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.
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: I. To assess the phenotype and function of the UD TGFbetai NK cells and correlate with clinical outcomes. II. To assess in vivo persistence of UD TGFbetai NK cells after adoptive transfer and correlate with clinical outcomes. III. To assess immune status, inflammatory cytokine levels, and anti-melanoma cell activity. OUTLINE: This is a phase I, dose-escalation study of UD TGFbetai NK cells followed by a phase II study. Patients receive UD TGFbetai NK cells intravenously (IV) over 30 minutes on day 1 and temozolomide orally (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. After completion of study treatment, patients are followed up every 6 months for up to 5 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
30
Given UD TGFbi NK cell IV
Given PO
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States
RECRUITINGDose 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.
Time frame: Up to 28 days
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.
Time frame: Up to 5 years
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.
Time frame: Up to 5 years
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.
Time frame: Up to 5 years
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).
Time frame: Up to 5 years
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.
Time frame: 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)
Survival will initially be modeled using Kaplan-Meier methods, resulting in median survival times with 95% CI, assuming sufficient events have occurred.
Time frame: 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)
The percentage of patients with adverse events as assessed by CTCAE V 5.0 criteria. Frequency and severity of AEs 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
Time frame: Up to 5 years
Pharmacokinetics (PK) parameters associated with UD TGFbetai NK cells (Phase I)
The samples will be analyzed using the Devyser Chimerism assay to identify the UD TGFbeta iNK cells. We will use graphical analyses as well as repeated measure models (linear or nonlinear mixed models, generalized estimating equations \[GEE\]) to assess the PK described above in relation to clinical treatment outcomes, recognizing some inherent limitations due to sample size.
Time frame: 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)
The Ohio State University Comprehensive Cancer Center
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