Pemetrexed, Carboplatin, and Bevacizumab as First-Line Therapy in Treating Older Patients With Stage IIIB or Stage IV Non-Small Cell Lung Cancer

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy, such as carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Pemetrexed may 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. Giving pemetrexed together with carboplatin and bevacizumab may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving pemetrexed together with carboplatin and bevacizumab works as first-line therapy in treating older patients with stage IIIB or stage IV non-small cell lung cancer.

Detailed Description
-----------------
OBJECTIVES: Primary To estimate the progression-free survival at 6 months in elderly patients with advanced nonsquamous cell non-small cell lung cancer treated with pemetrexed disodium, carboplatin, and bevacizumab as first-line therapy. Secondary To assess the adverse events profile and safety of this regimen in these patients. To estimate the confirmed antitumor response rate, as defined by RECIST criteria, and the overall survival of these patients. To compare the quality of life (QOL) of patients treated with this regimen vs the QOL of younger patients. To correlate QOL with toxicities, as defined by NCI CTCAE v3.0 criteria. Tertiary To evaluate polymorphisms in the genes that encode proteins involved in the cellular transport, activation, and cytotoxic activity of pemetrexed disodium and evaluate their relationship with treatment toxicity/efficacy and patient QOL. To evaluate polymorphisms in the genes involved in blood pressure regulation and their relationship with susceptibility to hypertension induced by anti-VEGF therapy. 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 up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with stable disease or partial or complete response after 6 courses may continue to receive pemetrexed disodium and bevacizumab every 21 days in the absence of disease progression or unacceptable toxicity. Tissue and blood samples are collected at baseline for pharmacogenetic analysis. Blood samples are used to evaluate functionally relevant polymorphisms in the genes that encode proteins involved in the transport and activation of pemetrexed disodium and in the genes that encode proteins involved in susceptibility to hypertension induced by bevacizumab. Tissue samples are used to evaluate expression and polymorphisms in pemetrexed disodium target genes (TS, DHFR, and GARFT). Quality of life is assessed at baseline and periodically during study. After completion of study therapy, patients are followed periodically for up to 5 years.

Official Title
-----------------
A Phase II First-Line Study of a Combination of Pemetrexed, Carboplatin and Bevacizumab in Advanced Nonsquamous NSCLC Evaluating Efficacy and Tolerability in Elderly Patients (Age ≥ 70 Yrs) With Good Performance Status (PS < 2)

Conditions
-----------------
Lung Cancer

Intervention / Treatment
-----------------
* Biological: bevacizumab
* Drug: carboplatin
* Drug: pemetrexed disodium


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically or cytologically confirmed nonsquamous cell non-small cell lung cancer (NSCLC) Stage IIIB (with pleural effusion) or IV disease Squamous cell carcinomas not allowed Adenosquamous histology allowed Clinically significant effusion (e.g., symptomatic pleural effusion or ascites) allowed provided it is drained before study treatment No symptomatic pleural and/or peritoneal effusion (≥ grade 2 dyspnea, as defined by NCI CTCAE v3.0 criteria) that is not amenable to drainage If effusion produces clinically significant measurable objective changes, such as hypoxia or estimated volume > 500 mL, effusion should be drained even if asymptomatic Measurable disease, defined as ≥ 1 lesion with longest diameter ≥ 2.0 cm by conventional techniques or ≥ 1.0 cm by spiral CT scan If the sole site of disease is in a previously irradiated field, must have evidence of disease progression/recurrence within the irradiated field OR presence of a new lesion outside the irradiated field No symptomatic, untreated, or uncontrolled CNS metastases CNS metastases that were previously treated with whole brain radiotherapy (WBRT) allowed Willing to enroll in NCCTG-N0392 PATIENT CHARACTERISTICS: ECOG performance status 0-1 Life expectancy ≥ 12 weeks ANC ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Hemoglobin ≥ 9 g/dL Total bilirubin ≤ 1.5 times upper limit of normal (ULN) OR direct bilirubin normal AST and ALT ≤ 3 times ULN (≤ 5 times ULN if liver has tumor involvement) Creatinine clearance ≥ 45 mL/min Not pregnant or nursing Fertile patients must use effective contraception during and for 3 months after completion of study treatment Able to take folic acid, vitamin B_12 supplementation, or dexamethasone Able to complete questionnaire(s) alone or with assistance Willing to provide biologic specimens as required by the study Willing to return to NCCTG participating center for follow-up No clinically significant infection No serious, nonhealing wounds, ulcers, or bone fractures No seizure disorder No second primary malignancy within the past 5 years, except for any of the following: Carcinoma in situ of the cervix Nonmelanomatous skin cancer History of melanoma allowed only if diagnosed and definitively treated ≥ 5 years ago with no subsequent evidence of recurrence Low-grade (Gleason score ≤ 6) localized prostate cancer (no nodal involvement) Previously treated stage I breast cancer No concurrent severe and/or uncontrolled medical condition, including any of the following: Hypertension, labile hypertension, or history of poor compliance with antihypertensive medication Angina pectoris Congestive heart failure within the past 3 months, unless ejection fraction > 40% Myocardial infarction within the past 6 months Cardiac arrhythmia Diabetes mellitus Interstitial pneumonia or extensive, symptomatic interstitial fibrosis of the lung Active or recent history of hemoptysis > ½ teaspoon per event Ongoing or active infection Psychiatric illness/social situation that would limit compliance with study requirements No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 12 months No diverticulitis within the past 12 months No stroke within the past 6 months No significant traumatic injury within the past 8 weeks Not at greater than normal risk of bleeding PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior radiotherapy to > 25% of bone marrow More than 2 weeks since prior radiotherapy and recovered (alopecia allowed) At least 2 weeks since prior WBRT At least 3 days since prior gamma knife radiosurgery (without WBRT) for brain metastases More than 4 weeks since prior administration of live or attenuated viral vaccine More than 8 weeks since prior major surgery (e.g., laparotomy) or open biopsy (> 4 weeks since minor surgery) Insertion of a vascular access device allowed No prior chemotherapy or systemic therapy for advanced lung cancer, except neoadjuvant or adjuvant chemotherapy No NSAID's 2 days prior to (5 days for long-acting NSAID's), the day of, and 2 days following protocol treatment More than 12 months since prior neoadjuvant therapy, adjuvant therapy, systemic chemotherapy, chemoradiotherapy, immunotherapy, or biologic therapy No concurrent anticoagulants Low-dose warfarin or heparin for deep venous thrombosis prophylaxis allowed

Ages Eligible for Study
-----------------
Minimum Age: 70 Years
Maximum Age: 120 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: pemetrexed + carboplatin + bevacizumab<br>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 up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with stable disease or partial or complete response after 6 courses may continue to receive pemetrexed disodium and bevacizumab every 21 days in the absence of disease progression or unacceptable toxicity. | Biological: bevacizumab<br> <br> Drug: carboplatin<br> <br> Drug: pemetrexed disodium<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival at 6 Months | Estimated using the Binomial point estimator (number of successes divided by the total number of evaluable patients). A patient is classified as a success if alive and progression-free at 6 months. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Confirmed Tumor Response Defined as an Objective Status of Complete Response or Partial Response on Two Consecutive Evaluations | Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria: Complete Response (CR): disappearance of all target and non-target lesions and no new lesions. Partial Response (PR): disappearance of all target lesions, persistence of one or more non-target lesions, and no new lesions; or at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD, no appearance of one/more new lesions, unequivocal progression of existing non-target lesions, and no new lesions. | Duration of study until progression (up to 5 years) | 
| Duration of Response | Duration of response for responders was defined as the time from the date of the first objective status assessment of a confirmed CR or PR to the first date of disease progression. Duration of response will be censored at the date of last post-therapy follow-up visit for responders who have not had disease progression. Duration of response will be calculated for all evaluable patients who have achieved an objective confirmed response. | Up to 5 years | 
| Number of Grade 3 or Higher Adverse Events Occurring in >=10% of Patients | Adverse events were assessed by Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grading: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening, Grade 5=Death. | Up to 2.5 years | 
| Time to Treatment Failure | Time to treatment failure was defined to be the time from date of registration to the date at which the patient is removed from the treatment due to progression, toxicity, refusal or death from any cause. | Up to 5 years | 
| Progression-free Survival | Progression-free survival was defined as the time from study enrollment to the first date of disease progression or death as a result of any cause, whichever occurs first. Progression-free survival will be censored at the date of the last contact for patients who are still alive and who have not had disease progression. | Up to 5 years | 
| Overall Survival | Overall survival was defined as the time from study enrollment to the time of death from any cause. Overall survival will be censored at the date of the last follow-up visit for patients who are still alive or lost to follow-up. | Up to 5 years | 
| Change From Baseline to Cycle 3 in Quality of Life (QOL) as Assessed by the Lung Cancer Symptom Scale | Lung Cancer Symptom Scale (LCSS) consist of 9 items that assess the symptoms of lung cancer during the past days on a 10-points scale with 0 as no symptoms and 10 as worse symptoms. The individual item score was translated onto a 0-100 point scale with lower values indicating worse symptoms. An average of the aggregate score of all 9 items was used for a total score. Change from baseline to cycle 3 was calculated by subtracting the baseline scores from the scores at cycle 3. | Baseline and Cycle 3 | 
| Change From Baseline to Cycle 5 in Quality of Life (QOL) as Assessed by the Lung Cancer Symptom Scale | Lung Cancer Symptom Scale (LCSS) consist of 9 items that assess the symptoms of lung cancer during the past days on a 10-points scale with 0 as no symptoms and 10 as worse symptoms. The individual item score was translated onto a 0-100 point scale with lower values indicating worse symptoms. An average of the aggregate score of all 9 items was used for a total score. Change from baseline to cycle 5 was calculated by subtracting the baseline scores from the scores at cycle 5. | Baseline and Cycle 5 | 
| Change From Baseline to Cycle 3 in Overall Quality of Life Assessed by Linear Analogue Self Assessment (LASA) | The overall quality of life (QOL) question was on a 10-points scale with 0=as bad as it can be and 10=as good as it can be. The QOL scores was translated onto a 0 to 100 point scale, with lower values indicating worse symptoms. Change from baseline to cycle 3 was calculated by subtracting the baseline scores from the scores at cycle 3. | Baseline and Cycle 3 | 
| Change From Baseline to Cycle 5 in Overall Quality of Life Assessed by Linear Analogue Self Assessment (LASA) | The overall quality of life (QOL) question was on a 10-points scale with 0=as bad as it can be and 10=as good as it can be. The QOL scores was translated onto a 0 to 100 point scale, with lower values indicating worse symptoms. Change from baseline to cycle 5 was calculated by subtracting the baseline scores from the scores at cycle 5. | Baseline and Cycle 5 | 
| Change From Baseline to Cycle 3 in Fatigue Assessed by Treatment-specific Adverse Events Scale | The single-item fatigue question was on a 10-points scale with 0=no fatigue and 10=as bad as you can imagine. The item scores was translated onto a 0 to 100 point scale, with lower values indicating worse symptoms. Change from baseline to cycle 3 was calculated by subtracting the baseline scores from the scores at cycle 3. | Baseline and Cycle 3 | 
| Change From Baseline to Cycle 5 in Fatigue Assessed by Treatment-specific Adverse Events Scale | The single-item fatigue question was on a 10-points scale with 0=no fatigue and 10=as bad as you can imagine. The item scores was translated onto a 0 to 100 point scale, with lower values indicating worse symptoms. Change from baseline to cycle 5 was calculated by subtracting the baseline scores from the scores at cycle 5. | Baseline and Cycle 5 | 
| Change From Baseline to Cycle 3 in Neuropathy Assessed by Treatment-specific Adverse Events Scale | The single-item neuropathy question was on a 10-points scale with 0=no numbness or tingling in fingers and toes and 10=worst numbness or tingling in fingers and toes imaginable. The item scores was translated onto a 0 to 100 point scale, with lower values indicating worse symptoms. Change from baseline to cycle 3 was calculated by subtracting the baseline scores from the scores at cycle 3. | Baseline and Cycle 3 | 
| Change From Baseline to Cycle 5 in Neuropathy Assessed by Treatment-specific Adverse Events Scale | The single-item neuropathy question was on a 10-points scale with 0=no numbness or tingling in fingers and toes and 10=worst numbness or tingling in fingers and toes imaginable. The item scores was translated onto a 0 to 100 point scale, with lower values indicating worse symptoms. Change from baseline to cycle 5 was calculated by subtracting the baseline scores from the scores at cycle 5. | Baseline and Cycle 5 | 
| Change From Baseline to Cycle 3 in Nausea Assessed by Treatment-specific Adverse Events Scale | The single-item nausea question was on a 10-points scale with 0=no nausea and 10=as bad as you can imagine. The item scores was translated onto a 0 to 100 point scale, with lower values indicating worse symptoms. Change from baseline to cycle 3 was calculated by subtracting the baseline scores from the scores at cycle 3. | Baseline and Cycle 3 | 
| Change From Baseline to Cycle 5 in Nausea Assessed by Treatment-specific Adverse Events Scale | The single-item nausea question was on a 10-points scale with 0=no nausea and 10=as bad as you can imagine. The item scores was translated onto a 0 to 100 point scale, with lower values indicating worse symptoms. Change from baseline to cycle 5 was calculated by subtracting the baseline scores from the scores at cycle 5. | Baseline and Cycle 5 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
stage IIIB non-small cell lung cancer, stage IV non-small cell lung cancer, recurrent non-small cell lung cancer, adenocarcinoma of the lung, adenosquamous cell lung cancer