Phase I Study of Cytoreductive Surgery and Hyperthermic Intraoperative Chemotherapy With Pemetrexed and Cisplatin for Malignant Pleural Mesotheliomas
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 7
- 试验地点
- 1
- 主要终点
- Number of participants with Dose-Limiting Toxicity (DLT)
研究概览
简要总结
Primary Objective
To determine the maximum tolerated dose (MTD) of intrathoracic administration of pemetrexed when given in conjunction with cisplatin in patients with resectable malignant pleural mesothelioma MPM.
Secondary Objectives
To determine the toxicity and grades associated with cytoreductive surgery and Hyperthermic Intraoperative Chemotherapy HIOC with cisplatin and pemetrexed in patients with resectable MPM.
To assess overall survival and progression-free survival after PD or EPP and HIOC with cisplatin and pemetrexed for MPM
Correlative Objectives
To characterize the pharmacokinetics and pharmacodynamics of pemetrexed when administered as a hyperthermic intrathoracic lavage after PD or EPP
To determine whether the degree of thymidylate synthase and ERCC1 gene expression in MPM tissue correlates with clinical response to pemetrexed.
详细描述
TREATMENT PLAN
PREOPERATIVE HYDRATION According to our observations, preoperative hydration reduces the risk of nephrotoxicity from intrathoracic infusion of hyperthermic cisplatin. Therefore, all patients will be admitted the night before surgery and receive intravenous hydration.
CYTOREDUCTIVE SURGERY
Eligible patients will undergo an extrapleural pneumonectomy (EPP) or pleurectomy/decortication (PD) by a Baylor College of Medicine board-certified thoracic surgeon. Patients will be given ondansetron 8mg x 1 dose after induction of anesthesia, before initiation of chemotherapy lavage. The anti-emetics will be adjusted if grade III toxicity is still encountered. Patients will then undergo cytoreductive surgery (PD or EPP) with curative intent. In the event that not all of the tumor can be removed then the investigators will allow a total of 1 cm3 or less of disease in one or more areas. If the tumor is unresectable and debulking cannot be obtained, then the patient will receive additional treatment off protocol. Mediastinal lymph node sampling will be performed. In the event that the diaphragm and pericardium are resected, they will be reconstructed with polytetrafluoroethylene (PTFE).
RENAL PROTECTION STRATEGY
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
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Histologically proven malignant pleural mesothelioma MPM that is considered resectable according to the following criteria:
- •Confined to one pleural space
- •No chest wall invasion
- •No transdiaphragmatic involvement
- •No invasion of mediastinal structures
- •Age ≥ 18 years
- •Eastern Cooperative Oncology Group performance status 0-1 (Appendix A)
- •Adequate cardiopulmonary reserve defined as follows as assessed within 4 months of study entry:
- •Predicted postoperative forced expiratory volume FEV1 > 1L
- •Normal left ventricular function (Ejection Fraction EF ≥ 45%) and right ventricular function
- •No pulmonary hypertension noted on preoperative transthoracic echocardiography
- •Must have adequate hematologic, renal and hepatic function as defined by the following laboratory values (completed within 60 days of surgery) Hematologic: Hemoglobin ≥ 9.0 g/dL, absolute neutrophil count (ANC) ≥ 1500/mm3, platelet count ≥ 100,000/mm Renal: Calculated creatinine clearance ≥ 60 mL/min
- •The creatinine clearance CrCl is determined by the Cockcroft-Gault formula:
- •Creatinine Clearance CrCl (mL)/min) = weight (kg) x (140-age) 72 x serum creatinine (mg/dL)
- •Creatinine Clearance CrCl (mL)/min) = weight (kg) x (140-age) x 0.85 72 x serum creatinine (mg/dL)
- •Hepatic: Total bilirubin < 1.5 times the upper limit of institutional normal value; Aspartate aminotransferase AST (Serum glutamic oxaloacetic transaminase SGOT) and alanine aminotransferase ALT (Serum glutamic pyruvic transaminase SGPT) < 3 times the upper limit of the institutional normal Coagulation: international normalized ratio INR ≤ 1.5 in patients not utilizing systemic anticoagulation as part of their medical regimen
- •Women of child bearing potential and sexually active males must use an accepted and effective non-hormonal method of contraception
- •Patients must be deemed by the investigators to be fully recovered from both acute and late effects of any prior surgery, radiotherapy, or other antineoplastic therapy
- •Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
- •The ability to interrupt non-steroidal anti-inflammatory drugs NSAIDS 2 days before (5 days for long-acting NSAIDs), the day of, and 2 days following administration of Pemetrexed.
- •The ability to take folic acid, Vitamin B12, and dexamethasone according to protocol.
排除标准
- •Not pregnant or breastfeeding - the drugs used in this study are Pregnancy Category D (clear evidence of risk in pregnancy). A negative pregnancy test is required within 14 days of registration for pre- or perimenopausal (i.e., last menstrual period within one year of registration) women.
- •Patients with a history of another neoplasm, with the exception of non-metastatic, non-melanoma skin cancers, carcinoma in situ of the cervix, or cancer cured by surgery or small field radiotherapy, within 5 years of registration will be excluded.
- •Patients with uncontrolled cardiovascular disease (a history of hospitalization for acute myocardial infarction, arrhythmia, or congestive heart failure within 3 months prior to registration) will be excluded
- •Registered patients with an active infection or with a fever of ≥ 38.5°C within 24 hours of the first scheduled day of protocol initiation will be excluded until their infection and/or fever resolves.
- •Any other medical condition, including mental illness or substance abuse, deemed by the Investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results.
- •Inability to interrupt use of non-steroidal anti-inflammatory drugs (NSAIDS)
- •Peripheral neuropathy >/= Grade 2 (Common Terminology Criteria for Adverse Events CTCAE)
- •Systemic chemotherapy within 3 weeks of registration
- •Prior Allergies: History of allergic reactions attributed to compounds of similar chemical or biologic composition to cisplatin and pemetrexed
- •Presence of third space fluid which cannot be controlled by drainage.
研究组 & 干预措施
Pemetrexed (300 mg/m2) and Cisplatin (175 mg/m2)
Pemetrexed and cisplatin will be admixed together in 1 liter of normal saline. The admixture of pemetrexed/cisplatin is stable for 4 hours and should be prepared and delivered immediately before use in the OR. The length of the pemetrexed/cisplatin lavage will be 1 hour.
干预措施: Pemetrexed (Drug)
Pemetrexed (300 mg/m2) and Cisplatin (175 mg/m2)
Pemetrexed and cisplatin will be admixed together in 1 liter of normal saline. The admixture of pemetrexed/cisplatin is stable for 4 hours and should be prepared and delivered immediately before use in the OR. The length of the pemetrexed/cisplatin lavage will be 1 hour.
干预措施: Cisplatin (Drug)
Pemetrexed (400 mg/m2) and Cisplatin (175 mg/m2)
Pemetrexed and cisplatin will be admixed together in 1 liter of normal saline. The admixture of pemetrexed/cisplatin is stable for 4 hours and should be prepared and delivered immediately before use in the OR. The length of the pemetrexed/cisplatin lavage will be 1 hour.
干预措施: Pemetrexed (Drug)
Pemetrexed (400 mg/m2) and Cisplatin (175 mg/m2)
Pemetrexed and cisplatin will be admixed together in 1 liter of normal saline. The admixture of pemetrexed/cisplatin is stable for 4 hours and should be prepared and delivered immediately before use in the OR. The length of the pemetrexed/cisplatin lavage will be 1 hour.
干预措施: Cisplatin (Drug)
结局指标
主要结局
Number of participants with Dose-Limiting Toxicity (DLT)
时间窗: from the first day of treatment until 4 weeks after the treatment
Dose limiting toxicity (DLT) is defined as: 1) Grade 4 treatment-related hematologic toxicity that lasts more than for 5 days or grade 3 thrombocytopenia with grade 3 or 4 bleeding, 2) Febrile neutropenia, 3) Grade 3 or greater treatment related non-hematologic toxicity with the following exceptions:Grade 3 diarrhea is a dose limiting toxicity DLT only if the patient was compliant with an anti-diarrheal program consistent with best clinical practice; Grade 3 or 4 nausea and vomiting is a dose limiting toxicity DLT only if the patient was compliant with an antiemetic program consistent with best clinical practice; Alopecia
次要结局
未报告次要终点
研究者
Shawn Groth
Assistant Professor
Baylor College of Medicine