Phase I Trial of Intraperitoneal Administration of a) a CEA-Expressing Derivative, and b) a NIS-Expressing Derivative Manufactured From a Genetically Engineered Strain of Measles Virus in Patients With Recurrent Ovarian Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Mayo Clinic
- 入组人数
- 37
- 试验地点
- 1
- 主要终点
- Dose Limiting Toxicity
研究概览
简要总结
RATIONALE: A gene-modified virus may be able to kill tumor cells without damaging normal cells.
PURPOSE: This phase I trial is studying the side effects and best dose of an attenuated oncolytic measles virus therapy and oncolytic virus therapy in treating patients with progressive, recurrent, or refractory ovarian epithelial cancer or primary peritoneal cancer (measles virus vaccine therapy study closed as of 06/02/2008).
详细描述
OBJECTIVES:
- Determine the safety and toxicity of recombinant carcinoembryonic antigen (CEA)-expressing measles virus (MV-CEA) and oncolytic measles virus encoding thyroidal sodium iodide symporter (MV-NIS) in patients with progressive, recurrent, or refractory ovarian epithelial or primary peritoneal cavity cancer ( MV-CEA closed as of 06/02/2008).
- Determine the maximum-tolerated dose of MV-CEA and MV-NIS in these patients ( MV-CEA closed as of 06/02/2008).
- Characterize viral gene expression at each dose level as manifested by CEA titers in these patients.
- Assess viremia, viral replication, and measles virus shedding or persistence after study therapy.
- Determine humoral and cellular immune response to the injected virus in these patients.
- Assess, preliminarily, the antitumor efficacy of this therapy, by assessing CA-125 levels, radiographic response, and time to progression, in these patients.
- Determine the time course of viral gene expression and virus elimination and biodistribution of virally infected cells at various time points after infection with MV-NIS using single photon emission computed tomography (SPECT/CT) imaging.
- Assess viremia, viral replication, and measles virus shedding/persistence following intraperitoneal administration of MV-NIS.
OUTLINE: This is a dose-escalation study.
Patients receive recombinant carcinoembryonic antigen-expressing measles virus (MV-CEA) or oncolytic measles virus encoding thyroidal sodium iodide symporter (MV-NIS) intraperitoneally over 30 minutes on day 1. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity ( MV-CEA closed as of 06/02/2008).
Cohorts of 3-6 patients receive escalating doses of MV-CEA until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity ( MV-CEA closed as of 06/02/2008).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 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 120 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 years.
- •Must have persistent, recurrent or progressive ovarian cancer or primary peritoneal cancer after prior treatment with platinum and taxol compounds. Histologic confirmation of the original primary tumor is required. Prior bilateral oophorectomy is required.
- •Patients with the following histologic epithelial cell types are eligible: Serous adenocarcinoma, endometroid adenocarcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, transitional cell carcinoma, malignant Brenner's Tumor, or adenocarcinoma NOS
- •The following laboratory values obtained ≤7 days prior to registration:
- •ANC ≥ 1500/μL
- •PLT ≥ 100,000/μL
- •Total bilirubin ≤ upper normal limit
- •AST ≤ 2 x ULN
- •Creatinine ≤ 1.5 x ULN
- •Hgb ≥ 9.0 g/dL
- •Ability to provide informed consent.
- •Willingness to return to Mayo Clinic Rochester for follow-up.
- •Life expectancy ≥ 12 weeks.
- •Must have anti-measles immunity as demonstrated by serum IgG anti-measles antibody levels of ≥ 20.0 EU/ml as determined by Enzyme Immunoassay (Diamedix, FL).
- •Must have normal serum CEA levels (<5 mg/ml) both at the time of study entry and in any prior testing. (NOTE: Not applicable for the MV-NIS cohort.)
- •Willingness to provide all biologic specimens as required by the protocol.
- •Measurable disease by exam or CT scan, or, for patients with CA-125 elevation or with microscopic residual but without measurable disease on imaging, willingness to undergo laparoscopy for evaluation of treatment effect if no radiographic progression after 6 treatment cycles.
- •CD4 count ≥200/μL or ≥15% of peripheral blood lymphocytes
排除标准
- •Epithelial tumors of low malignant potential, stromal tumors, and germ cell tumors of the ovary.
- •Known standard therapy for the patient's disease that is potentially curative or definitely capable of extending life expectancy. Subjects will be excluded if this is their first relapse and they have recurred >6 mo from completion of primary (adjuvant) chemotherapy.
- •ECOG performance status (PS) 3 or
- •Active infection ≤5 days prior to registration.
- •History of tuberculosis or history of PPD positivity.
- •History of other malignancy ≤5 years except for non-melanoma skin cancer or carcinoma in situ of the cervix.
- •Any of the following prior therapies:
- •Chemotherapy ≤ 3 weeks prior to study entry
- •Immunotherapy ≤ 4 weeks prior to study entry
- •Biologic therapy ≤ 4 weeks prior to study entry
- •Extensive abdominal surgery if it includes enterotomy(ies) <3 weeks prior to study entry. This criterion does not apply to placement of the peritoneal port-a-cath or lysis of adhesions at the time of study entry.
- •Any viral or gene therapy prior to study entry
- •Failure to fully recover from acute, reversible effects of prior chemotherapy regardless of interval since last treatment.
- •New York Heart Association classification III or IV, known symptomatic coronary artery disease, or symptoms of coronary artery disease on systems review, or known cardiac arrhythmias (atrial fibrillation or SVT).
- •Requiring blood product support.
- •CNS metastases or seizure disorder.
- •HIV-positive test result, or history of other immunodeficiency.
- •History of organ transplantation.
- •History of chronic hepatitis B or C.
- •Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational (utilized for a non-FDA-approved indication and in the context of a research investigation).
- •Any concurrent medications which could interfere with the trial.
- •Intra-abdominal disease > 8 cm in diameter at the time of registration, intrahepatic disease, or disease beyond the abdominal cavity.
- •Treatment with oral/systemic corticosteroids, with the exception of topical or inhaled steroids.
- •Exposure to household contacts ≤15 months old or household contact with known immunodeficiency.
- •Allergy to measles vaccine or history of severe reaction to prior measles vaccination.
- •Allergy to iodine. This does not include reactions to intravenous contrast materials.
研究组 & 干预措施
Experimental Arm
干预措施: reverse transcriptase-polymerase chain reaction (Genetic)
Experimental Arm
干预措施: laboratory biomarker analysis (Other)
Experimental Arm
干预措施: oncolytic measles virus encoding thyroidal sodium iodide symporter (Biological)
Experimental Arm
干预措施: carcinoembryonic antigen-expressing measles virus (Biological)
结局指标
主要结局
Dose Limiting Toxicity
时间窗: up to 12 months after last treatment
If one patient experiences a Dose limiting Toxicity(DLT), up to three additional patients will be treated at the same dose level. If DLT is observed in only one of six patients treated at a given dose level, the next cohort of three patients will be treated at the next higher dose level. If two or more patients experience DLT at a particular dose level, then the dose escalation will cease and any subsequent patients will be treated at a lower dose level. Thus finding the Max tolerated dose
次要结局
- Time to Progression(up to 12 months after last treatment)
- Number of Responses (Complete and Partial, Stable and Progressive Disease)(up to 12 months after last treatment)
- Change in CA-125 Levels From Baseline to Last Recorded Value (up to 18 Months)(baseline and up to 18 months)