This phase I trial tests the safety, side effects, best dose of MUC1-activated T cells in treating patients with ovarian cancer that has come back after a period of improvement (relapsed) or that remains despite treatment (resistant). T cells are infection fighting blood cells that can kill tumor cells. The T cells given in this study will come from the patient and are made in a laboratory to recognize MUC1, a protein on the surface of tumor cells that plays a key role in tumor cell growth. These MUC1-activated T cells may help the body's immune system identify and kill MUC1 expressing ovarian tumor cells.
PRIMARY OBJECTIVE: I. To determine the maximum tolerated dose (MTD) of autologous MUC1-activated T-cells (in-house, manufactured MUC1-activated T cells) in patients with relapsed/refractory MUC1-expressing ovarian cancer. SECONDARY OBJECTIVES: I. Obtain preliminary efficacy associated with MUC1-targeting peripheral blood mononuclear cells (PBMC)-derived T cells in conjunction with cyclophosphamide (CTX) in MUC1-expressing ovarian cancer patients as measured by objective response rate (best overall response of either partial response \[PR\] or complete response \[CR\]), duration of response, clinical benefit rate (CR, PR or stable disease \[SD\]), time to disease progression, progression free survival (PFS), and overall survival (OS). II. Determine feasibility of in-house production and administration of MUC1-targeting PBMC-derived T cells and ability to proceed with T cell dose escalation. III. Evaluate the safety profile of in-house, manufactured MUC1-activated T cells in patients with relapsed/refractory MUC1-expressing ovarian cancer, including all grades of neurotoxicity (immune effector cell associated neurotoxicity \[ICANS\]) and cytokine release syndrome (CRS) as determined by American Society for Transplantation and Cellular Therapy (ASTCT) criteria (Lee 2018). IV. Evaluate the preliminary efficacy of MUC1 T cells in patients that have received bridging therapy compared to those that did not receive bridging therapy. CORRELATIVE OBJECTIVES: I. Determine whether culture expansion generated T cell receptor (TCR) oligoclonality through TCR Vbeta Analyses; whether such T cells persist in the circulation following adoptive transfer; and whether such persistence significantly correlates to objective responses. II. Determine whether MUC1-activated T cells results in systemic inflammatory signaling by characterizing the changes in serum cytokine levels over time. III. Determine whether T cells recognizing MUC1 in an MHC-restricted manner in culture (intracellular IFN-γ assays, enzyme-linked immunosorbent spot assay \[ELISpot\]) correspond to therapeutic efficacy upon subsequent adoptive transfer. IV. Determine the immunophenotype of the pre-infusion cell product (day 0 and day 19), assessing cellular differentiation, activation, effector molecules, and exhaustion markers, and assess whether any parameters correlate with objective responses. V. Determine the cytokine production at a single-cell level of the pre-infusion cell product (day 0 and day 19). VI. Evaluate the immunophenotype of diagnostic tumor material, post-T cell infusion biopsy material, post-relapse tumor material, and ascites (when available). VII. Determine whether MUC1-activated T cell infusion is associated with changes in peripheral blood immune cell subsets. VIII. Assess hospital resource utilization and health economics. VIIIa. Total number of hospitalizations, intensive care unit (ICU) admissions and length of stay in hospital and ICU, time between cell collection and infusion, and total cost of product. OUTLINE: This is a dose-escalation study. Patients undergo leukapheresis over 4 hours within 14 days after registration. Patients receive cyclophosphamide intravenously (IV) over 60 minutes on days -5 to -3 or bendamustine IV over 10 minutes on days -5 and -4 or -4 and -3. Patients receive MUC1-activated T cells IV over 10-60 minutes on day 0 or days 0 and 21. Patients also undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) during screening, and blood sample collection throughout the trial. In addition, patients may undergo computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET)/CT as clinically indicated throughout the trial. Patients may also undergo collection of ascites on study and during follow up. Patients are followed up at 30 and 60 days from day 28, then every 3 months for 2 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
12
Given IV
Given IV
Undergo blood and possible ascites sample collection
Undergo CT or PET/CT
Given IV
Undergo ECHO
Undergo leukapheresis
Undergo MRI
Undergo MUGA
Undergo PET/CT
Mayo Clinic in Arizona
Scottsdale, Arizona, United States
RECRUITINGDose-limiting toxicities (DLT)
Adverse events (AEs) will be defined per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 guidelines. DLT will be defined as an AE if at least possibly related to MUC1-activated T cells.
Time frame: Up to 28 days after T cell infusion
Maximum tolerated dose (MTD)
MTD is the highest dose of a drug or treatment that does not cause unacceptable side effects. MTD will be determined using the Bayesian optimal interval (BOIN) design.
Time frame: Up to 28 days after T cell infusion
Objective response rate
Tumor response will be based on combined imaging (Response Evaluation Criteria in Solid Tumors \[RECIST\] version \[v\] 1.1) and tumor markers (CA-125). Objective response rate will be defined as the proportion of patients with an overall best response of complete response (CR) or partial response (PR). Objective response rate will be summarized by descriptive summary statistics. The proportion of patients who achieve an overall as well as specific type of response will be estimated along with corresponding 95% exact binomial confidence intervals.
Time frame: Up to 2 years
Incidence of AEs
AEs will be defined per CTCAE v 5.0 guidelines. CRS and neurotoxicity will be graded using ASTCT criteria. The maximum grade for each type of AE will be recorded for each patient, and frequency tables will be reviewed to determine patterns by dose level and overall. The rate of grade 3 or higher non-hematologic adverse events, and the rate of grade 4 or higher adverse event (hematologic and non-hematologic) will be computed each with corresponding 95% exact binomial confidence intervals.
Time frame: Up to 2 years
Toxicity profile
Toxicities will be defined per CTCAE v5 as adverse events considered to be at least possibly related to study treatment. Overall toxicity incidence will be as well as toxicity profiles by dose level will be summarized.
Time frame: Up to 2 years
Clinical benefit rate
Tumor response will be based on combined imaging RECIST v 1.1 and tumor markers (CA-125). Clinical benefit rate will be defined as the proportion of patients with an overall best response of CR, PR or stable disease. Clinical benefit rate will be summarized by descriptive summary statistics. The proportion of patients who achieve an overall as well as specific type of response will be estimated along with corresponding 95% exact binomial confidence intervals.
Time frame: Up to 2 years
Time to clinical response
Tumor response will be based on combined imaging RECIST v 1.1 and tumor markers (CA-125). Will be estimated using the method of Kaplan-Meier.
Time frame: From registration to objective response (overall CR or PR), assessed up to 2 years
Progression-free survival
Tumor response will be based on combined imaging RECIST v 1.1 and tumor markers (CA-125). The distribution of survival time will be estimated using the method of Kaplan-Meier (overall and by dose level).
Time frame: From registration to disease progression or death due to any cause, assessed up to 2 years
Time to progression
Tumor response will be based on combined imaging RECIST v 1.1 and tumor markers (CA-125). Time to progression will be estimated using the method of Kaplan-Meier (overall and by dose level).
Time frame: From registration to disease progression, assessed up to 2 years
Overall survival
Tumor response will be based on combined imaging RECIST v 1.1 and tumor markers (CA-125). The distribution of overall survival will be estimated using the method of Kaplan-Meier (overall and by dose level).
Time frame: From registration to death due to any cause, assessed up to 2 years
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