Modified Immune Cells (TAG72-CAR T Cells) for the Treatment of Patients With Platinum Resistant Epithelial Ovarian Cancer

Study Overview
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Brief Summary
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This phase I trial tests the safety, side effects, and best dose of TAG72-chimeric antigen receptor (CAR) T cells in treating patients with epithelial ovarian cancer that remains despite treatment with platinum therapy (platinum 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 will have a new gene put in them that makes them able to recognize TAG72, a protein on the surface of tumor cells. These TAG72-specific T cells may help the body's immune system identify and kill TAG72+ cancer cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of TAG72-CAR T cells in participants with recurrent epithelial ovarian cancer (EOC). II To determine the maximum tolerated dose (MTD). III. To identify the recommended phase 2 dose (RP2D). SECONDARY OBJECTIVES: I. Persistence of CAR T cells in blood and peritoneal cavity pre- and 28 days post-infusion. II. Response based on Immune-Related Response Criteria (irRC). III. Estimate the 6 month progression free survival rate. IV. Estimate median overall survival. V. TAG72 expression on tumor cells by immunohistochemistry (IHC) and/or flow cytometry; VI. Describe the serum cytokine profile pre- and post-CAR T cell infusion to assess potential cytokine release syndrome (CRS) toxicity and CAR T cell effector function. EXPLORATORY OBJECTIVES: I. Phenotypes and frequencies of immune cell subsets in the peripheral blood pre- and post- therapy: analysis will include CD4:CD8 ratios, differentiation status (CD62L, CD27, CD45 RA/RO), and exhaustion markers (PD1, Tim3, LAG3), trafficking (CCR7, alpha4beta7), proliferation markers (ki67) and effector functions (cytotoxicity, Th1/Th2 cytokines, and CD107a degranulation) on endogenous and CAR+ T cells. II. Phenotype of tumor-infiltrating lymphocytes (TILs). III. Gene expression (by RNA-seq) of circulating tumor cells (CTCs). IV. Circulating cell-free deoxyribonucleic acid (cfDNA) in peripheral blood by whole exome sequencing. V. CAR immunogenicity based on the presence of anti-TAG72 CAR antibodies or T cell mediated immune responses. OUTLINE: This is a dose-escalation study of TAG72-CAR T cells. Patients receive fludarabine intravenously (IV) and cyclophosphamide IV on days -5 to -3. Patients receive TAG72-CAR T cells IP on day 0. After completion of study treatment, patients are followed up at 1, 7, 14, 21, 28, 60 and 90 days, 6, 9, and 12 months, then for up to 15 years.

Official Title
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A Phase 1 Study to Evaluate TAG72-Targeting Chimeric Antigen Receptor (CAR) T Cells in Patients With Advanced Epithelial Ovarian Cancer

Conditions
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Platinum-Resistant Ovarian Carcinoma

Intervention / Treatment
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* Biological: Chimeric Antigen Receptor T-cells
* Drug: Cyclophosphamide
* Drug: Fludarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must have the ability to understand and the willingness to sign a written informed consent Note: For research participants who do not speak English, a short form consent may be used with a City of Hope (COH) certified interpreter/translator to proceed with Pre-screening for TAG72 tumor expression, while the request for a translated full consent is processed. However, the research participant can proceed with lymphodepletion (if applicable) and CAR T cell infusion only after the translated full Screening/ Leukapheresis/ Treatment consent form is signed Agreement to allow the use of archival tissue from diagnostic tumor biopsies. If unavailable exceptions may be granted with study principal investigator (PI) approval Age >= 18 years Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2 or Karnofsky performance status (KPS) >= 70% Documented platinum resistant EOC (defined as disease that has progressed within six months of completing platinum therapy, or lack of response or disease progression while receiving the most recent platinum based therapy, respectively). Progression must be determined radiographically. Participant must have at least 1 measurable lesion Documented TAG72+ (> 1% cells >= +1 intensity) tumor expression by IHC (MAb CC49) as evaluated by COH Pathology Core In addition to platinum agents, participant must have received and failed, or have been intolerant to taxanes, liposomal doxorubicin or other agents known to confer clinical benefit. Participants are not required to fail all of these agents if, in the investigator's opinion, they would benefit from treatment on the current protocol No known contraindications to leukapheresis, steroids or tocilizumab Participant of reproductive potential must agree to use acceptable birth control methods throughout study therapy and for 3 months after final dose of study treatment Total serum bilirubin =< 2.0 mg/dL (performed within 42 days of signing the screening and leukapheresis consent) Patients with Gilbert syndrome may be included if their total bilirubin is < 3.0 x upper limit of normal (ULN) and direct bilirubin =< 1.5 x ULN Aspartate aminotransferase (AST) =< 5 x ULN (performed within 42 days of signing the screening and leukapheresis consent) Alanine aminotransferase (ALT) =< 5 x ULN (performed within 42 days of signing the screening and leukapheresis consent) Coagulation Parameters: Participants not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5xULN Creatinine clearance of >= 50 mL/min per the Cockcroft-Gault formula (performed within 42 days of signing the screening and leukapheresis consent) Cardiac function (12 lead-electrocardiogram [ECG]) without acute abnormalities requiring investigation or intervention (performed within 42 days of signing the screening and leukapheresis consent) Left ventricular ejection fraction > 40% (performed within 42 days of signing the screening and leukapheresis consent) Exclusion Criteria: Participant has not yet recovered from toxicities of prior therapy Participant with clinically significant arrhythmia or arrhythmias not stable on medical management within two weeks of signing the screening and leukapheresis consent Participant with known history or prior diagnosis of optic neuritis or other immunologic or inflammatory disease affecting the central nervous system, including seizure disorder Active autoimmune disease requiring systemic immunosuppressive therapy History of allergic reactions attributed to compounds of similar chemical or biologic composition or other agents used in this study Current signs and/or symptoms of bowel obstruction History of inflammatory bowel disease History of gastrointestinal perforation or symptomatic diverticular disease confirmed by CT or colonoscopy History of intra-abdominal abscess within the past 3 months. Patients with known peritoneal adhesions that preclude the placement of an intraperitoneal catheter in the opinion of the surgeon placing the intraperitoneal catheter. Participant with clinically significant arrhythmia or arrhythmias not stable on medical management within two weeks of signing the screening/leukapheresis/Treatment consent. Participant with known history or prior diagnosis of optic neuritis or other immunologic or inflammatory disease affecting the central nervous system, including seizure disorder. Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia, and participants on therapeutic anti-coagulation. History of stroke or intracranial hemorrhage within 6 months prior to signing the screening/ leukapheresis/Treatment consent History of other malignancies, except for malignancy surgically resected (or treated with other modalities) with curative intent with no known active disease present for >= 3 years, basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin Uncontrolled active infection Active hepatitis B or hepatitis C infection Human immunodeficiency virus (HIV) infection Any other condition that would, in the Investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns with clinical study procedures. Massive ascites requiring therapeutic paracentesis will not be cause for ineligibility, per se, but will be evaluated on an individual basis. Investigators who have questions regarding assessing ascites are asked to speak with the Principal Investigator. Prospective participants who, in the opinion of the Investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (TAG72-CAR T cells)<br>Patients receive fludarabine IV and cyclophosphamide IV on days -5 to -3. Patients receive TAG72-CAR T cells IP on day 0. | Biological: Chimeric Antigen Receptor T-cells<br>* Receive TAG72-CAR T cells IP<br>* Other names: Chimeric-antigen Receptor T-lymphocytes;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Fludarabine<br>* Given IV<br>* Other names: Fluradosa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting toxicities (DLTs) | Rates and associated 90% Clopper and Pearson binomial confidence limits will be estimated. | Up to 28 days | 
| Incidence of adverse events | Adverse Events are graded using NCI CTCAE v.5. | Up to 1 year post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Persistence of CAR T cells | Defined as CAR T cells > 0.1% of total CD3 cells by flow-cytometry. | Up to 28 days post treatment | 
| Expansion of CAR T cells | Max log10 copies/ug of genomic DNA | Up to 1 year post treatment | 
| Response (iRECIST) | Assessed based on Immune-Related Response Criteria. Rates and associated 90% Clopper and Pearson binomial confidence limits will be estimated. | Up to 1 year post treatment | 
| Overall survival (OS) | Defined as death from all causes from first treatment date (either lymphodepletion or CAR T cell infusion, as applicable. Kaplan Meier methods will be used to estimate median OS, and graph the results. | Up to 1 year post treatment | 
| Progression-free survival (PFS) | Defined as survival without biochemical (CA125) or radiographic evidence of disease progression or relapse from first treatment date (either lymphodepletion or CAR T cell infusion, as applicable). Rates and associated 90% Clopper and Pearson binomial confidence limits will be estimated. | Up to 6 months post treatment | 
| Serum cytokine profile | Serum cytokine profile before and after CAR T cell infusion: to assess potential cytokine release syndrome (CRS) toxicity and CAR T cell effector function, sequential serum samples will be analyzed for Th1/Th2 cytokines (e.g., IL-12, IFNgamma, TNFalpha, IL-10, IL-4, IL-5) by bead array | Up to 1 year post treatment |