * NSAIDs known to inhibit platelet function, including any of the following: * Dipyridamole * Ticlopidine * Clopidogrel * Cilostazol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression Free Survival | Approximately every 3 weeks until disease progression or death. Median follow up of 13 months (range 0.8 to 34.4 months) | Progression Free Survival (PFS) in patients treated with the combination of carboplatin, pemetrexed and bevacizumab is defined as the time from registration to the time of documented disease progression or death from any cause. Patients that were lost to follow up or withdrew consent were censored at that point. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | Every two cycles until disease progression. Median follow up of 13 months (range 0.8 to 34.4 months) | Overall Response Rate (ORR) of patients treated with carboplatin, pemetrexed, and bevacizumab combination is defined as the number of patients who's best response is a Complete Response (CR) plus Partial Response (PR)as recorded from the start of treatment until disease progression as assessed by RECIST 1.0. CR=Disappearance of all target lesions for a minimum of 4 weeks. PR=At least a 30% decrease in the sum of the longest diameter (LD) of target lesions for a minimum of 4 weeks, taking as reference the baseline sum LD. No simultaneous increase in the size of any lesion or the appearance of a new lesion may occur. |
| Toxicity of Carboplatin, Pemetrexed and Bevacizumab Combination Treatment | From treatment initiation, at the beginning of each cycle where one cycle equals 21 days until 30 days post treatment (range of cycles 1-51) | To characterize the toxicity profile of carboplatin, pemetrexed and bevacizumab combination treatment. Toxicity data will be collected from initiation of treatment, every cycle, until 30 days post last treatment. Adverse events will be graded according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 3.0 (CTCAE v3.0). Only toxicity determined to be a least possibility related to at least one study drug and grade 3 or 4 was collected for this outcome measure. In general adverse events (AEs) will be graded according to the following: 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 Rate | During treatment and then every 3 months x 2 years, then every 6 months x 3 years or until death. | Overall Survival (OS) Rate of carboplatin, pemetrexed and bevacizumab combination treatment is defined from the time of registration to the study until death from any cause. Patients that are lost to follow up will be censored from last documentation of survival status. |
| Duration of Response | From documentation of response, every two cycles (1 cycle = 21 days) until progressive disease with range of cycles completed 1-51. | Duration of Response for patients treated with the combination of carboplatin, pemetrexed and bevacizumab is measured from the time measurement criteria are met for Complete Response or Partial Response (whichever is first recorded) until the first date of documented progressive disease. |
Countries
United States
Participant flow
Recruitment details
The study opened for accrual on June 1, 2005 with an accrual goal of 50 patients. The first patient enrolled started treatment on July 28, 2005. The study was closed permanently on July 10, 2007 when accrual had been met with 51 patients registered and 50 patients treated on study.
Participants by arm
| Arm | Count |
|---|---|
| Treatment With Carboplatin + Pemetrexed + Bevacizumab Carboplatin + Pemetrexed + Bevacizumab
Patients will receive 6 cycles where (1 cycle is 21 days) of :
Bevacizumab: 15 mg/kg administered intravenously over 30 - 90 minutes on day 1 of each cycle Carboplatin: Administered intravenously at a dose of AUC=6 over 30 minutes on day 1 of each cycle Pemetrexed: Administered intravenously at a dose of 500 mg/m2 over 10 minutes on day 1 of each cycle
Patients without progression will go into the maintenance phase and receive cycles of the following where 1 cycle is 21 days:
Bevacizumab: 15 mg/kg administered intravenously over 30 - 90 minutes on day 1 of each cycle Pemetrexed: Administered intravenously at a dose of 500 mg/m2 over 10 minutes on day 1 of each cycle | 51 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Follow-up for 5 Years | Death | 41 |
| Follow-up for 5 Years | Lost to Follow-up | 1 |
| Follow-up for 5 Years | Other | 7 |
| Treatment | Adverse Event | 5 |
| Treatment | Death | 2 |
| Treatment | Progressive Disease | 11 |
| Treatment | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Treatment With Carboplatin + Pemetrexed + Bevacizumab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 23 Participants |
| Age, Categorical Between 18 and 65 years | 28 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 41 Participants |
| Region of Enrollment United States | 51 participants |
| Sex: Female, Male Female | 28 Participants |
| Sex: Female, Male Male | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 41 / 50 |
| other Total, other adverse events | 50 / 50 |
| serious Total, serious adverse events | 22 / 50 |
Outcome results
Primary
Median Progression Free Survival
Progression Free Survival (PFS) in patients treated with the combination of carboplatin, pemetrexed and bevacizumab is defined as the time from registration to the time of documented disease progression or death from any cause. Patients that were lost to follow up or withdrew consent were censored at that point.
Time frame: Approximately every 3 weeks until disease progression or death. Median follow up of 13 months (range 0.8 to 34.4 months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment With Carboplatin + Pemetrexed + Bevacizumab | Median Progression Free Survival | 7.8 Months |
Secondary
Duration of Response
Duration of Response for patients treated with the combination of carboplatin, pemetrexed and bevacizumab is measured from the time measurement criteria are met for Complete Response or Partial Response (whichever is first recorded) until the first date of documented progressive disease.
Time frame: From documentation of response, every two cycles (1 cycle = 21 days) until progressive disease with range of cycles completed 1-51.
Population: Patients with response were included in this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment With Carboplatin + Pemetrexed + Bevacizumab | Duration of Response | 7.7 Months |
Secondary
Overall Response Rate
Overall Response Rate (ORR) of patients treated with carboplatin, pemetrexed, and bevacizumab combination is defined as the number of patients who's best response is a Complete Response (CR) plus Partial Response (PR)as recorded from the start of treatment until disease progression as assessed by RECIST 1.0. CR=Disappearance of all target lesions for a minimum of 4 weeks. PR=At least a 30% decrease in the sum of the longest diameter (LD) of target lesions for a minimum of 4 weeks, taking as reference the baseline sum LD. No simultaneous increase in the size of any lesion or the appearance of a new lesion may occur.
Time frame: Every two cycles until disease progression. Median follow up of 13 months (range 0.8 to 34.4 months)
Population: One patient received less than one cycle and was determined to not be evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment With Carboplatin + Pemetrexed + Bevacizumab | Overall Response Rate | 27 Participants |
Secondary
Overall Survival Rate
Overall Survival (OS) Rate of carboplatin, pemetrexed and bevacizumab combination treatment is defined from the time of registration to the study until death from any cause. Patients that are lost to follow up will be censored from last documentation of survival status.
Time frame: During treatment and then every 3 months x 2 years, then every 6 months x 3 years or until death.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment With Carboplatin + Pemetrexed + Bevacizumab | Overall Survival Rate | 14.1 Months |
Secondary
Toxicity of Carboplatin, Pemetrexed and Bevacizumab Combination Treatment
To characterize the toxicity profile of carboplatin, pemetrexed and bevacizumab combination treatment. Toxicity data will be collected from initiation of treatment, every cycle, until 30 days post last treatment. Adverse events will be graded according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 3.0 (CTCAE v3.0). Only toxicity determined to be a least possibility related to at least one study drug and grade 3 or 4 was collected for this outcome measure. In general adverse events (AEs) will be graded according to the following: 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
Time frame: From treatment initiation, at the beginning of each cycle where one cycle equals 21 days until 30 days post treatment (range of cycles 1-51)
Population: This includes AEs observed before there was an amendment of the protocol to exclude patients with histories of diverticulitis or clinically significant diverticular disease. Any patient that received one dose of study drug is evaluable for this objective.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment With Carboplatin + Pemetrexed + Bevacizumab | Toxicity of Carboplatin, Pemetrexed and Bevacizumab Combination Treatment | Anemia | 3 Participants |
| Treatment With Carboplatin + Pemetrexed + Bevacizumab | Toxicity of Carboplatin, Pemetrexed and Bevacizumab Combination Treatment | Thrombocytopenia | 4 Participants |
| Treatment With Carboplatin + Pemetrexed + Bevacizumab | Toxicity of Carboplatin, Pemetrexed and Bevacizumab Combination Treatment | Neutropenia | 2 Participants |
| Treatment With Carboplatin + Pemetrexed + Bevacizumab | Toxicity of Carboplatin, Pemetrexed and Bevacizumab Combination Treatment | Venous Thrombosis | 3 Participants |
| Treatment With Carboplatin + Pemetrexed + Bevacizumab | Toxicity of Carboplatin, Pemetrexed and Bevacizumab Combination Treatment | Fatigue | 4 Participants |
| Treatment With Carboplatin + Pemetrexed + Bevacizumab | Toxicity of Carboplatin, Pemetrexed and Bevacizumab Combination Treatment | Diverticulitis | 4 Participants |
| Treatment With Carboplatin + Pemetrexed + Bevacizumab | Toxicity of Carboplatin, Pemetrexed and Bevacizumab Combination Treatment | Infection | 5 Participants |
| Treatment With Carboplatin + Pemetrexed + Bevacizumab | Toxicity of Carboplatin, Pemetrexed and Bevacizumab Combination Treatment | Proteinuria | 1 Participants |
| Treatment With Carboplatin + Pemetrexed + Bevacizumab | Toxicity of Carboplatin, Pemetrexed and Bevacizumab Combination Treatment | Arterial Thrombosis | 1 Participants |
| Treatment With Carboplatin + Pemetrexed + Bevacizumab | Toxicity of Carboplatin, Pemetrexed and Bevacizumab Combination Treatment | Increased Creatinine Levels | 1 Participants |
Post Hoc
Overall Survival Rate at 6, 12, 18, and 24 Months
Overall Survival (OS) Rate of carboplatin, pemetrexed and bevacizumab combination treatment will be defined as the percentage of patients with documentation of status of alive at the following timepoints from registration to the study: 6 months 12 months 18 months 24 months
Time frame: 6, 12,18, and 24 months from treatment initiation
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment With Carboplatin + Pemetrexed + Bevacizumab | Overall Survival Rate at 6, 12, 18, and 24 Months | 6 Months | 86 percentage of patients alive |
| Treatment With Carboplatin + Pemetrexed + Bevacizumab | Overall Survival Rate at 6, 12, 18, and 24 Months | 12 Months | 61 percentage of patients alive |
| Treatment With Carboplatin + Pemetrexed + Bevacizumab | Overall Survival Rate at 6, 12, 18, and 24 Months | 18 Months | 38 percentage of patients alive |
| Treatment With Carboplatin + Pemetrexed + Bevacizumab | Overall Survival Rate at 6, 12, 18, and 24 Months | 24 Months | 26 percentage of patients alive |
Post Hoc
Progression Free Survival at 6, 12, 18, 24 Months
Progression Free Survival (PFS) Rate of carboplatin, pemetrexed and bevacizumab combination treatment is defined as the percentage of patients without progression at the following time points from registration to the study: 6 months 12 months 18 months 24 months.
Time frame: 6, 12,18, and 24 months from treatment initiation
Population: One patient received less than one cycle and was determined to not be evaluable for this objective.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment With Carboplatin + Pemetrexed + Bevacizumab | Progression Free Survival at 6, 12, 18, 24 Months | 6 Months | 59 percentage of patients with PFS |
| Treatment With Carboplatin + Pemetrexed + Bevacizumab | Progression Free Survival at 6, 12, 18, 24 Months | 12 Months | 34 percentage of patients with PFS |
| Treatment With Carboplatin + Pemetrexed + Bevacizumab | Progression Free Survival at 6, 12, 18, 24 Months | 18 Months | 27 percentage of patients with PFS |
| Treatment With Carboplatin + Pemetrexed + Bevacizumab | Progression Free Survival at 6, 12, 18, 24 Months | 24 Months | 19 percentage of patients with PFS |