UF-KURE19 CAR-T Cells for Treatment of Non-Hodgkin Lymphomas

Inclusion Criteria

• PHASE I COHORT: Male or female patients aged 18 years or older
• PHASE I COHORT: Participants must have histologically confirmed, CD19 positive (by immunohistochemistry [IHC] or flow cytometry) 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 relapse ≤ 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
• PHASE I COHORT: Eastern Cooperative Oncology Group (ECOG) Performance status =< 2
• PHASE I COHORT: At least one measurable lesion according to Lugano Revised Response Criteria for Malignant Lymphoma
• PHASE I COHORT: Minimum of 2 weeks since prior radiation therapy or systemic therapy to treat malignancy at the time of leukapheresis
• PHASE I COHORT: Total bilirubin =< 1.5 X institutional upper limit of normal
• PHASE I COHORT: Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal
• PHASE I COHORT: Calculated creatinine clearance >= 30mL/min estimated by the Cockcroft-Gault formula
• PHASE I COHORT: Cardiac ejection fraction of >= 45%, and no more than trivial (or trace, minimal or mild) pericardial effusion, as determined by an echocardiogram
• PHASE I COHORT: 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
• PHASE I COHORT: Subjects (or legal guardians) must have the ability to understand and the willingness to sign a written informed consent document
• PHASE I COHORT: 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
• PHASE I COHORT: For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below: * 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
• PHASE IB COHORT 1: Male or female patients aged 18 years or older
• PHASE IB COHORT 1: Participants must have histologically confirmed, CD19 positive (by IHC or flow cytometry) NHL that meets at least one of the following treatment indications AND there will be a preference for subjects with LBCL including: Diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B * 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 relapse ≤ 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
• PHASE IB COHORT 1: Participants must exhibit both of the following: * Nodal lesion: >= 1.5 cm or non-nodal lesion: >= 1.0 cm * Fludeoxyglucose (FDG) avid disease: Deauville score of 3, 4, or 5 is required. If Deauville score of 3, Sponsor must confirm eligibility
• PHASE IB COHORT 1: ECOG performance status ≤ 2
• PHASE IB COHORT 1: Minimum of 2 weeks since prior radiation therapy or systemic therapy to treat malignancy at the time of leukapheresis
• PHASE IB COHORT 1: Total bilirubin ≤ 1.5X institutional upper limit of normal
• PHASE IB COHORT 1: AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional upper limit of normal
• PHASE IB COHORT 1: Calculated creatinine clearance ≥ 30mL/min estimated by the Cockcroft – Gault formula
• PHASE IB COHORT 1: Cardiac ejection fraction of ≥ 45%, and no more than trivial (or trace, minimal or mild) pericardial effusion, as determined by an echocardiogram
• PHASE IB COHORT 1: 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
• PHASE IB COHORT 1: Subjects (or legal guardians) must have the ability to understand and the willingness to sign a written informed consent document
• PHASE IB COHORT 1: 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
• PHASE IB COHORT 1: For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below: * 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
• PHASE IB COHORT 2 REGISTRATION STEP 1: Male or female patients aged 18 years or older
• PHASE IB COHORT 2 REGISTRATION STEP 1: Participants must have histologically confirmed, CD19 positive (by IHC or flow cytometry) NHL that meets the following treatment indications: * DHL/THL: Newly diagnosed LBCL with MYC and BCL2 rearrangements (DHL) or MYC/BCL2/BCL6 rearrangements (THL) that have received no more than 4 cycles of first-line standard of care treatment
• PHASE IB COHORT 2 REGISTRATION STEP 1: Subjects must exhibit both of the following: * Nodal lesion: >= 1.5 cm or non-nodal lesion: >= 1.0 cm * FDG avid disease: Deauville score of 3, 4, or 5 is required. If Deauville score of 3, sponsor must confirm eligibility
• PHASE IB COHORT 2 REGISTRATION STEP 1: ECOG performance status ≤ 2 * Out-of-range clinical or laboratory conditions (e.g. ECOG performance status, creatinine clearance) may be allowed for the step 1 registration if they are considered likely temporary and are approved by the sponsor
• PHASE IB COHORT 2 REGISTRATION STEP 1: Minimum of 2 weeks since prior radiation therapy or systemic therapy to treat malignancy at the time of leukapheresis
• PHASE IB COHORT 2 REGISTRATION STEP 1: Total bilirubin ≤ 1.5 X institutional upper limit of normal * Out-of-range clinical or laboratory conditions (e.g. ECOG performance status, creatinine clearance) may be allowed for the step 1 registration if they are considered likely temporary and are approved by the sponsor
• PHASE IB COHORT 2 REGISTRATION STEP 1: AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional upper limit of normal * Out-of-range clinical or laboratory conditions (e.g. ECOG performance status, creatinine clearance) may be allowed for the step 1 registration if they are considered likely temporary and are approved by the sponsor
• PHASE IB COHORT 2 REGISTRATION STEP 1: Calculated creatinine clearance ≥ 30mL/min estimated by the Cockcroft – Gault formula * Out-of-range clinical or laboratory conditions (e.g. ECOG performance status, creatinine clearance) may be allowed for the step 1 registration if they are considered likely temporary and are approved by the sponsor
• PHASE IB COHORT 2 REGISTRATION STEP 1: Cardiac ejection fraction of ≥ 45%, and no more than trivial (or trace, minimal or mild) pericardial effusion, as determined by an echocardiogram * Out-of-range clinical or laboratory conditions (e.g. ECOG performance status, creatinine clearance) may be allowed for the step 1 registration if they are considered likely temporary and are approved by the sponsor
• PHASE IB COHORT 2 REGISTRATION STEP 1: 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 * Out-of-range clinical or laboratory conditions (e.g. ECOG performance status, creatinine clearance) may be allowed for the step 1 registration if they are considered likely temporary and are approved by the sponsor
• PHASE IB COHORT 2 REGISTRATION STEP 1: Subjects (or legal guardians) must have the ability to understand and the willingness to sign a written informed consent document
• PHASE IB COHORT 2 REGISTRATION STEP 1: 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
• PHASE IB COHORT 2 REGISTRATION STEP 1: For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below: * 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
• PHASE IB COHORT 2 REGISTRATION STEP 2: Must meet all inclusion/exclusion criteria noted in registration step 1, without exception for out-of-range clinical or laboratory conditions
• PHASE IB COHORT 2 REGISTRATION STEP 2: Must fail to achieve a CR after 2-4 cycles of first-line standard of care (SOC) treatment determined by a post-treatment PET/CT (and/or CT). Patients in CR will not proceed to step 2 registration or receive UF-KURE19

Exclusion Criteria

• PHASE I COHORT: Autologous stem cell transplant within 6 weeks of informed consent
• PHASE I COHORT: History of allogeneic hematopoietic stem cell transplantation
• PHASE I COHORT: Active central nervous system or leptomeningeal involvement by lymphoma. Subjects with untreated brain metastases/central nervous system (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 cerebral spinal fluid (CSF) evaluation and contrast-enhanced magnetic resonance imaging (MRI) imaging for at least 90 days prior to registration
• PHASE I COHORT: Second active malignancy, other than non-melanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast)
• PHASE I COHORT: Less than 28 days elapsed between prior treatment with investigational agent(s) and leukapheresis
• PHASE I COHORT: New York Heart Association class III-IV congestive heart failure
• PHASE I COHORT: 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
• PHASE I COHORT: Known human immunodeficiency virus infection or acquired immunodeficiency syndrome related illness
• PHASE I COHORT: 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
• PHASE I COHORT: Evidence of myelodysplastic syndrome or cytogenetic abnormality indicative of myelodysplasia on the most recent bone marrow biopsy prior to initiation of therapy
• PHASE I COHORT: 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)
• PHASE I COHORT: 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
• PHASE I COHORT: 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
• PHASE I COHORT: 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 15 mg prednisone equivalent] within the last 6 months
• PHASE I COHORT: Circulating malignant B cells in peripheral blood detected by complete blood count at the time of subject enrollment
• PHASE IB COHORT 1: Autologous stem cell transplant within 6 weeks of informed consent
• PHASE IB COHORT 1: History of allogeneic hematopoietic stem cell transplantation
• PHASE IB COHORT 1: 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 contrastenhanced MRI imaging for at least 90 days prior to registration
• PHASE IB COHORT 1: Second active malignancy, other than non-melanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast)
• PHASE IB COHORT 1: Less than 28 days elapsed between prior treatment with investigational agent(s) and leukapheresis
• PHASE IB COHORT 1: New York Heart Association class III-IV congestive heart failure
• PHASE IB COHORT 1: 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
• PHASE IB COHORT 1: Known human immunodeficiency virus infection or acquired immunodeficiency syndrome related illness
• PHASE IB COHORT 1: 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
• PHASE IB COHORT 1: Evidence of myelodysplastic syndrome or cytogenetic abnormality indicative of myelodysplasia on the most recent bone marrow biopsy prior to initiation of therapy
• PHASE IB COHORT 1: 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)
• PHASE IB COHORT 1: 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
• PHASE IB COHORT 1: 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
• PHASE IB COHORT 1: 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
• PHASE IB COHORT 1: Circulating malignant B cells in peripheral blood detected by complete blood count at the time of subject enrollment
• PHASE IB COHORT 2 REGISTRATION STEP 1: Autologous stem cell transplant within 6 weeks of informed consent
• PHASE IB COHORT 2 REGISTRATION STEP 1: History of allogeneic hematopoietic stem cell transplantation
• PHASE IB COHORT 2 REGISTRATION STEP 1: 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
• PHASE IB COHORT 2 REGISTRATION STEP 1: Second active malignancy, other than non-melanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast)
• PHASE IB COHORT 2 REGISTRATION STEP 1: Less than 28 days elapsed between prior treatment with investigational agent(s) and leukapheresis
• PHASE IB COHORT 2 REGISTRATION STEP 1: New York Heart Association class III-IV congestive heart failure
• PHASE IB COHORT 2 REGISTRATION STEP 1: 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
• PHASE IB COHORT 2 REGISTRATION STEP 1: Known human immunodeficiency virus infection or acquired immunodeficiency syndrome related illness
• PHASE IB COHORT 2 REGISTRATION STEP 1: 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
• PHASE IB COHORT 2 REGISTRATION STEP 1: Evidence of myelodysplastic syndrome or cytogenetic abnormality indicative of myelodysplasia on the most recent bone marrow biopsy prior to initiation of therapy
• PHASE IB COHORT 2 REGISTRATION STEP 1: 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)
• PHASE IB COHORT 2 REGISTRATION STEP 1: 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
• PHASE IB COHORT 2 REGISTRATION STEP 1: 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
• PHASE IB COHORT 2 REGISTRATION STEP 1: 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
• PHASE IB COHORT 2 REGISTRATION STEP 1: Circulating malignant B cells in peripheral blood detected by complete blood count at the time of subject enrollment