Non-Small Cell Lung Cancer
Conditions
Keywords
Non-Small Cell Lung Cancer
Brief summary
The primary objective is to determine the progression free survival with pemetrexed, and gemcitabine plus bevacizumab as first-line chemotherapy in elderly patients with Stage IIIB/IV non-small cell lung cancer (NSCLC). The secondary objectives are to determine the overall response rate; overall survival; chemotherapy induced toxicity profile of this combination; time to progression; and patient reported symptom burden.
Interventions
DRUGPemetrexed and Gemcitabine plus Bevacizumab
Bevacizumab 10 mg/kg will be given intravenously according to weight. Pemetrexed 500 mg/m\^2 and gemcitabine 1500 mg/m\^2 will be given intravenously according to weight and height. All agents are administered every 2 weeks.
Sponsors
Eli Lilly and Company
Genentech, Inc.
Accelerated Community Oncology Research Network
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient provides voluntary written informed consent before performance of any study-related procedure not part of normal medical care. * Patient ≥ 65 years of age with ECOG of 0 to 1 * Patient must have histologically/cytologically confirmed Stage IIIB/IV NSCLC. * Patient has measurable disease defined as at least 1 lesion that can be accurately measured in at least 1 dimension (by CT or MRI) & used to assess response as defined by RECIST criteria. Tumors within a previously irradiated field will be designated nontarget lesions. * Patient has not received radiotherapy within 2 weeks(4 weeks required for brain metastases radiotherapy)of initial chemotherapy dosing for this study, and all acute toxicities due to prior radiotherapy have resolved prior to initial chemotherapy dosing. * Patient has a negative serum pregnancy test or has undergone hysterectomy at time of enrollment. * Greater than 12 weeks life expectancy. * Patient has recovered from any recent surgery for at least 30 days & is free of active infection requiring antibiotics. * Patient must be willing/able to discontinue use of NSAIDS prior to study drug dosing. * Patient must be able to take folic acid, Vitamin B12, & dexamethasone per protocol. * Patient must exhibit no greater than Grade 1 peripheral neuropathy.
Exclusion criteria
* Prior systemic or other concurrent chemo for metastatic NSCLC(Prior Tarceva is not allowed).Prior adjuvant chemo acceptable as long as \> 12 months since completion and no prior pemetrexed, gemcitabine or bevacizumab. * Lung carcinoma of squamous cell histology(mixed tumors will be categorized by the predominant cell type unless small cell elements are present, in which case the patient is ineligible; sputum cytology alone is acceptable.Patients with extrathoracic-only squamous cell NSCLC are eligible.Patients with only peripheral lung lesions (of any NSCLC histology) will also be eligible(a peripheral lesion is defined as a lesion in which the epicenter of the tumor is ≤ 2 cm from the costal or diaphragmatic pleura in a three-dimensional orientation based on each lobe of the lung and is \> 2 cm from the trachea, main, and lobar bronchi). * Hemoptysis within 1 month prior to study enrollment * Ongoing treatment with full-dose warfarin or its equivalent i.e., unfractionated and/or low molecular weight heparin.(Low dose warfarin 1 mg given for prophylaxis is allowed). * Hypersensitivity to any component of Alimta, gemcitabine &/or bevacizumab, &/or cannot tolerate folic acid, corticosteroids or Vitamin B12 supplements. * Currently/have recently taken long-acting NSAID (Ibuprofen ≤ 400 mg QID acceptable) or aspirin (\>325mg/day) within 5 days of initial pemetrexed administration. * Clinically significant pericardial/pleural effusion or ascites unless able to be drained before study entry. * Presence of third space fluid which cannot be controlled by drainage. * Core biopsy/other minor surgical procedure(excluding placement of a vascular access device)within 7 days prior to study enrollment. * Active infection or fever ≥ 38.5°C within 3 days of first scheduled day of protocol treatment. * Serious, non-healing wound, ulcer, or untreated bone fracture. * NYHA Grade II or greater CHF * Inadequately controlled hypertension (defined as systolic blood pressure \> 150 &/or diastolic blood pressure \> 100mmHg on antihypertensive meds) * Any prior history of hypertensive crisis or hypertensive encephalopathy. * History of MI, CVA, TIA, or unstable angina within 6 months of study enrollment. * Significant vascular disease (aortic aneurysm, aortic dissection or recent peripheral arterial thrombosis.) * Symptomatic peripheral vascular disease * Known bleeding diathesis or coagulopathy * Presence of CNS(central nervous system) except for treated brain metastases. Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging(MRI or CT)during the screening period.Anticonvulsants(stable dose)are allowed.Treatment for brain metastases may include whole brain radiotherapy(WBRT),radiosurgery(RS;Gamma Knife,LINAC,or equivalent)or a combination as deemed appropriate by the treating physician.Radiotherapy must be completed at least 4 weeks prior to study enrollment and all acute radiotherapy toxicities resolved.Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 will be excluded. * A major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 or anticipation of need for major surgical procedure during the course of the study. * Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to enrollment. * History of prior malignancy within the past 5 years except for curatively treated basal cell carcinoma of the skin, cervical intra-epithelial neoplasia, or localized prostate cancer with a current prostate specific antigen of \< 1.0 mg/dL on 2 successive evaluations, at least 3 months apart, with the most recent evaluation no more than 4 weeks prior to entry. * Have received radiotherapy to more than 25% of their bone marrow. * Receiving concurrent investigational therapy or has received investigational therapy within 30 days of the first scheduled day of protocol treatment * Pregnant/lactating. * Any other medical condition deemed by the Investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate/participate in the study, or interfere with interpretation of the results. * History of allogeneic transplant. * Known HIV infection or Hepatitis B or C.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | PFS was measured from day 1 of treatment until time of progression (assessed every 8 weeks) or death, whichever came first, assessed up to 15 months. | PFS is defined as the duration of time from start of treatment to time of progression or death, whichever comes first. Progression is defined per RECIST criteria v1.0 as a measurable increase in the smallest diameter of any target lesion, progression of existing non-target lesions, or the appearance of 1 or more new lesions. The median progression free survival is the parameter used to describe PFS. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression (TTP) | TTP was measured from day 1 of treatment until time of progression (assessed every 8 weeks), assessed up to 15 months. | Time to progression is defined as the time from treatment start until objective tumor progression. Progression is defined per RECIST criteria v1.0 as a measurable increase in the smallest diameter of any target lesion, progression of existing non-target lesions, or the appearance of 1 or more new lesions. The median time to progression is the parameter used to describe TTP. |
| Overall Survival (OS) | OS was measured from day 1 of treatment until time of death, assessed up to 20 months. | Overall survival is defined as the time from treatment start until death from any cause. The median overall survival time is used to measure OS. |
| Overall Response | Response to treatment was assessed after every 8 weeks of treatment, up to 50 weeks. | Response was evaluated via changes from baseline in radiological tumor measurements performed after every 4th treatment cycle and at the end of treatment or time of progression. Response was evaluated using RECIST version 1.0 guidelines, where complete response (CR) is the disappearance of all target lesions; partial response (PR) is \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD) is neither sufficient shrinkage in sum of LD of target lesions to be PR nor increase of \>=20%; Progressive Disease (PD) is the increase in existing lesions or new lesions. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) by Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status | PFS was measured from day 1 of treatment until time of progression (assessed every 8 weeks) or death, whichever came first, assessed up to 15 months. | PFS is defined as the duration of time from start of treatment to time of progression or death, whichever comes first. The median progression free survival is the parameter used to describe PFS. ECOG performance status describes how daily living activities of the patient are affected by disease. ECOG of 0 means the patient is fully active without restriction. ECOG of 1 means the patient is restricted in physically strenuous activity but is able to carry out light work. The investigator assigned the ECOG score at baseline (i.e., before the patient started study treatment). |
| Overall Survival (OS) by Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status | OS was measured from day 1 of treatment until time of death, assessed up to 20 months. | Overall survival is defined as the time from treatment start until death from any cause. The median overall survival time is used to measure OS. ECOG performance status describes how daily living activities of the patient are affected by disease. ECOG of 0 means the patient is fully active without restriction. ECOG of 1 means the patient is restricted in physically strenuous activity but is able to carry out light work. The investigator assigned the ECOG score at baseline (i.e., before the patient started study treatment). |
Countries
United States
Participant flow
Recruitment details
9 community oncology research sites across the US within the ACORN network participated in this study. Enrollment started in August 2007 and was completed in September 2009.
Pre-assignment details
Informed consent was obtained from all subjects. All subjects underwent screening procedures to verify eligibility.
Participants by arm
| Arm | Count |
|---|---|
| Pemetrexed, Gemcitabine, and Bevacizumab All subjects received treatment with pemetrexed 500 mg/m\^2, gemcitabine 1500 mg/m\^2, and bevacizumab 10 mg/kg every 2 weeks. | 48 |
| Total | 48 |
Baseline characteristics
| Characteristic | Pemetrexed, Gemcitabine, and Bevacizumab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 48 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age Continuous | 72.60 years STANDARD_DEVIATION 5.2 |
| Region of Enrollment United States | 48 participants |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 46 / 48 |
| serious Total, serious adverse events | 26 / 48 |
Outcome results
Primary
Progression Free Survival (PFS)
PFS is defined as the duration of time from start of treatment to time of progression or death, whichever comes first. Progression is defined per RECIST criteria v1.0 as a measurable increase in the smallest diameter of any target lesion, progression of existing non-target lesions, or the appearance of 1 or more new lesions. The median progression free survival is the parameter used to describe PFS.
Time frame: PFS was measured from day 1 of treatment until time of progression (assessed every 8 weeks) or death, whichever came first, assessed up to 15 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed, Gemcitabine, and Bevacizumab | Progression Free Survival (PFS) | 4.90 Months |
Secondary
Overall Response
Response was evaluated via changes from baseline in radiological tumor measurements performed after every 4th treatment cycle and at the end of treatment or time of progression. Response was evaluated using RECIST version 1.0 guidelines, where complete response (CR) is the disappearance of all target lesions; partial response (PR) is \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD) is neither sufficient shrinkage in sum of LD of target lesions to be PR nor increase of \>=20%; Progressive Disease (PD) is the increase in existing lesions or new lesions.
Time frame: Response to treatment was assessed after every 8 weeks of treatment, up to 50 weeks.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pemetrexed, Gemcitabine, and Bevacizumab | Overall Response | Partial response (PR) | 17 Participants |
| Pemetrexed, Gemcitabine, and Bevacizumab | Overall Response | Not evaluable (NE) | 4 Participants |
| Pemetrexed, Gemcitabine, and Bevacizumab | Overall Response | Complete response (CR) | 0 Participants |
| Pemetrexed, Gemcitabine, and Bevacizumab | Overall Response | Stable disease (SD) | 21 Participants |
| Pemetrexed, Gemcitabine, and Bevacizumab | Overall Response | Progressive disease (PD) | 6 Participants |
Secondary
Overall Survival (OS)
Overall survival is defined as the time from treatment start until death from any cause. The median overall survival time is used to measure OS.
Time frame: OS was measured from day 1 of treatment until time of death, assessed up to 20 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed, Gemcitabine, and Bevacizumab | Overall Survival (OS) | 8.78 Months |
Secondary
Time to Progression (TTP)
Time to progression is defined as the time from treatment start until objective tumor progression. Progression is defined per RECIST criteria v1.0 as a measurable increase in the smallest diameter of any target lesion, progression of existing non-target lesions, or the appearance of 1 or more new lesions. The median time to progression is the parameter used to describe TTP.
Time frame: TTP was measured from day 1 of treatment until time of progression (assessed every 8 weeks), assessed up to 15 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed, Gemcitabine, and Bevacizumab | Time to Progression (TTP) | 5.56 Months |
Other Pre-specified
Overall Survival (OS) by Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status
Overall survival is defined as the time from treatment start until death from any cause. The median overall survival time is used to measure OS. ECOG performance status describes how daily living activities of the patient are affected by disease. ECOG of 0 means the patient is fully active without restriction. ECOG of 1 means the patient is restricted in physically strenuous activity but is able to carry out light work. The investigator assigned the ECOG score at baseline (i.e., before the patient started study treatment).
Time frame: OS was measured from day 1 of treatment until time of death, assessed up to 20 months.
Population: Note that N=18 patients for the Baseline ECOG performance status 0 group, and N=30 patients for the Baseline ECOG performance status 1 group.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pemetrexed, Gemcitabine, and Bevacizumab | Overall Survival (OS) by Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline ECOG performance status 0 (N=18) | 19.87 Months |
| Pemetrexed, Gemcitabine, and Bevacizumab | Overall Survival (OS) by Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline ECOG performance status 1 (N=30) | 6.71 Months |
Comparison: Within Group 1 (N=48), patients with an ECOG of 0 at baseline (N=18) were compared to patients with an ECOG of 1 at baseline (N=30).p-value: 0.0041Log Rank
Other Pre-specified
Progression Free Survival (PFS) by Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status
PFS is defined as the duration of time from start of treatment to time of progression or death, whichever comes first. The median progression free survival is the parameter used to describe PFS. ECOG performance status describes how daily living activities of the patient are affected by disease. ECOG of 0 means the patient is fully active without restriction. ECOG of 1 means the patient is restricted in physically strenuous activity but is able to carry out light work. The investigator assigned the ECOG score at baseline (i.e., before the patient started study treatment).
Time frame: PFS was measured from day 1 of treatment until time of progression (assessed every 8 weeks) or death, whichever came first, assessed up to 15 months.
Population: Note that N=18 patients for the Baseline ECOG performance status 0 group, and N=30 patients for the Baseline ECOG performance status 1 group.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pemetrexed, Gemcitabine, and Bevacizumab | Progression Free Survival (PFS) by Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline ECOG performance status 0 (N=18) | 7.57 Months |
| Pemetrexed, Gemcitabine, and Bevacizumab | Progression Free Survival (PFS) by Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline ECOG performance status 1 (N=30) | 4.67 Months |
Comparison: Within Group 1 (N=48), patients with an ECOG of 0 at baseline (N=18) were compared to patients with an ECOG of 1 at baseline (N=30).p-value: 0.02Log Rank