Combination Chemotherapy With or Without Maintenance Sunitinib Malate (NSC 736511) for Untreated Extensive Stage Small Cell Lung Cancer: A Phase IB/Randomized Phase II Study
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 156
- 试验地点
- 250
- 主要终点
- Maximum Tolerated of Sunitinib Combined With Cisplatin and Etoposide (Phase I)
研究概览
简要总结
This partially randomized phase I/II trial studies the side effects and best dose of sunitinib malate and to see how well it works when given together with cisplatin or carboplatin and etoposide in treating patients with extensive-stage small cell lung cancer. Drugs used in chemotherapy, such as cisplatin, carboplatin, and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Sunitinib malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. It is not yet known whether cisplatin or carboplatin and etoposide are more effective when given with or without sunitinib malate in treating small cell lung cancer.
详细描述
PRIMARY OBJECTIVES:
I. To determine the phase II dose for sunitinib (sunitinib malate) combined with cisplatin and etoposide. (Phase IB) II. To compare the progression-free survival of patients with extensive stage small cell lung cancer treated with cisplatin or carboplatin and etoposide followed by maintenance sunitinib to patients receiving the same chemotherapy followed by placebo. (Phase II)
SECONDARY OBJECTIVES:
I. To assess the single agent response rate for sunitinib given as monotherapy after chemotherapy. (Phase II) II. To assess the overall survival of patients treated with cisplatin or carboplatin and etoposide followed by sunitinib. (Phase II) III. To evaluate the toxicity and tolerability of maintenance sunitinib after cisplatin or carboplatin and etoposide. (Phase II) IV. To determine the association between vascular endothelial growth factor (VEGF) plasma levels and tumor response. (Phase II)
OUTLINE: This is a phase I, dose-escalation study of sunitinib malate followed by a randomized phase II study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
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
- •All patients must have histologically or cytologically documented small cell lung cancer
- •Eligible disease stages: the extensive disease classification for this protocol includes all patients with disease sites not defined as limited stage; limited stage disease category includes patients with disease restricted to one hemithorax with regional lymph node metastases, including hilar, ipsilateral and contralateral mediastinal, and/or ipsilateral supraclavicular nodes; extensive stage patients are defined as those patients with extrathoracic metastatic, malignant pleural effusion, bilateral or contralateral supraclavicular adenopathy or contralateral hilar adenopathy
- •All patients must have measurable disease:
- •Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan
- •Lesions that are considered non-measurable, which would make the patient not eligible, include the following:
- •Bone lesions
- •Leptomeningeal disease
- •Pleural/pericardial effusion
- •Lymphangitis cutis/pulmonis
- •Abdominal masses that are not confirmed and followed by imaging techniques
- •Cystic lesions
- •No prior chemotherapy for small cell lung cancer (SCLC)
- •Radiation therapy must have been completed at least one week before initiation of protocol therapy
- •Common Toxicity Criteria (CTC) performance status:
- •Phase IB: 0-1
- •Phase II: 0-2
- •No "currently active" second malignancy other than non-melanoma skin cancers
- •No history of brain metastases, spinal cord compression, or carcinomatous meningitis
- •No ongoing cardiac dysrhythmias, atrial fibrillation, or QTc interval >= 500 msec; the use of agents with proarrhythmic potential (e.g., quinidine, procainamide, disopyramide, sotalol, probucol, pedridel, haloperidol, risperidone, indapamide, flecainide) is not recommended while on protocol therapy
- •Patients with class I New York Heart Association (NYHA) are eligible; patients with a history of class II NYHA are eligible, provided they meet the following criteria:
- •Patients with a history of class II heart failure who are asymptomatic on treatment
- •Patients with prior anthracycline exposure
- •Patients who have received central thoracic radiation that included the heart in the radiotherapy port
- •Patients with a history of class III or IV NYHA heart failure within 12 months prior to registration are not eligible
- •Additionally, no myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft or stenting, cerebrovascular accident including transient ischemic attack, or pulmonary embolism within the last year
- •Patients with hypertension that cannot be controlled by medications (> 150/100 mmHg despite optimal medical therapy) are not eligible
- •Patients who require use of therapeutic doses of coumarin-derivative anticoagulants such as warfarin are excluded, although doses of up to 2 mg daily are permitted for prophylaxis of thrombosis; Note: Low molecular weight heparin is permitted provided the patient's prothrombin time (PT) international normalized ratio (INR) is =< 1.5
- •No evidence of hemoptysis within 4 weeks prior to starting study treatment; patients with blood-tinged or blood streaked sputum will be permitted on study if the hemoptysis amounts to less than 5 mL of blood per episode and less than 10 mL of blood per 24-hour period in the best estimate of the investigator
- •None of the following within 28 days of treatment: abdominal fistula, gastrointestinal perforation, intra-abdominal abscess, serious or non-healing wound, ulcer, or bone fracture
- •The use of the following specific inhibitors and inducers of cytochrome p450, family 3, subfamily A, polypeptide 4 (CYP3A4) is not permitted; the following inhibitors of CYP3A4 are prohibited within 7 days before and during treatment with sunitinib: azole antifungals (ketoconazole, itraconazole), diltiazem, clarithromycin, erythromycin, verapamil, delavirdine, and human immunodeficiency virus (HIV) protease inhibitors (indinavir, saquinavir, ritonavir, atazanavir, nelfinavir); the following inducers of CYP3A4 are prohibited within 12 days before beginning and during treatment with sunitinib: rifampin, rifabutin, carbamazepine, phenobarbital, phenytoin, St. John's Wort, efavirenz, tipranavir
- •Other inhibitors and inducers of CYP3A4 may be used if necessary, but there use is discouraged
- •Non-pregnant and non-nursing
- •Granulocytes >= 1,500/ul
- •Platelets >= 100,000/ul
- •Creatinine clearance >= 70 ml/min
- •Total bilirubin =< 1.5 mg/dl
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN) (patients w/ liver metastases may have AST/ALT =< 5 x ULN)
- •Partial thromboplastin time (PTT) =< 1.5 x ULN
排除标准
- 未提供
研究组 & 干预措施
Arm I (Combination Chemotherapy + Sunitinib Maintenance)
Participants will receive the following combination chemotherapy for 4-6 cycles (21 days):
Cisplatin 80 mg/m^2 by IV over 1 hour on day 1 every cycle OR Carboplatin AUC = 5* by IV Etoposide 100 mg/m^2 by IV over 1 hour on days 1, 2, and 3 every cycle
Maintenance: Following 4-6 cycles of combination chemotherapy, start sunitinib at 150 mg on day 1, then 37.5 daily until disease progression.
干预措施: Cisplatin (Drug)
Arm I (Combination Chemotherapy + Sunitinib Maintenance)
Participants will receive the following combination chemotherapy for 4-6 cycles (21 days):
Cisplatin 80 mg/m^2 by IV over 1 hour on day 1 every cycle OR Carboplatin AUC = 5* by IV Etoposide 100 mg/m^2 by IV over 1 hour on days 1, 2, and 3 every cycle
Maintenance: Following 4-6 cycles of combination chemotherapy, start sunitinib at 150 mg on day 1, then 37.5 daily until disease progression.
干预措施: Laboratory Biomarker Analysis (Other)
Arm II (Combination Chemotherapy + Placebo Maintenance)
Participants will receive the following combination chemotherapy for 4-6 cycles (21 days):
Cisplatin 80 mg/m^2 by IV over 1 hour on day 1 every cycle OR Carboplatin AUC = 5* by IV Etoposide 100 mg/m2 by IV over 1 hour on days 1, 2, and 3 every cycle
Maintenance: Following 4-6 cycles of combination chemotherapy, start placebo at 150 mg on day 1, then 37.5 daily until disease progression.
干预措施: Laboratory Biomarker Analysis (Other)
Arm II (Combination Chemotherapy + Placebo Maintenance)
Participants will receive the following combination chemotherapy for 4-6 cycles (21 days):
Cisplatin 80 mg/m^2 by IV over 1 hour on day 1 every cycle OR Carboplatin AUC = 5* by IV Etoposide 100 mg/m2 by IV over 1 hour on days 1, 2, and 3 every cycle
Maintenance: Following 4-6 cycles of combination chemotherapy, start placebo at 150 mg on day 1, then 37.5 daily until disease progression.
干预措施: Placebo Administration (Other)
Arm I (Combination Chemotherapy + Sunitinib Maintenance)
Participants will receive the following combination chemotherapy for 4-6 cycles (21 days):
Cisplatin 80 mg/m^2 by IV over 1 hour on day 1 every cycle OR Carboplatin AUC = 5* by IV Etoposide 100 mg/m^2 by IV over 1 hour on days 1, 2, and 3 every cycle
Maintenance: Following 4-6 cycles of combination chemotherapy, start sunitinib at 150 mg on day 1, then 37.5 daily until disease progression.
干预措施: Etoposide (Drug)
Arm I (Combination Chemotherapy + Sunitinib Maintenance)
Participants will receive the following combination chemotherapy for 4-6 cycles (21 days):
Cisplatin 80 mg/m^2 by IV over 1 hour on day 1 every cycle OR Carboplatin AUC = 5* by IV Etoposide 100 mg/m^2 by IV over 1 hour on days 1, 2, and 3 every cycle
Maintenance: Following 4-6 cycles of combination chemotherapy, start sunitinib at 150 mg on day 1, then 37.5 daily until disease progression.
干预措施: Sunitinib Malate (Drug)
Arm II (Combination Chemotherapy + Placebo Maintenance)
Participants will receive the following combination chemotherapy for 4-6 cycles (21 days):
Cisplatin 80 mg/m^2 by IV over 1 hour on day 1 every cycle OR Carboplatin AUC = 5* by IV Etoposide 100 mg/m2 by IV over 1 hour on days 1, 2, and 3 every cycle
Maintenance: Following 4-6 cycles of combination chemotherapy, start placebo at 150 mg on day 1, then 37.5 daily until disease progression.
干预措施: Carboplatin (Drug)
Arm I (Combination Chemotherapy + Sunitinib Maintenance)
Participants will receive the following combination chemotherapy for 4-6 cycles (21 days):
Cisplatin 80 mg/m^2 by IV over 1 hour on day 1 every cycle OR Carboplatin AUC = 5* by IV Etoposide 100 mg/m^2 by IV over 1 hour on days 1, 2, and 3 every cycle
Maintenance: Following 4-6 cycles of combination chemotherapy, start sunitinib at 150 mg on day 1, then 37.5 daily until disease progression.
干预措施: Carboplatin (Drug)
Arm II (Combination Chemotherapy + Placebo Maintenance)
Participants will receive the following combination chemotherapy for 4-6 cycles (21 days):
Cisplatin 80 mg/m^2 by IV over 1 hour on day 1 every cycle OR Carboplatin AUC = 5* by IV Etoposide 100 mg/m2 by IV over 1 hour on days 1, 2, and 3 every cycle
Maintenance: Following 4-6 cycles of combination chemotherapy, start placebo at 150 mg on day 1, then 37.5 daily until disease progression.
干预措施: Etoposide (Drug)
Arm II (Combination Chemotherapy + Placebo Maintenance)
Participants will receive the following combination chemotherapy for 4-6 cycles (21 days):
Cisplatin 80 mg/m^2 by IV over 1 hour on day 1 every cycle OR Carboplatin AUC = 5* by IV Etoposide 100 mg/m2 by IV over 1 hour on days 1, 2, and 3 every cycle
Maintenance: Following 4-6 cycles of combination chemotherapy, start placebo at 150 mg on day 1, then 37.5 daily until disease progression.
干预措施: Cisplatin (Drug)
结局指标
主要结局
Maximum Tolerated of Sunitinib Combined With Cisplatin and Etoposide (Phase I)
时间窗: 21 days
The maximum tolerated dose is defined at the highest sunitinib dose at which less than one third of participants develop a dose limiting toxicity (DLT). A DLT is defined as: delay of beginning cycle 2 of chemotherapy by \> 7 days due to neutropenia, grade 4 hematologic toxicity lasting greater than 1 week (chemotherapy alone would be expected to cause significant grade 4 hematologic toxicity) or grade 3 or 4 nonhematologic toxicity (excluding grade 3 or 4 fatigue if the patient is found to be hypothyroid and responds to fatigue \< grade 3 with thyroid replacement therapy).
Progression-free Survival (Phase II)
时间窗: Up to 3 years
Progression free survival (PFS) was defined as the time from maintenance randomization to progression or death of any cause. Progression free and alive patients were censored at the date of last follow-up. The median PFS with 95% CI was estimated using the Kaplan Meier method.
次要结局
- Number of Participants With Overall Tumor Response(Up to 3 years)
- Overall Survival(Up to 3 years)