Pharmacogenomic & Phase II Study of Gemcitabine and Pemetrexed in Non-Small-Cell Lung Cancer.

Study Overview
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Brief Summary
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This study will evaluate the efficacy and safety of chemotherapy given prior to having lung cancer surgically removed. Patients with resectable non-small cell lung cancer will receive gemcitabine and pemetrexed together for 4 times biweekly. Patients will be seen by a medical oncologist prior to each cycle of chemotherapy given. The medical oncologist will review patient's bloodwork and symptoms prior to approving next cycle of chemotherapy. All patients will then be evaluated with scans to determine response to chemotherapy and to determine if patient is a surgical candidate. These patients will then proceed to surgery to have the lung cancer removed. Follow up visits include bloodwork, scans, and a visit with the medical oncologist every three months for two years, then every six months for three years to monitor for disease recurrence.

Detailed Description
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This study will evaluate the efficacy and safety of neoadjuvant chemotherapy with gemcitabine and pemetrexed given together 4-times biweekly in patients with resectable NSCLC. All patients will be seen by members of the Thoracic Oncology Program at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, and they will be discussed in our weekly multidisciplinary thoracic oncology conference. The conference includes pathologists, radiologists, thoracic surgeons, pulmonologists, radiation oncologists, medical oncologists, oncology nurse specialists, case managers, social workers, and clinical trials coordinators. They will have initial tests as outlined in the study timetable. Patients will receive gemcitabine biweekly on days 1, 15, 29, and 43 at a dose of 1,500 mg/m2. They will also receive pemetrexed at a dose of 500 mg/m2 on days 1, 15, 29, and 43. Gemcitabine will be given first over a period of 30 minutes i.v. followed by pemetrexed over 10 minutes i.v. All patients will get a post induction chemotherapy PET scan, CT scan, and PFT's including a DLCO. They will then go on to thoracotomy including bronchoscopy and mediastinal lymph node dissection between days 64 and 77 if the tumor is deemed completely resectable on restaging studies. The administration of chemotherapy at the earliest time (neoadjuvant or induction chemotherapy) following diagnosis in an effort to reduce the risk of disease recurrence. This approach also allows for investigations of molecular parameters that may affect response to chemotherapy and patients' survival. It is our hypothesis that the expression of genes associated with activation, inactivation, and efficacy of the drugs gemcitabine and pemetrexed will predict response to therapy and prognosis. We further hypothesize that the expression of these genes will be altered during chemotherapy, and that the global assessment of tumor proliferation, apoptosis, and genome damage is associated with response to therapy. We propose a phase II study of neoadjuvant chemotherapy with gemcitabine and pemetrexed in patients with resectable NSCLC, specifically correlating molecular and genetic parameters to the primary clinical study endpoint disease response (radiographic CR+PR) and the secondary endpoints complete pathological response at surgery, disease-free survival, and overall survival.

Official Title
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Phase II Study of Neoadjuvant Chemotherapy With Gemcitabine and Pemetrexed in Resectable Non-Small-Cell Lung Cancer (NSCLC) With Pharmacogenomic Correlates.

Conditions
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Lung Cancer

Intervention / Treatment
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* Drug: Gemcitabine
* Drug: Pemetrexed
* Procedure: Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Microscopically confirmed non-small cell carcinoma of the lung, which may be confirmed at the initial bronchoscopy and mediastinoscopy, or by transthoracic needle biopsy. No prior therapy for lung cancer. Patients must have disease stages IB (T2N0M0), IIA (T1N1M0), IIB (T2N1M0 and T3N0M0), or IIIA (T3N1M0 and T1-3N2M0). Patients with 2 lesions in one lobe (T4) (Stage IIIB) are eligible. Patients must be deemed medically fit for surgical resection by a thoracic surgeon. Patients must have an ECOG performance status of Zero or One. Patients must have measurable or evaluable disease. Measurable Disease: Any mass reproducibly measurable in one diameter (RECIST criteria). Evaluable disease: Lesions apparent on chest CT, which do not meet the criteria for measurability. These include ill-defined masses associated with post obstructive changes. Age >18 years. Patient must be able to understand and sign the informed consent. Patients must be >12 weeks from prior major surgery, such as a coronary artery bypass graft. Exclusion Criteria: White blood cell count <3000/mm3 Platelet count <100,000/mm3 Hemoglobin <9.0 g/dl Creatinine >1.5 mg/dl Total bilirubin >1.5 mg/dl SGOT, SGPT, or AP >1.5 x upper limit of normal Metastatic disease (except peribronchial/hilar lymph nodes=N1 and ipsilateral/subcarinal mediastinal lymph nodes=N2) or malignant pleural effusion detected on preoperative evaluation. Non-malignant effusions are cytology negative, are non-bloody, and are transudates. Effusions visible only on CT and not large enough for safe thoracentesis will not result in ineligibility. Exudative effusions, even if cytologically negative are excluded. Pleural fluid is considered exudative if: the ratio of pleural fluid protein to serum protein is >0.5 or the ratio of pleural fluid LDH to serum to serum LDH >0.6 or Pleural fluid LDH is >200 IU/liter. A staging PET scan will be used to exclude patients. If there are multiple areas of FDG uptake outside the area of the primary tumor and the hilar and ipsilateral mediastinal lymph nodes, the patient will be excluded by virtue of having metastatic disease. If however, only one area shows an increase in FDG uptake, the area of concern will need further evaluation such as a biopsy to exclude metastatic disease. N3 lymph nodes (contralateral mediastinal/hilar and supraclavicular/scalene) or T4 primary tumor (malignant pleural effusion or mediastinal invasion) by clinical staging criteria (N3 as seen on CT or PET scan, which may be proven by mediastinoscopy at the investigators discretion). Pregnancy. Other active malignancy within 2 years with the exceptions of non-melanoma skin cancer and cervical carcinoma in situ. Psychologic, familial, sociologic, or geographic conditions, which do not permit biweekly medical follow-up and adherence to the study protocol. Prior radiation therapy for any cancer to the thorax.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pre-Surgery Chemotherapy<br> | Drug: Gemcitabine<br>* Gemcitabine (GemzarR) 1500 mg/m2<br>* Other names: Gemzar®;Drug: Pemetrexed<br>* Pemetrexed (AlimtaR) 500 mg/m2<br>* Other names: Alimta®;Procedure: Surgery<br>* When the chemotherapy treatment is completed, the patient's tumor response will be evaluated by a CT scan, pulmonary function test, and another PET scan between days 50 and 63 (during weeks 8 and 9). If there is no growth or spread of the cancer on any of these tests, patients will then proceed to have surgery by week 10 to remove the cancer.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Response - Radiographic | Number of participants with partial or Complete Response. Complete response (CR) is defined as the total disappearance of all malignant and evaluable clinical evidence of cancer without the development of any new malignant lesions documented on the post chemotherapy chest CT and PET scan. Partial response (PR) (measurable disease only): When compared with pre-treatment measurements, a reduction of >30% in the sum of the largest diameters of all measurable lesions and absence of new lesions. | 06/20/2008 Index date for patients enrolled between 04/2004 and 04/2006 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Response - Pathologic | Number of participants with Pathologic Complete Response. Pathologic complete response (pCR) is defined by a surgical pathology specimen, which consists of equal to or more than 95% fibrosis and necrosis. | 06/20/2008 Index date for patients enrolled between 04/2004 and 04/2006 | 
| Survival - Disease Free | Disease-free survival (DFS) is defined as the period of time from surgery to the time when disease recurrence is clearly documented. A histologic confirmation is required in equivalent cases. | 06/20/2008 Index date for patients enrolled between 04/2004 and 04/2006 | 
| Survival - Overall | Median range of number of participants with Overall Survival. Overall survival (OS) will be defined as the period of time from the first day of drug treatment to the date of death of the patient. Patients taken off study will be followed quarterly until death for survival data. | 06/20/2008 Index date for patients enrolled between 04/2004 and 04/2006 | 
| Toxicity | Number of participants with toxicity ≥ Grade 3 after gemcitabine plus pemetrexed induction chemotherapy. | 06/20/2008 Index date for patients enrolled between 04/2004 and 04/2006 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-Small-Cell Lung Cancer, resectable, NSCLC