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.
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)
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)
Single group
Natural Killer Cell Therapy
Biological/VaccineGiven UD TGFbi NK cell IV
Temozolomide
DrugGiven PO
Dose limited toxicities (Phase I)
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.
Incidence of adverse events (AEs) (Phase I)
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.
Proportion of subjects who achieve an intracranial complete response or partial response (Phase II)
Assessed using modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria.
Incidence of adverse events of universal donor (UD) TGFbetai natural killer (NK) cells when delivered with temozolomide as a lymphodepleting agent (Phase I)
Assessed using CTCAE V5.0. 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.
Extracranial response rate (Phase II)
Assessed using RECIST criteria. Will be calculated as the proportion of patients who achieve a response to therapy divided by the total number of evaluable patients. An evaluable patient is defined as an eligible patient who has received at least one dose of therapy. All evaluable patients will be included in calculating the response rate for the study along with corresponding 95% binomial CIs (assuming that the number of patients who respond is binomially distributed).
Progression free survival (PFS) (intracranial, extracranial, overall) (Phase II)
Survival will initially be modeled using Kaplan-Meier methods, resulting in median survival times with 95% confidence interval (CI), assuming sufficient events have occurred.
Overall Survival (OS) (Phase II)
Survival will initially be modeled using Kaplan-Meier methods, resulting in median survival times with 95% CI, assuming sufficient events have occurred.
Phenotype and function of the UD TGFbetai NK cells
Will be correlated with clinical outcomes. Graphical analyses will be largely used to assess potential patterns and relationships. All continuous measurements will be summarized using mean +/- standard error of the mean (SEM), range, and median at each time point. Associations with clinical outcomes will be evaluated using two-sample t test or Fisher exact test.
Persistence of UD TGFbetai NK cells
Graphical analyses will be largely used to assess potential patterns and relationships. All continuous measurements will be summarized using mean +/- SEM, range, and median at each time point. Associations with clinical outcomes will be evaluated using two-sample t test or Fisher exact test.
Distribution of UD TGFbetai NK cells in the cerebrospinal fluid (CSF)
Graphical analyses will be largely used to assess potential patterns and relationships. All continuous measurements will be summarized using mean +/- SEM, range, and median at each time point. Associations with clinical outcomes will be evaluated using two-sample t test or Fisher exact test.
Immune activation post infusion
Graphical analyses will be largely used to assess potential patterns and relationships. All continuous measurements will be summarized using mean +/- SEM, range, and median at each time point. Associations with clinical outcomes will be evaluated using two-sample t test or Fisher exact test.
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Kari Kendra
Lead sponsor
Ohio State University Comprehensive Cancer Center
Sponsor institution
