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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Platinum-Resistant Ovarian Carcinoma
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Fludarabine; Biological: Chimeric Antigen Receptor T-cells

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 33
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Lorna Rodriguez; Phone Number: 626-359-8111; Email: lorrodriguez@coh.org

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • Recruiting
      • City of Hope Medical Center
      • Contact: Lorna C. Rodriguez; Phone Number: 626-456-4673; Email: lorrodriguez@coh.org
      • Contact: Email: lorrodriguez@coh.org
      • Principal Investigator: Lorna Rodriguez

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (TAG72-CAR T cells); Patients receive fludarabine IV and cyclophosphamide IV on days -5 to -3. Patients receive TAG72-CAR T cells IP on day 0.

Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Drug: Fludarabine; Given IV; Other Names: Fluradosa; Biological: Chimeric Antigen Receptor T-cells; Receive TAG72-CAR T cells IP; Other Names: CAR T Cell; CAR T Cells; CAR T-cells; CAR-modified T-cells; CAR-T Cell; CAR-T Cells; Chimeric-antigen Receptor T-lymphocytes

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phenotype of tumor-infiltrating lymphocytes	Will provide descriptive statistics for exploratory studies.	Up to 1 year post treatment
Gene expression	Assessed by ribonucleic acid sequencing (RNA-seq) of circulating tumor cells (CTCs). Will provide descriptive statistics for exploratory studies.	Up to 1 year post treatment
Phenotypes and frequencies of immune cell subsets in the peripheral bloodpre- 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. Will provide descriptive statistics for exploratory studies. Data will be presented as % of total cells, or as cell/mL blood or peritoneal fluid.	Up to 1 year post treatment
Circulating cell-free deoxyribonucleic acid in peripheral blood	Assessed by whole exome sequencing.	Up to 1 year post treatment
CAR immunogenicity	Assessed based on the presence of anti-TAG72 CAR antibodies or T cell mediated immune responses.	Up to 1 year post treatment
Microbial changes (Stool)	Microbial changes in stool associated with CAR T cell therapy	Up to 1 year post treatment

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Lorna Rodriguez, City of Hope Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): May 5, 2022
• Primary Completion (Anticipated): April 5, 2026
• Study Completion (Anticipated): April 5, 2027

Study Registration Dates

• First Submitted: December 8, 2021
• First Submitted That Met QC Criteria: January 26, 2022
• First Posted (Actual): February 4, 2022

Study Record Updates

• Last Update Posted (Estimate): May 11, 2023
• Last Update Submitted That Met QC Criteria: May 9, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Fludarabine
• Other Study ID Numbers: 20034 (Other Identifier: City of Hope Medical Center); P30CA033572 (U.S. NIH Grant/Contract); NCI-2021-10838 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); R01CA266874 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No