Pilot Study Targeting Residual Hypermethylation in Early Stage Non-Small Cell Lung Cancer As Part of Adjuvant Therapy and Preventive Strategy
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 6
- 试验地点
- 1
- 主要终点
- Percentage of Patients Showing a Presence of Methylated Tumor Suppressor Genes in Their Tumor Tissue and/or Serum Achieving Partial or Complete Response to Protocol Therapy.
研究概览
简要总结
The trial investigates the feasibility and efficacy of targeting Non-Small Cell Lung Cancer (NSCLC) "driven" by epigenetic changes. The investigators study the impact of 5-azacitidine (Vidaza®, Celgene, Summit, NJ, USA) in combination with conventional cytotoxic chemotherapy in a sequential fashion. The study population consists of all NSCLC patients who undergo "curative" lung cancer resection and whose tumors harbor hypermethylation in any of the protocol-specific genes (samples will be banked for additional molecular testing including other 21 loci which have shown to be important in lung carcinogenesis.
详细描述
Adjuvant chemotherapy has become an essential part for the treatment of stage IB-IIIA NSCLC patients based on 4 randomized clinical trials showing survival advantage for patients who received adjuvant CT, oncologists initially started to adapt this modality of treatment for pathologically stage IB-IIIA NSCLC patients [4]. Herein, NSCLC patients will be treated in the adjuvant setting with conventional doublet platinum-based chemotherapy followed by 5-azacitidine, a demethylating agent. The planned dosages to be used in this trial have been extensively studied in previously conducted clinical trials involving all therapeutic agents.
All patients will undergo thorough surgical resection of the primary lung tumor, and evidence of promoter hypermethylation of gene(s) must be present in the tumor specimen and/or blood sample (plasma or WBC). The collection of tumor specimen will be considered a priority to correlate the tumor "methylation pattern/profile" with the serum "methylation pattern/profile". If tumor specimen is not available for any reason, but the patient has at least one of the 9 targeted genes hypermethylated in the serum, the patient is eligible to be enrolled into the trial.
Treatment will consist of 2 parts:
Part A. Adjuvant chemotherapy.
Following surgical resection of NSCLC and test positive for promoter hypermethylation in at least one (1) of the targeted TSGs described, patient will start adjuvant conventional chemotherapy (doublet platinum-based chemotherapy) for stage IB-IIIA NSCLC. In the case a patient with stage IB refuses adjuvant chemotherapy, the patient still can be enrolled into Part B of the study if he/she understands the concept of the trial and sign an informed consent.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must have a pathologic diagnosis of NSCLC.
- •Patients must have surgical resection for NSCLC (stage I-IIIA) and tumor specimen (ideally) and/or blood sample available for biological correlative studies.
- •Patient's tumor specimen and/or blood sample must show hypermethylation in at least one (1) of the following genes: DAPK, RASSF1A, CDKN2A (p16INK4a), GATA-4, GATA-5, SPARC, MGMT, APC, and hMLH
- •Patient's age must be 18 years or greater.
- •Patients must have adequate organ and marrow function prior to be enrolled into the trial, as defined below:
- •Absolute neutrophil count (ANC) > 1500/mm3
- •Platelets > 100,000/mm3
- •Hemoglobin > 8.0 g/dL (with packed red blood cell transfusion or use of erythropoietin stimulating agents allowed)
- •Serum creatinine < 2.0 mg/dl.
- •Total bilirubin < 2.0 mg/dl.
- •AST/ALT < 2 x the upper limits of institutional normal.
- •ECOG performance status of 0, 1, or
- •Estimated survival of > 12 months.
- •Patients must be able to understand and agree to sign an IRB-approved informed consent form, including permission to draw blood sample for correlative studies during active treatment and follow-up.
- •Women of child-bearing potential and men must agree to use adequate contraceptive method (hormonal or barrier method of birth control) prior to study entry for the duration of study.
- •Women of childbearing potential must have a negative serum pregnancy test prior to start targeted therapy with 5-azacitidine.
- •Patients with HIV infection (but not AIDS) are eligible for this trial. Therefore, no HIV testing will be required.
排除标准
- •Patients who are not candidates for surgical resection.
- •Patients who have received radiation therapy.
- •No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, breast DCIS adequately treated, or other cancer for which the subject has been disease-free ≥ 5 years.
- •Subjects should not have a significant history of cardiac disease (e.g., unstable angina, congestive heart failure, or uncontrolled arrhythmias).
- •Subjects must not have an uncontrolled seizure disorder, or active neurological disease.
- •Patients who have significant systemic infections including AIDS.
- •Pregnant and/or lactating women.
- •Known or suspected hypersensitivity to azacitidine or mannitol.
- •Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical illnesses.
研究组 & 干预措施
Adjuvant Chemotherapy + Vidaza
干预措施: Cisplatin (Drug)
Adjuvant Chemotherapy + Vidaza
干预措施: Carboplatin (Drug)
Adjuvant Chemotherapy + Vidaza
干预措施: Paclitaxel (Drug)
Adjuvant Chemotherapy + Vidaza
干预措施: Vidaza (Drug)
Adjuvant Chemotherapy + Vidaza
干预措施: Tumor Specimen for Methylation Analysis (Procedure)
Adjuvant Chemotherapy + Vidaza
干预措施: Blood Sample for Methylation Analysis (Procedure)
Adjuvant Chemotherapy + Vidaza
干预措施: Vinorelbine (Drug)
Adjuvant Chemotherapy + Vidaza
干预措施: Docetaxel (Drug)
Adjuvant Chemotherapy + Vidaza
干预措施: Pemetrexed (Drug)
结局指标
主要结局
Percentage of Patients Showing a Presence of Methylated Tumor Suppressor Genes in Their Tumor Tissue and/or Serum Achieving Partial or Complete Response to Protocol Therapy.
时间窗: Up to 2 years
To determine the feasibility and efficacy of incorporating a demethylating agent (5-azacitidine; Vidaza®, Celgene, Summit, NJ, USA) as part of adjuvant therapy in patients diagnosed with NSCLC who harbor methylated tumor supressor genes (TSGs) in their tumor tissue and/or serum. Response to be evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.0.
Degree of Demethylation in Patient Tumor Tissue and/or Serum Induced by 5-azacitidine on Specific Tumor Specific Genes (TSGs)
时间窗: Up to 2 years
To measure the grade of demethylation induced by 5-azaciditine on specific TSGs by analyzing plasma DNA, and global demethylation by analyzing WBC DNA, and determine the duration of this effect.
次要结局
未报告次要终点
研究者
Ikechukwu Akunyili
Assistant Professor of Clinical
University of Miami