Fulvestrant and Anastrozole as Consolidation Therapy in Postmenopausal Women With Advanced Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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This research study will test whether dual anti-estrogen therapy (anastrozole and fulvestrant) slows the time to when the cancer progresses.

Detailed Description
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Women invited to participate in this study must be post-menopausal and be 18 years of age or older. The study is being performed on a total of 100 individuals. Of this group, 75 will be in the Treatment Groups using Fulvestrant/Anastrozole with our without bevacizumab and 25 will be in the Best Supportive Care groups receiving no treatment or just bevacizumab at the University of Pittsburgh Medical Center.

Official Title
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A Phase II Randomized Trial of Fulvestrant and Anastrozole as Consolidation Therapy in Postmenopausal Women With Advanced Non-small Cell Lung Cancer Who Have Received First-line Platinum-based Chemotherapy With or Without Bevacizumab

Conditions
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Non-small Cell Lung Cancer, Postmenopausal Women

Intervention / Treatment
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* Drug: fulvestrant (Faslodex)
* Drug: anastrozole (Arimidex)
* Drug: Bevacizumab (Avastin)
* Drug: Best supportive care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic or cytologic diagnosis of non-small cell lung cancer (NSCLC) (no component of small cell). Patients must have stage IIIB (with malignant pleural effusion), stage IV NSCLC (as staged by the AJCC Cancer Staging Manual. 6th ed, appendix 1) or stage IV NSCLC as staged by the new AJCC staging system Patients with recurrent NSCLC should have recurred 12 months or more after completion of prior chemotherapy given in the context of curative therapy (chemoradiotherapy or adjuvant therapy) are eligible Patients should have been treated with 4 cycles of induction chemotherapy utilizing the following regimens: carboplatin/paclitaxel, carboplatin/gemcitabine, carboplatin/paclitaxel + bevacizumab, carboplatin/gemcitabine + bevacizumab, or carboplatin/pemetrexed +/- bevacizumab, (see Section 3.2 for acceptable doses and schedules) and should have CR, PR, or SD as best response. Patients should not have progressed on prior chemotherapy for metastatic or recurrent NSCLC. Must be postmenopausal female, as defined by the following criteria: Prior bilateral oophorectomy or Age greater than 60 years old Age less than 60 years old and amenorrheic for 12 or more months in the absence of chemotherapy or ovarian suppression with FSH and estradiol in the postmenopausal range. Registration/randomization should be within 6 weeks of beginning of last cycle of chemotherapy Documented evidence of a tumor response of CR, PR, or SD. Tumor assessment must occur between Cycle 4 (Day 1) of induction therapy and the date of randomization. Tumor assessment will be per RECIST (Appendix 3) by the treating physician. This response does not have to be confirmed in order for the patient to be randomized; however, unconfirmed responses will be stratified in the stable disease strata. Positron emission tomography (PET) scans and ultrasound may not be used for lesion measurements for response determination ECOG performance status 0, 1 or 2. At least 18 years of age. Adequate organ function, including the following: Adequate bone marrow reserve: absolute neutrophil (segmented and bands) count (ANC) greater than or equal to 1.0 x10^9/L, platelets greater than or equal to 75 x10^9/L, and hemoglobin greater than or equal to 9 g/dL. Hepatic: bilirubin less than or equal to 1.5 times the upper limit of normal (ULN), alkaline phosphatase (ALP), aspartate transaminase (AST), and alanine transaminase (ALT) less than or equal to 2.0 Renal: calculated creatinine clearance (CrCl) ≥45 mL/min based on the standard Cockcroft and Gault formula (Cockcroft and Gault 1976). Prior radiotherapy must be completed at least 3 weeks before study enrollment. Patients must have recovered from the acute toxic effects of the treatment prior to study enrollment. Signed informed consent document on file. Patient compliance and geographic proximity that allow adequate follow up. Patient must receive on-study therapy no earlier than 21 days and no later than 42 days from their last cycle (Day 1) of induction therapy. Patients must have archival tissue samples. Tumor tissue will be submitted for assessment of ERa, ERb, PR, VEGF and aromatase expression. The patient must also agree to mandatory correlative blood samples at baseline, 5 weeks, 9 weeks, 13 weeks and at the time of progression. Cisplatin may be used instead of carboplatin as part of the initial induction chemotherapy regimen, at the discretion of the treating physician investigator. The dose and schedule of cisplatin will be according to the standard of care for patients with stage IIIB with malignant pleural effusion or stage IV NSCLC as staged by the AJCC Cancer Staging Manual, 6th ed, appendix 1, that is equivalent to stage IV NSCLC as staged by the new 7th ed AJCC staging system. Exclusion Criteria: Male gender With the exception of those chemotherapies listed as Inclusion criterion (4) No other concomitant biological therapy (e.g. cetuximab) is allowed. Have received experimental treatment within the last 30 days at the time of study entry. Inability to comply with protocol or study procedures. A serious concomitant systemic disorder that, in the opinion of the investigator, would compromise the patient's ability to complete the study. Concurrent administration of any other antitumor therapy (except arm B, who are allowed to continue with bevacizumab). Pregnant or breast feeding. Have a prior malignancy other than NSCLC, carcinoma in situ of the cervix, or nonmelanoma skin cancer, unless that prior malignancy was diagnosed and definitively treated at least 5 years previously with no subsequent evidence of recurrence. Patients with two or more deep vein thromboses, or an active deep vein thrombosis. Patients taking hormone replacement therapy or other hormonal therapies The International Normalized Ratio (INR) must be < 1.6 within 28 days prior to registration. Patients with bleeding diathesis (i.e., disseminated intravascular coagulation [DIC], clotting factor deficiency) or a history of recent history of hemoptysis (1/2 tsp of red blood). Patients on stable long term anticoagulation prior to starting this trial are allowed. History of hypersensitivity to active or inactive excipients of fulvestrant (ie castor oil or Mannitol). Treatment of NSCLC with squamous cell histology with bevacizumab. No progressive Brain or CNS metastases No other concurrent anticancer therapy is allowed other than Bevacizumab

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm B, Group 1<br>Best supportive care only: antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, and/or nutritional support PRN | Drug: Best supportive care<br>* Subjects will not receive any chemotherapy for NSCLC nor will they received anti-cancer surgery, immunotherapy, radiotherapy or hormonal therapy. Among the therapies they may take are therapies considered acceptable include, but are not limited to, antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, and/or nutritional support (enteral or parenteral<br>* Other names: Antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, and/or nutritional support;|
| Active Comparator: Arm B, Group 2<br>Best supportive care and Bevacizumab 15mg/kg every 21 days | Drug: Bevacizumab (Avastin)<br>* Bevacizumab (Avastin) 15 mg/kg IV, every 21 days<br>Drug: Best supportive care<br>* Subjects will not receive any chemotherapy for NSCLC nor will they received anti-cancer surgery, immunotherapy, radiotherapy or hormonal therapy. Among the therapies they may take are therapies considered acceptable include, but are not limited to, antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, and/or nutritional support (enteral or parenteral<br>* Other names: Antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, and/or nutritional support;|
| Experimental: Arm A, Group 1<br>Fulvestrant and anastrozole only | Drug: fulvestrant (Faslodex)<br>* Fulvestrant (Faslodex) IM 250 mg monthly after a loading dose of 500 mg on day 1 and 250 mg on day 15 of cycle 1.<br>Drug: anastrozole (Arimidex)<br>* Anastrozole (Arimidex) 1 mg orally QD<br>|
| Experimental: Arm A, Group 2<br>Fulvestrant, anastrozole and Bevacizumab | Drug: fulvestrant (Faslodex)<br>* Fulvestrant (Faslodex) IM 250 mg monthly after a loading dose of 500 mg on day 1 and 250 mg on day 15 of cycle 1.<br>Drug: anastrozole (Arimidex)<br>* Anastrozole (Arimidex) 1 mg orally QD<br>Drug: Bevacizumab (Avastin)<br>* Bevacizumab (Avastin) 15 mg/kg IV, every 21 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Evaluate the Progression-free Survival. |  | 1.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Evaluate the Time to Overall Survival, Time to Progression, and Toxicities |  | 1.5 years | 
| To Evaluate the Levels of 17b-estradiol, VEGF, E-selectin, Thrombospondin-1 and IGF-1, and Other Biomarkers in the Plasma. |  | 1.5 years | 
| To Evaluate Biomarkers (ERa, ERb, PR, VEGF and Aromatase Expression) in Baseline, Archival Tumor Tissue and Correlate Their Expression With Progression-free Survival, Time to Progression, and Overall Survival. |  | 1.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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advanced non-small cell lung cancer, postmenopausal, bevacizumab, fulvestrant, anastrozole