A Phase I/II Study of Ex-Vivo Expanded Allogeneic Universal Donor (UD) TGFbi NK Cell Infusions in Combination With Temozolomide as a Lymphodepleting Agent in Patients With Melanoma Metastatic to the Brain
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 24
- 试验地点
- 2
- 主要终点
- Incidence of adverse events (AEs) (Phase I)
研究概览
简要总结
This phase I/II trial tests the safety, side effects, and best dose of universal donor UD TGFbetai natural killer (NK) cells, and whether UD TGFbetai NK cells with temozolomide works to shrink tumors in patients with stage IV melanoma that has spread to the brain (metastatic to the brain). NK cells are immune cells that contribute to anti-tumor immunity by recognizing and destroying transformed or stressed cells. Temozolomide is in a class of medications called alkylating agents. It works by slowing or stopping the growth of cancer cells in the body. Giving UD TGFbetai NK cell and temozolomide may work better in treating patients with stage IV melanoma.
详细描述
PRIMARY OBJECTIVES:
I. To confirm the safety and tolerability of UD TGFbetai NK cells in combination with temozolomide as a lymphodepleting agent in patients with melanoma metastatic to the brain and to determine the recommended phase 2 dose (RP2D). (Phase 1) II. To determine the intracranial response rate. (Phase 2)
SECONDARY OBJECTIVES:
I. To define the toxicities of UD TGFbetai NK cells when delivered with temozolomide as a lymphodepleting agent. (Phase 1) II. To define the pharmacokinetics (pK) associated with UD TGFbetai NK cells when used in combination with temozolomide as a lymphodepleting agent in patients with metastatic melanoma. (Phase 1) III. To determine the extracranial response rate. (Phase 2) IV. To determine progression free survival (PFS) (intracranial, extracranial, overall). (Phase 2) V. To assess overall survival (OS). (Phase 2) VI. To continue to assess the safety of temozolomide in combination with UD TGFbetai NK cells in a patient with melanoma metastatic to the brain. (Phase 2)
EXPLORATORY/CORRELATIVE OBJECTIVES:
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed melanoma with stage IV disease
- •Radiologically confirmed brain metastasis (n >= 1) with at least one measurable central nervous system (CNS) lesion >= 10 mm on T1-weighted gadolinium enhanced magnetic resonance imaging (MRI) and unequivocal evidence of progression
- •No indication for stereotactic radiotherapy
- •At least 4 weeks from any anticancer treatment (cytotoxic chemotherapy, signal transduction inhibitors, immunotherapy or radiation)
- •Absolute neutrophil count (ANC) 1 x 10^9/L
- •Platelets > 100,000/L
- •Hemoglobin (Hgb) >= 10 g/dL
- •Creatinine =< 1.5 x upper limit of normal (ULN)
- •Albumin >= 2.5 g/dL
- •Serum bilirubin < 1.5 x ULN unless due to Gilbert's syndrome
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 5 x ULN if documented liver metastases or < 3 X ULN without liver metastasis
- •> 18 years old (y/o)
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
- •Females of reproductive age must agree to the use of an effective contraceptive method while on treatment, beginning 2 weeks before the first dose of investigational product and for 28 days after the final dose of investigational product for women. Males able to father a child must practice adequate methods of contraception or completely abstain from intercourse from the first dose of investigational treatment until one week after the final dose of investigational treatment
- •Women of childbearing potential must have a negative serum pregnancy test within 14 days of enrollment and/or urine pregnancy test 48 hours prior to the administration of the first study treatment
- •Patient information and written informed consent form signed
排除标准
- •Planned or concurrent systemic treatment or radiation therapy
- •If requiring corticosteroids for cerebral edema, patients must be on a stable dose. Lowest dose of steroids needed to control CNS edema is recommended. Doses above 4 mg daily need to be cleared by principal investigator (PI) of the study
- •Known contra-indication to MRI
- •Patients with non-melanoma malignancies are excluded unless a complete remission has been achieved at least 3 years prior to study entry and no additional therapy is required or anticipated during the study period (exceptions include: non-melanoma skin cancers, in situ bladder cancer, in situ gastric cancer, in situ colon cancers, in situ cervical cancers/dysplasia, or in situ breast carcinoma)
- •Patients with other concurrent severe and/or uncontrolled medical disease which could compromise participation in the study, such as:
- •Active infection
- •Current active hepatic or renal disease
- •Pregnant women, women who are likely to become pregnant or are breastfeeding
- •Patients with significantly altered mental status prohibiting the understanding of the study or with psychological, familial, sociological, or geographical conditions potentially hampering ability to consent, compliance with the study protocol, and follow-up schedule; those conditions should be discussed with the patient before remigration in the trial
- •Patients who received any other investigational drugs within the 30 days prior to screening visit
- •Leptomeningeal metastases diagnosed by MRI
- •Inclusion in another therapeutic protocol within 30 days
- •If steroids are necessary to control symptoms related to CNS metastases, patients should be on the lowest dose of steroids necessary to control symptoms
研究组 & 干预措施
Treatment (UD TGFbetai NK cells, temozolomide)
Patients receive UD TGFbetai NK cells IV over 30 minutes on day 1 and temozolomide PO daily on days 1-5. Treatment with UD TGFbetai NK cells repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Cycles of temozolomide repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Temozolomide (Drug)
Treatment (UD TGFbetai NK cells, temozolomide)
Patients receive UD TGFbetai NK cells IV over 30 minutes on day 1 and temozolomide PO daily on days 1-5. Treatment with UD TGFbetai NK cells repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Cycles of temozolomide repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Natural Killer Cell Therapy (Biological)
结局指标
主要结局
Incidence of adverse events (AEs) (Phase I)
时间窗: Up to 5 years
Assessed using CTCAE version (V)4.0. All toxicities will be summarized as the percentage of patients experiencing each type and grade of event according to dose level. Patients who receive at least one dose of treatment will be included in the analysis. Frequency and severity of AEs and tolerability of the regimen will be collected and summarized by descriptive statistics. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.
Dose limited toxicities (Phase I)
时间窗: Up to 28 days
Toxicity will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) criteria, version 4.03. The CTCAE provides descriptive terminology and a grading scale for each adverse event listed. All toxicities will be summarized as the percentage of patients experiencing each type and grade of event according to dose level.
Proportion of subjects who achieve an intracranial complete response or partial response (Phase II)
时间窗: Up to 5 years
Assessed using modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria.
次要结局
- Incidence of adverse events of universal donor (UD) TGFbetai natural killer (NK) cells when delivered with temozolomide as a lymphodepleting agent (Phase I)(Up to 5 years)
- Extracranial response rate (Phase II)(Up to 5 years)
- Progression free survival (PFS) (intracranial, extracranial, overall) (Phase II)(From initiation of therapy to the time of Response Evaluation Criteria in Solid Tumors (RECIST) progression or death, assessed up to 5 years)
- Overall Survival (OS) (Phase II)(From initiation of therapy to death, assessed up to 5 years)
- Percentage of patients with adverse events of the combination temozolomide and UD TGFbetai NK cells (Phase II)(Up to 5 years)
- Pharmacokinetics (PK) parameters associated with UD TGFbetai NK cells (Phase I)(Within 1 hour prior to UD TGFbetai NK infusions and within 30 minutes post infusion on cycle 1, day 15 (C1D15), C1D17, and C1D19] and prior to cycle 2 day 1 and cycle 3 day 1. (Each cycle is 28 days))
研究者
Kari Kendra
Principal Investigator
Ohio State University Comprehensive Cancer Center