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

Study Overview
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Brief Summary
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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 The CAR-T cells that will be reinfused into the body are modified using a lentivirus that is no longer active.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.

Official Title
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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

Conditions
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Non Hodgkin Lymphoma

Intervention / Treatment
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* Biological: UF-KURE19 CAR-T cells
* Drug: Fludarabine
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients aged 18 years or older. Subjects must have histologically confirmed, CD19 positive, non-Hodgkin lymphoma on the most recent biopsy and disease that is relapsed after 2 or more lines of therapy or refractory to chemotherapy (defined as progressive disease or stable disease lasting ≤6 months, as best response to most recent chemotherapy regimen); or relapsed disease after initial therapy that is ineligible to receive hematopoietic stem cell transplantation (HSCT) due to comorbidities or age. 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 evidence of 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 meningeal 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 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 myelodysplasia 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: UF-KURE19 CAR-T cell infusion<br>The maximum tolerated dose (MTD) of UF-KURE19 will be determined using a dose-escalation 3+3 design and will be administered on Day 0. 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: 17.5 x 10^6 UF-KURE19 CAR-T Cell Dose (CAR positive cells) Level 1 (starting dose): 35 x 10^6 UF-KURE19 CAR-T Cell Dose Level 2: 70 x 10^6 UF-KURE19 CAR-T Cell Dose Participants less than 50 kg: Level -1: 11.5 x 10^6 UF-KURE19 CAR-T Cell Dose Level 1: 23 x 10^6 UF-KURE19 CAR-T Cell Dose Level 2: 46 x 10^6 UF-KURE19 CAR-T Cell Dose | Biological: UF-KURE19 CAR-T cells<br>* 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<br>Drug: Fludarabine<br>* 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.<br>* Other names: Fludarabine Phosphate;Drug: Cyclophosphamide<br>* The mechanism of action is thought to involve cross-linking of tumor cell DNA<br>* Other names: Cycloblastin®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommend MTD dose of UF-KURE19 CAR-T Cells | The MTD is therefore defined as the dose level immediately below that in which ≥ 2/6 subjects experience a DLT. | Up to 28 days after treatment | 
| Toxicities associated with the MTD of UF-KURE19 CAR-T Cells | Toxicities will be reported as specific adverse events as a result of the MTD 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 | 
| Progression-free survival (PFS) | Progression-free Survival (PFS) is defined as the time from entry onto study until lymphoma progression or death from any cause. PFS reflects tumor growth and, therefore, occurs prior to the endpoint of overall survival. | Up to 12 months after treatment | 
| Overall Survival | Time from entry onto study until death (from any cause). | Up to 15 years after treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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UF-KURE19, CD19 CAR-T cells, Non Hodgkin Lymphoma