Non Small Cell Lung Cancer
Conditions
Brief summary
The purpose of this study is to look for an improvement in progression free survival with the combination of bevacizumab, carboplatin and pemetrexed in patients with newly diagnosed advanced/metastatic non small cell lung cancer. Overall survival and safety will also be assessed.
Detailed description
Carboplatin: AUC 5 IV over 30-60 minutes on day 1 Pemetrexed: 500mg/M2 IV over 10 minutes on day 1 Bevacizumab: 15mg/kg IV over 90 minutes on day 1 (if rate is tolerated the 2nd dose may be decreased to 60 minutes and subsequent doses to 30 minutes This regimen will be administered every 6 weeks for up to a maximum of 6 cycles if the patient tolerates the treatment and has stable disease. Bevacizumab will be continues if tolerated for up to 1 year at every 3 week intervals. Folic acid 1mg by mouth daily, Vitamin B12 1000 ug IM every 9 weeks and Dexamethasone 4mg by mouth twice a day and and antiemetic may be prescribed by the physician investigator to help reduce side effects associated with the Pemetrexed. The Folic acid and Vitamin B12 will continue until 3 weeks after the end of treatment. Physical exams, vital signs and blood work will be done prior to each chemotherapy cycle. A urine dipstick to check for protein in the urine will be done prior to the first treatment and before cycles 3 and 5. A CAT scan of the chest will be done pretreatment, prior to cycles 3 and 5 and at the end of treatment.
Interventions
DRUGCarboplatin, Pemetrexed and Bevacizumab
Carboplatin AUC 5 IV day 1 over 30-60 minutes Pemetrexed 500 mg/M2 IV day 1 over 10 minutes Bevacizumab 15 mg /kg IV day over 90 minutes dose 1, 60 minutes dose 2, 30 minutes subsequent doses. Repeat every 3 weeks for total of 6 cycles
Sponsors
Eli Lilly and Company
Christiana Care Health Services
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Advanced stage NSCLC (IIIB with malignant pleural effusion; T4 \[on basis on satellite lesion\] N2, 3; or stage IV) excluding squamous cell histology, with measurable or evaluable disease. * Prior chemotherapy therapy for early stage disease with one regimen is acceptable if it was completed at least 6 months prior to study entry. * Palliative radiotherapy to painful bony metastases will be permitted prior to study entry if completed prior to initiation of study treatment, and there are no residual sequelae of therapy such as bone marrow suppression. * Life expectancy of at least 3 months. * ECOG Performance status 0-1. * Age 18 or higher. * Willingness to use appropriate contraception to avoid pregnancy during the study (female patient or female partner of a male patient) * Patients must have normal organ and marrow function as defined below: leukocytes greater than or equal to3,000/µl ANC greater than or equal to 1,500/µl platelets greater than or equal to 100,000/µl total bilirubin within normal institutional limits AST(SGOT)/ALT(SGPT) ≤ 2.5 x institutional upper limit of normal creatinine within normal institutional limits OR creatinine clearance ≥ 45 mL/min/1.73 m2 for patients with creatinine levels above institutional normal * Ability to sign informed consent * Ability to take folic acid, Vitamin B12 and dexamethasone as per protocol * Ability to interrupt NSAIDS 2 days before (5 days for long-acting NSAIDs), the day of, and 2 days following administration of Alimta.
Exclusion criteria
Patients meeting any of the following criteria are ineligible for study entry: * Prior cytotoxic treatment for advanced NSCLC. One prior regimen (up to 4 cycles) of neoadjuvant or adjuvant therapy for early stage disease will be allowed if completed at least 6 months prior to study entry. * Prior definitive chest irradiation (radiation of rib or spine mets permitted) * Known brain metastases (unless previously resected and radiated) * Prior treatment with bevacizumab or pemetrexed * History of allergic reactions or sensitivity attributed to compounds of similar chemical or biologic composition to bevacizumab or carboplatin * Current, recent (within 4 weeks of the first infusion of this study), or planned participation in any other experimental drug study. * Concomitant chemotherapy, radiotherapy or investigational agents. * Evidence of bleeding diathesis or coagulopathy. * Use of anti-coagulant agents warfarin (1mg, by mouth, daily for port maintenance permitted), heparin (ASA, NSAID permitted). * Pregnant (positive pregnancy test) or lactating women. * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, anticipation of need for major surgical procedure during the course of the study. * Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to day 0. * Urine protein creatinine ratio 1.0 at screening. -History of abdominal fistula, gastrointestinal perforation, or intra- abdominal abscess within 6 months prior to Day 0. * Serious, non-healing wound, ulcer, or bone fracture. * Lung carcinoma of squamous cell histology or any histology in close proximity to a major vessel, or with significant cavitation as assessed by treating investigator in consultation with an attending radiologist. -Recent history of hemoptysis (bright red blood of 1/2 teaspoon or more)- within one month of study entry * Significant co-morbidities including: Blood pressure of 150/100 mmHg Unstable angina New York Heart Association (NYHA) Grade II or greater congestive heart failure (see Appendix B) History of myocardial infarction within 6 months History of stroke within 6 months Clinically significant peripheral vascular disease * Psychiatric illness/social situations that would limit compliance with study requirements. * Another active malignancy except for non-melanoma skin cancers. * Clinically significant pleural, pericardial, and/or peritoneal effusions unless drained or controlled prior to study entry. * Undrainable, clinically relevant effusions and presence of third space fluid which cannot be controlled by drainage. * Hepatic impairment as evidenced by Bilirubin greater than 1.5 times the upper limit of normal Transaminases greater than 3.0 times limit of normal (ULN), except in presence of known hepatic metastasis, wherein may be up to 5 times ULN * Any CTCAE Version 3.0 Grade 3 or 4 non hematologic toxicity
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1 year). | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1 year). |
| Overall Survival | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1 year). | Overal survival was defined as time between the date of treatment assignment and the date of death |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Complete and Partial Tumor Responses | Patients were enrolled over a 24 month period for treatment visits. After end of treatment visits, subjects were seen or contacted every 3 months for survival data. Median follow up was 49 weeks (6 weeks to death. | A complete response (CR),was disappearance of all target lesions on CT scan and absence of appearance of any new lesion was required. Partial response (PR) was assessed by at least a 30% decrease in the sum of the longest diameter (LD) of target lesions without appearance of any new lesions. Progressive disease (PD) was defined as at least a 20% increase in the sum of the LD of target lesions or the appearance of one or more new lesions. Patients were assessed to have stable disease if neither sufficient decrease to qualify for PR nor sufficient increase to qualify for PD, without appearance of new lesions. Patients who received one or more cycles were evaluable for response. |
| Number of Participants With Adverse Events | Subjects were seen or contacted every 3 months with medain follow up of 49 weeks. | Measured by adverse events such as grade 4 toxicities, hospitalizations for toxicities, fever and neutropenia events, and clinically significant bleeding/thrombotic events. |
Participant flow
Recruitment details
Between November 2007 and March 2012, 50 patients were enrolled in the phase II trial of carboplatin, pemetrexed and bevacizumab. Patients were enrolled over a 24month period.
Pre-assignment details
Carboplatin, Penetrexed and Bevacizumab in Advanced Non-Squamous Non-Small Cell Lung Cancer
Participants by arm
| Arm | Count |
|---|---|
| Carboplatin, Bevacicumab, Premetrexed Patients (age \>18yo) were from 2007 to 2012.. Measurable disease Evaluable disease Stage IV Palliative RT NO brain metastases | 50 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
Baseline characteristics
| Characteristic | Carboplatin, Bevacicumab, Premetrexed |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 24 Participants |
| Age, Categorical Between 18 and 65 years | 26 Participants |
| ECOG Performance ECOG Performance Staus Scale 0 | 6 Participants |
| ECOG Performance ECOG Performance Stsus Scale =1 | 44 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 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 | 0 Participants |
| Race (NIH/OMB) White | 45 Participants |
| Sex: Female, Male SEX Female | 24 Participants |
| Sex: Female, Male SEX Male | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 50 |
| other Total, other adverse events | 3 / 50 |
| serious Total, serious adverse events | 4 / 50 |
Outcome results
Primary
Overall Survival
Overal survival was defined as time between the date of treatment assignment and the date of death
Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1 year).
Population: Nonsquamous stage IV disease, Male, Female,\>18 years of age, white, african american,with ECOG of 0 or 1
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carboplatin, Bevacicumab, Premetrexed | Overall Survival | 49 weeks |
Primary
Progression Free Survival
From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1 year).
Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1 year).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carboplatin, Bevacicumab, Premetrexed | Progression Free Survival | 28 weeks |
Secondary
Number of Participants With Adverse Events
Measured by adverse events such as grade 4 toxicities, hospitalizations for toxicities, fever and neutropenia events, and clinically significant bleeding/thrombotic events.
Time frame: Subjects were seen or contacted every 3 months with medain follow up of 49 weeks.
Population: four patients discontinued treatment because of treatment related adverse events.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Carboplatin, Bevacicumab, Premetrexed | Number of Participants With Adverse Events | Thrombocytopenia | 1 Participants |
| Carboplatin, Bevacicumab, Premetrexed | Number of Participants With Adverse Events | Respiratory distress | 1 Participants |
| Carboplatin, Bevacicumab, Premetrexed | Number of Participants With Adverse Events | Grade 3 diarrhea | 1 Participants |
| Carboplatin, Bevacicumab, Premetrexed | Number of Participants With Adverse Events | fatigue | 1 Participants |
Secondary
Number of Participants With Complete and Partial Tumor Responses
A complete response (CR),was disappearance of all target lesions on CT scan and absence of appearance of any new lesion was required. Partial response (PR) was assessed by at least a 30% decrease in the sum of the longest diameter (LD) of target lesions without appearance of any new lesions. Progressive disease (PD) was defined as at least a 20% increase in the sum of the LD of target lesions or the appearance of one or more new lesions. Patients were assessed to have stable disease if neither sufficient decrease to qualify for PR nor sufficient increase to qualify for PD, without appearance of new lesions. Patients who received one or more cycles were evaluable for response.
Time frame: Patients were enrolled over a 24 month period for treatment visits. After end of treatment visits, subjects were seen or contacted every 3 months for survival data. Median follow up was 49 weeks (6 weeks to death.
Population: Number of Participants with Complete and Partial Tumor Responses
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Carboplatin, Bevacicumab, Premetrexed | Number of Participants With Complete and Partial Tumor Responses | Complete Response | 1 Participants |
| Carboplatin, Bevacicumab, Premetrexed | Number of Participants With Complete and Partial Tumor Responses | Partial Response | 27 Participants |