Evaluate the Safety of UF-KURE19 Cells in Non-Hodgkin Lymphomas

A Phase 1 Single Arm, Open Label Study to Evaluate the Safety of UF-KURE19 Cells in Patients With Relapsed or Refractory B Cell Non-Hodgkin Lymphomas

This treatment uses T cells already present in the participant's body that have been modified outside of the body by a lentivirus and then returned by an infusion to target the cancer. Lentivirus is a family of viruses that can be used by scientists to alter cells. The specific type of cells that will be used is called UF-KURE19 chimeric antigen receptor T cells (CAR-T cells). The CAR-T cells that will be reinfused into the body are modified using a lentivirus that is no longer active. The investigators are evaluating UF-KURE19 because it uses a process that is shorter than other approved CAR-T cells. While the shorter manufacture time can be an advantage, the safety of this approach has not been demonstrated.

Study Overview

• Status: Recruiting
• Conditions: Non Hodgkin Lymphoma
• Intervention / Treatment: Biological: UF-KURE19 CAR-T cells; Drug: Fludarabine; Drug: Cyclophosphamide

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Paolo Caimi, MD; Phone Number: 216-347-5571; Email: caimip@ccf.org
• Study Contact Backup: Name: Changchun Deng, MD, PhD; Phone Number: 216-844-0139; Email: changchun.deng@uhhospitals.org

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Recruiting
      • University of Iowa/Holden Comprehensive Cancer Center
      • Contact: Umar Farooq, MD; Email: umar-farooq@uiowa.edu
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Recruiting
      • University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center
      • Contact: Regina Carlisle, RN; Phone Number: 216-844-5432
      • Contact: Changchun Deng, MD; Phone Number: 216-844-0139; Email: changchun.deng@uhhospitals.org
    • Cleveland, Ohio, United States, 44195
      • Recruiting
      • Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center
      • Contact: Paolo Caimi, MD; Phone Number: 216-347-5571; Email: caimip@ccf.org

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Male or female patients aged 18 years or older.

• Participants must have histologically confirmed, CD19 positive relapsed or refractory NHL that meets at least one of the following treatment indications.

  • Relapsed after 2 or more lines of chemotherapy, or:

  • Refractory to chemotherapy, defined as:

    • Progressive disease while receiving last chemotherapy, or Persistent disease after first line chemotherapy treatment with curative intent or stable disease lasting ≤6 months after last chemotherapy, or relapse within 6 months of last chemotherapy, or disease progression or elapse ≤12 months after prior autologous stem cell transplant, or:

  • Relapsed disease that is ineligible to receive hematopoietic stem cell transplantation due to comorbidities or age or patient preference
• Subjects must have a CD3% ≥ 15% of total PBMCs (monocytes + lymphocytes).
• ECOG Performance status ≤ 2
• At least one measurable lesion according to Lugano Revised Response Criteria for Malignant Lymphoma.
• Minimum of 2 weeks since prior radiation therapy or systemic therapy to treat malignancy at the time of leukapheresis.
• Total bilirubin ≤ 1.5X institutional upper limit of normal.
• AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional upper limit of normal.
• Calculated creatinine clearance ≥ 30mL/min estimated by the Cockcroft - Gault formula.
• Cardiac ejection fraction of ≥45%, and no more than trivial (or trace, minimal or mild)pericardial effusion, as determined by an echocardiogram.
• Adequate pulmonary function, defined as ≤ Grade 1 dyspnea (unless considered secondary to lymphoma) and oxygen saturation (SaO2) ≥ 92% on room air. If pulmonary function tests (PFTs) are performed based on the clinical judgment of the treating physician, patients with forced expiratory volume in 1 second (FEV1) ≥ 50% of predicted and diffusing capacity for carbon monoxide (DLCO) (corrected for hemoglobin) of ≥ 40% of predicted will be eligible.
• Subjects (or legal guardians) must have the ability to understand and the willingness to sign a written informed consent document.
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of < 1% per year during the treatment period and for at least 90 days after the UF-KURE19 CAR-T cell infusion. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (< 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined: With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for at least 6 months after the UF-KURE19 CAR-T cell infusion. Men must refrain from donating sperm during this same period. With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 6 months after the UF-KURE19 CAR-T cell infusion to avoid potential embryonal or fetal exposure. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

Exclusion Criteria:

• Autologous stem cell transplant within 6 weeks of informed consent
• History of allogeneic hematopoietic stem cell transplantation.
• Active central nervous system or leptomeningeal involvement by lymphoma. Subjects with untreated brain metastases/CNS disease will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with a history of CNS or meningeal involvement must be in a documented remission by CSF evaluation and contrast-enhanced MRI imaging for at least 90 days prior to registration.
• Second active malignancy, other than non-melanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast).
• Less than 28 days elapsed between prior treatment with investigational agent(s) and leukapheresis.
• New York Heart Association class III-IV congestive heart failure.
• Cardiovascular disorders including unstable angina pectoris, clinically significant cardiac arrhythmias, myocardial infarction or stroke (including transient ischemic attack, or other ischemic event) within 6 months prior to registration.
• Known human immunodeficiency virus infection or acquired immunodeficiency syndrome related illness.
• Pregnant or breastfeeding women are excluded from this study because CAR-T cell therapy may be associated with the potential for teratogenic or abortifacient effects. Women of childbearing potential must have a negative serum pregnancy test. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with CAR-T cells, breastfeeding should be discontinued. These potential risks may also apply to other agents used in this study.
• Evidence of myelodysplastic syndrome or cytogenetic abnormality indicative of myelodysplasia on any bone marrow biopsy prior to initiation of therapy.
• Serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive patients will be excluded).
• Patients with history of clinically relevant CNS pathology such as epilepsy, seizure disorders, paresis, aphasia, uncontrolled cerebrovascular disease, severe brain injuries, dementia and Parkinson's disease.
• Subjects with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, pulmonary abnormalities or psychiatric illness/social situations that would limit compliance with study requirements.
• History of active autoimmune disease (i.e. rheumatoid arthritis, systemic lupus erythematosus) with requirement of systemic immunosuppressive medications other than low dose steroids [i.e. maximum of 15mg prednisone equivalent] within the last 6 months.
• Circulating malignant B cells in peripheral blood detected by complete blood count at the time of subject enrollment.

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: UF-KURE19 CAR-T cell infusion; The safety and manufacturing feasability of UF-KURE19 will be determined with up to 10 patients being enrolled. Lymphodepleting therapy will begin on Days -4 to -2 with each weight category of participants receiving 30mg/m2/IV of Fludarabine and 500mg/m2/IV of Cyclophosphamide regardless of the level of UF-KURE19 CAR-T cell dosing. Dosing: Participants greater than or equal to 50 kg: Level -1: 8.5 x 10^6 UF-KURE19 CAR-T Cell Dose (CAR positive cells); Level 1 : 17.5 x 10^6 UF-KURE19 CAR-T Cell Dose Participants less than 50 kg: Level -1: 5.5 x 10^6 UF-KURE19 CAR-T Cell Dose; Level 1: 11.5 x 10^6 UF-KURE19 CAR-T Cell Dose

Biological: UF-KURE19 CAR-T cells; UF-KURE19 cells are initially generated from a starting autologous apheresis sample. T cells are activated and transduced with Kure19 lentiviral vector that consists of a 3rd generation vector with an scFV (FMC63) that targets CD19. The product is harvested at 17-20hr after culture and cryopreserved; Drug: Fludarabine; Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. This metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA primase, thus inhibiting DNA synthesis.; Other Names: Fludara®; Fludarabine Phosphate; Drug: Cyclophosphamide; The mechanism of action is thought to involve cross-linking of tumor cell DNA; Other Names: Neosar®; Cytoxan ®; Endoxan®; Procytox®; Revimmune®; Cycloblastin®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recommend dose(s) of UF-KURE19 CAR-T Cells	Safety will be assessed by the number of DLT experienced at the target dose which is hypothesized to be less than 33%.	Up to 28 days after treatment
Toxicities associated with the target dose of UF-KURE19 CAR-T Cells	Toxicities will be reported as specific adverse events as a result of the target dose of UF-KURE19 CAR-T Cells. An adverse event (AE) is any unfavorable or unintended event, physical or psychological, associated with a research study, which causes harm or injury to a research participant as a result of the participant's involvement in a research study.	Up to 12 months after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of UF-KURE19 CAR-T cells manufacture success	Defined as the percentage of UF-Kure19 CAR-T patient products manufactured that meet the release criteria.	2 weeks after culture of UF-KURE19 CAR-T cells
Incidence of treatment- emergent AEs (TEAEs)	Number of serious adverse events (SAEs), therapy - related AEs, Grade 3 or 4 TEAEs, TEAEs with an outcome of death and TEAEs leading to study discontinuation.	Up to 12 months after treatment
Overall Response	The number of subjects with partial response (PR) and complete response (CR). Using the 2014 Lugano Response Criteria for Malignant Lymphoma, partial response is defined as a decrease in the size of a tumor or in the amount of cancer in the body and complete response is defined as a complete disappearance of all detectable clinical evidence of disease, and disease-related symptoms if present prior to therapy.	Up to 12 months after treatment

Collaborators and Investigators

• Sponsor: Changchun Deng, MD
• Investigators: Principal Investigator: Changchun Deng, MD, PhD, University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): April 26, 2023
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: May 27, 2022
• First Submitted That Met QC Criteria: May 27, 2022
• First Posted (Actual): June 1, 2022

Study Record Updates

• Last Update Posted (Actual): March 29, 2024
• Last Update Submitted That Met QC Criteria: March 28, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Non Hodgkin Lymphoma; UF-KURE19; CD19 CAR-T cells
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Lymphoma, Non-Hodgkin; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Fludarabine; Fludarabine phosphate
• Other Study ID Numbers: CASE2422

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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