Phase I Trial of Intratumoral Administration of a Measles Virus Derivative Expressing the Helicobacter Pylori Neutrophil-Activating Protein (NAP) (MV-s-NAP) in Patients With Metastatic Breast Cancer
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- Mayo Clinic
- 入组人数
- 54
- 试验地点
- 2
- 主要终点
- Maximum tolerated dose
研究概览
简要总结
This phase I trial investigates the side effects and best dose of using a modified measles virus, MV-s-NAP, in treating patients with invasive breast cancer that has spread to other places in the body (metastatic). Both the unmodified vaccination measles virus (MV-Edm) and this modified virus (MV-s-NAP) have been shown to multiply in and destroy breast cancer cells in the test tube and in research mice. MV-s-NAP has been altered by having an extra gene (piece of deoxyribonucleic acid [DNA]) so that virus can make a protein called helicobacter pylori neutrophil activating protein (NAP) which is normally expressed in inflammatory reactions. Monitoring blood, urine, tissue, and throat swab samples, and using imaging tests may help to determine whether MV-s-NAP has any impact on the amount of disease present in metastatic breast cancer patients.
详细描述
PRIMARY OBJECTIVES:
I. To determine the maximally tolerated dose (MTD) of intratumoral administration of an Edmonston strain measles virus genetically engineered to express NAP (oncolytic measles virus encoding helicobacter pylori neutrophil-activating protein (modified virus strain neutrophil activating protein [MV-s- NAP) in patients with metastatic breast cancer.
II. To determine the safety and toxicity of one-time intratumoral administration of MV-s-NAP in patients with metastatic breast cancer.
III. To determine the safety and toxicity of serial intratumoral administration of MV-s-NAP in patients with metastatic breast cancer.
SECONDARY OBJECTIVES:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- •Age >= 18 years
- •COHORT 1 ONLY: Pathologically confirmed invasive breast adenocarcinoma with documented estrogen receptor (ER)/progesterone receptor (PR) /HER2 status and radiographic evidence of distant metastatic disease
- •COHORTS 2 & 3 ONLY: Pathologically confirmed invasive breast adenocarcinoma with documented ER/PR/HER2 status and radiographic evidence of distant metastatic or recurrent disease
- •COHORT 1 ONLY: Radiographic evidence of distant metastatic disease (using 7th edition American Joint Committee on Cancer [AJCC] criteria) with two discrete sites of measurable disease
- •COHORTS 2 & 3 ONLY: Radiographic evidence of distant metastatic or recurrent disease (using 8th edition AJCC criteria) with at least one site of measurable disease
- •Prior therapies:
- •Patients with ER/PR positive, HER2 negative breast cancer must have progressed through at least one prior cytotoxic regimen for advanced disease and no longer be candidates for standard endocrine therapy or combination of endocrine therapy with other agents such as CDK4/6 inhibitors
- •Patients with HER2 positive breast cancer irrespective of ER/PR status must have received or no longer be candidates for HER2 directed therapy with trastuzumab or pertuzumab
- •Patients with ER/PR/HER2 negative breast cancer must have progressed through at least one prior cytotoxic regimen for advanced disease
- •COHORT 1: At least one site of recurrent/metastatic disease that measures > 1 cm in greatest dimension (> 2 cm for lung lesions) and is amenable to safe percutaneous intratumoral administration of MV-s-NAP as determined by an interventional radiologist
- •COHORTS 2 & 3 ONLY: At least 1 site of recurrent/metastatic disease measuring > 1 cm in greatest dimension [> 2 cm for lung lesions] (Note that if the lesion injected in cycle 1 is not amenable to re-injection, another lesion could be selected for injection
- •Absolute neutrophil count (ANC) >= 1500/uL (=< 7 days prior to registration)
- •Platelets (PLT >= 100,000/uL) (=< 7 days prior to registration)
- •Total bilirubin =< institutional upper limit of normal (=< 7 days prior to registration)
- •Aspartate aminotransferase (AST) =< 2 x upper limit of normal (ULN) (=< 7 days prior to registration)
- •Creatinine =< 1.5 x ULN (=< 7 days prior to registration)
- •Hemoglobin >= 9.0 g/dL (=< 7 days prior to registration)
- •Negative pregnancy test done =< 7 days prior to registration (for women of childbearing potential only)
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
- •Ability to provide informed written consent
- •Willingness to return to the Mayo Clinic enrolling institution for follow-up
- •Willingness to provide biologic samples for correlative research purposes
- •Life expectancy >= 12 weeks
- •Concomitant administration of a bone modifying agent (e.g., zoledronic acid or denosumab) is permitted for the prevention or management of skeletal related events in patients with bone metastases and documentation of tolerability with prior exposures
排除标准
- •Known standard therapy for the patient's disease that is potentially curative or definitely capable of extending life expectancy
- •Clinical or radiographic suspicion of impending visceral crisis due to invasion or compression by tumor
- •Active infection =< 5 days prior to registration
- •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 registration
- •Immunotherapy =< 4 weeks prior to registration
- •HER2 directed therapy =< 3 weeks prior to registration
- •Targeted therapy =< 2 weeks prior to registration (e.g., CDK4/6 inhibitors, everolimus)
- •Investigational agent =< 4 weeks prior to registration
- •Any viral or gene therapy prior to registration
- •Failure to fully recover from acute, reversible effects of prior systemic therapy 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 supraventricular tachycardia [SVT])
- •Untreated or progressive central nervous system (CNS) metastases
- •NOTE: Patients with a history of treated brain metastases (surgical resection, whole brain radiation, and/or stereotactic radiosurgery) are eligible only if they are asymptomatic and have stable MRI scans for 3 consecutive months, including < 28 days of study entry
- •Standing requirement for blood product support
- •Human immunodeficiency virus (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-Food and Drug Administration [FDA]-approved indication and in the context of a research investigation)
- •Any concurrent medications that the principal investigator determines could interfere with the trial
- •Treatment with oral/systemic corticosteroids, with the exception of topical or inhaled steroids or low dose systemic steroids for physiologic replacement (e.g., Prednisone ≤10 mg/day)
- •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
- •History of receiving the measles vaccination with the "killed vaccine" between 1963-1967 without subsequent re-immunization (2 doses) with the active, live vaccination."
研究组 & 干预措施
Cohort 2 (Every 21 day MV-s-NAP)
Patients receive MV-s-NAP IT on day 1 of each cycle. Cycles repeat every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, tumor biopsy, and blood and urine sample collection throughout the study. (CLOSED TO ACCRUAL 6/9/2025)
干预措施: Magnetic Resonance Imaging (Procedure)
Cohort 2 (Every 21 day MV-s-NAP)
Patients receive MV-s-NAP IT on day 1 of each cycle. Cycles repeat every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, tumor biopsy, and blood and urine sample collection throughout the study. (CLOSED TO ACCRUAL 6/9/2025)
干预措施: Biospecimen Collection (Procedure)
Cohort 1 (single treatment MV-s-NAP)
Patients receive MV-s-NAP IT on day 1 in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, tumor biopsy, and blood and urine sample collection throughout the study.
干预措施: Biospecimen Collection (Procedure)
Cohort 2 (Every 21 day MV-s-NAP)
Patients receive MV-s-NAP IT on day 1 of each cycle. Cycles repeat every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, tumor biopsy, and blood and urine sample collection throughout the study. (CLOSED TO ACCRUAL 6/9/2025)
干预措施: Computed Tomography (Procedure)
Cohort 1 (single treatment MV-s-NAP)
Patients receive MV-s-NAP IT on day 1 in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, tumor biopsy, and blood and urine sample collection throughout the study.
干预措施: Oncolytic Measles Virus Encoding Helicobacter pylori Neutrophil-activating Protein (Biological)
Cohort 2 (Every 21 day MV-s-NAP)
Patients receive MV-s-NAP IT on day 1 of each cycle. Cycles repeat every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, tumor biopsy, and blood and urine sample collection throughout the study. (CLOSED TO ACCRUAL 6/9/2025)
干预措施: Oncolytic Measles Virus Encoding Helicobacter pylori Neutrophil-activating Protein (Biological)
Cohort 3 (Every 14 day MV-s-NAP)
Patients receive MV-s-NAP IT on day 1 of each cycle. Cycles repeat every 14 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, tumor biopsy and blood and urine sample collection throughout the study.
干预措施: Biopsy (Procedure)
Cohort 3 (Every 14 day MV-s-NAP)
Patients receive MV-s-NAP IT on day 1 of each cycle. Cycles repeat every 14 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, tumor biopsy and blood and urine sample collection throughout the study.
干预措施: Computed Tomography (Procedure)
Cohort 3 (Every 14 day MV-s-NAP)
Patients receive MV-s-NAP IT on day 1 of each cycle. Cycles repeat every 14 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, tumor biopsy and blood and urine sample collection throughout the study.
干预措施: Magnetic Resonance Imaging (Procedure)
Cohort 3 (Every 14 day MV-s-NAP)
Patients receive MV-s-NAP IT on day 1 of each cycle. Cycles repeat every 14 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, tumor biopsy and blood and urine sample collection throughout the study.
干预措施: Biospecimen Collection (Procedure)
Cohort 3 (Every 14 day MV-s-NAP)
Patients receive MV-s-NAP IT on day 1 of each cycle. Cycles repeat every 14 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, tumor biopsy and blood and urine sample collection throughout the study.
干预措施: Oncolytic Measles Virus Encoding Helicobacter pylori Neutrophil-activating Protein (Biological)
Cohort 1 (single treatment MV-s-NAP)
Patients receive MV-s-NAP IT on day 1 in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, tumor biopsy, and blood and urine sample collection throughout the study.
干预措施: Computed Tomography (Procedure)
Cohort 1 (single treatment MV-s-NAP)
Patients receive MV-s-NAP IT on day 1 in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, tumor biopsy, and blood and urine sample collection throughout the study.
干预措施: Magnetic Resonance Imaging (Procedure)
Cohort 1 (single treatment MV-s-NAP)
Patients receive MV-s-NAP IT on day 1 in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, tumor biopsy, and blood and urine sample collection throughout the study.
干预措施: Biopsy (Procedure)
结局指标
主要结局
Maximum tolerated dose
时间窗: During the first cycle of treatment (each cycle = 21 days)
This is defined as the highest dose level among those under consideration where at most one of 6 patients develops a dose limiting toxicity, and two or more of the 3-6 patients treated at the next higher dose level develop a dose limiting toxicity.
Best tumor response
时间窗: Up to 2 years
The best tumor response in the injected and non-injected lesion will be determined using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Results will be tabulated for the entire cohort and by breast cancer subtype in terms of whether there was response in none of the lesions, only the injected lesion, or both lesions.
Measles virus viremia
时间窗: Up to 2 years
Defined as detection of any titer of virus by quantitative real time-polymerase chain reaction performed with patient peripheral blood mononuclear cells. Viremia will be examined in terms of the day and dose level it was detected, as well as the time to recovery.
Incidence of adverse events
时间窗: Up to 2 years
The maximum grade of each type of toxicity will be recorded for each patient. For each toxicity reported by dose level, the percentage of patients developing any degree of that toxicity, as well as the percentage of patients developing a severe (grade 3 or higher) toxicity, will be determined.
Peripheral immune response
时间窗: Up to 2 years
Peripheral immune response specific to measles virus is defined as detection of serum IgG anti-measles antibody levels of \> 20.0 EU/mL by the Enzyme Immunoassay. Peripheral anti-neutrophil activating protein (NAP) transgene response will be represented by antibody titers determined by an antigen-mediated enzyme linked immunosorbent assay against purified helicobacter pylori NAP antigen. Systemic induction of HMGB1 will also be determined. All of these factors will be examined in terms of the day and dose level they were detected, as well as the time to recovery. For each dose level, the point at which viral replication and measles virus shedding is no longer seen will be tabulated.
次要结局
- Tumor response(Up to 2 years)
- Progression-free survival (PFS)(Up to 2 years)
- Overall survival (OS)(Up to 2 years)