UltraCAR-T Cells (PRGN-3007) in Treating patients with Advanced Hematologic and Solid Tumor Malignancies

Inclusion Criteria

• Age 18 years and older
• Eastern Cooperative Oncology Group (ECOG) score of 0 or 1; or Karnofsky Performance Status (KPS) of >= 70%
• Life expectancy >= 12 weeks from the time of enrollment
• Calculated or measured creatinine clearance (absolute value) of >= 60 mL/minute
• Serum total bilirubin =< 1.5 x upper limit of normal (ULN) (=< 3.0 x ULN for patients with Gilbert's disease)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x ULN (or < 5 x ULN for patients with liver metastases)
• Documented ejection fraction > 50% (echocardiogram [ECHO]) or multi gated acquisition scan [MUGA])
• Baseline oxygen saturation of > 92% on room air
• Patients must be at least 2 weeks or 5 half-lives (whichever is shorter)post systemic steroids prior to enrollment except as premedication for contrast allergy
• Negative serum pregnancy test for women of child bearing potential (WOCBP). Fertile male and female patients must be willing to use a contraceptive method before, during, and for at least 12 months after the last T cell infusion
• All patients must have the ability to understand and willingness to sign a written informed consent form (ICF)
• CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) PATIENTS: Relapsed or refractory CLL indicated for treatment per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018 criteria and: * Must have at least 1 measurable lesion defined as >= 1.5 cm in at least one dimension * Must have received at least 1 (and not more than 6) prior treatment regimens with progression on treatment with a BTK inhibitor * Patients with stable disease or in partial response that have a known BTK resistance mutation (BTK or phospholipase Cgamma2 PLCgamma2]). Patients on BTK inhibitor therapy for less than 6 months are eligible if they are contraindicated or refuse treatment with venetoclax
• CLL PATIENTS: Patients must have confirmed ROR1 expression defined as any level of unequivocal detection in the neoplastic cells
• CLL PATIENTS: Absolute neutrophil count (ANC) >= 0.5 x 10^9/L
• CLL PATIENTS: Lymphocytes >= 300/mm^3
• CLL PATIENTS: Platelets >= 50 x 10^9/L
• CLL PATIENTS: Hemoglobin >= 8 g/dL, unless value is lower due to CLL disease
• ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) PATIENTS: Must have pathologically confirmed B-cell precursor ALL, and: * Relapsed or refractory, defined as failure to achieve a response (partial response [PR] or complete response [CR]) to the last treatment regimen * Patients with Philadelphia chromosome (Ph)+ disease will be eligible if they had disease intolerant to tyrosine kinase inhibitor (TKI) therapy, or if they had relapsed/refractory (R/R) disease despite treatment with >= 2 different TKIs * Must have received fewer than 3 prior treatment regimens in the relapsed setting
• ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) PATIENTS: Patient has to have measurable disease (at least 5% blast in bone marrow [BM])
• ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) PATIENTS: Patients must have confirmed ROR1 expression defined as any level of unequivocal detection in the neoplastic cells
• ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) PATIENTS: ANC >= 0.5 x 10^9/L
• ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) PATIENTS: Lymphocytes >= 300/mm^3
• ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) PATIENTS: Platelets >= 50 x 10^9/L
• ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) PATIENTS: Hemoglobin >= 8 g/dL, unless value is lower due to ALL disease
• MANTLE CELL LYMPHOMA (MCL) PATIENTS: Must have pathologically confirmed MCL, with documentation of either overexpression of cyclin D1 or presence of t(11;14), and: * Relapsed or refractory, defined as failure to achieve a response (PR or CR) to the last treatment regimen * Must have at least 1 measurable lesion, per Response Evaluation Criteria in Solid Tumors (RECIST) version(v)1.1. If the only measurable disease is lymph node disease, at least 1 lymph node should be >= 2 cm. Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy
• MCL PATIENTS: Must have received at least 2 prior lines for MCL. Prior lines must include: an anti-CD20 monoclonal antibody therapy, and one BTK inhibitor (ibrutinib, acalabrutinib or zanubrutinib)
• MCL PATIENTS: Patients must have confirmed ROR1 expression defined as any level of unequivocal detection in the neoplastic cells
• MCL PATIENTS: ANC >= 1000/mm^3
• MCL PATIENTS: Lymphocytes >= 300/mm^3
• MCL PATIENTS: Platelets >= 75,000/mm^3
• MCL PATIENTS: Hemoglobin >= 9 g/dL
• DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) PATIENTS: Must have pathologically confirmed diagnosis of DLBCL or high-grade B-cell lymphoma (HGBCL), including transformation from low grade lymphoma (including CLL), and: * Relapsed (i.e., progression) or refractory disease, defined as failure to achieve a response (PR or CR) to the last treatment regimen * Must have at least 1 measurable lesion, per RECIST v1.1. Nodal lesions must be >= 1.5 cm in at least 1 dimension. Extranodal lesions (outside lymph node or nodal mass, but including liver and spleen) must be >= 10 mm in long and short axis. Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy
• DLBCL PATIENTS: Must have received at least 2 prior lines for DLBCL, including anti-CD20 and anthracycline-based chemotherapy
• DLBCL PATIENTS: Patients are eligible if they are: 3 months after autologous transplant or at least one month after chimeric antigen receptor therapy (CAR-T)
• DLBCL PATIENTS: Patients must have confirmed ROR1 expression defined as any level of unequivocal detection in the neoplastic cells
• DLBCL PATIENTS: ANC >= 1000/mm^3
• DLBCL PATIENTS: Lymphocytes >= 300/mm^3
• DLBCL PATIENTS: Platelets >= 75,000/mm^3
• DLBCL PATIENTS: Hemoglobin >= 9 g/dL
• TRIPLE NEGATIVE BREAST CANCER (TNBC) PATIENTS: Locally advanced unresectable or metastatic histologically confirmed TNBC * Estrogen receptor (ER) and progesterone receptor (PR) immunohistochemistry (IHC) expression < 10% * HER2 0-2 by in situ hybridization (IHC) and/or negative in situ hybridization * Has received no more than 2 prior lines of systemic therapy in the metastatic setting
• TNBC PATIENTS: Patients must have sufficient archival tissue from a metastatic biopsy within 120 days of screening to provide ten slides (5 micron cuts) or be willing to undergo a fresh biopsy prior to initiating therapy. Patient must be willing to undergo an on-treatment biopsy within 4-6 weeks of initial dose of PRGN-3007 unless it is deemed unsafe or not feasible by the investigator or medical monitor
• TNBC PATIENTS: Patients must have >= 20% ROR1 expression on their screening metastatic biopsy specimen
• TNBC PATIENTS: Patients must be appropriate medical candidates for non-myeloablative lymphodepletion with cyclophosphamide in the opinion of the investigator
• TNBC PATIENTS: Measurable disease per RECIST 1.1 criteria
• TNBC PATIENTS: ANC >= 1500/mm^3
• TNBC PATIENTS: Lymphocytes >= 800/mm^3
• TNBC PATIENTS: Platelets >= 100,000/mm^3
• TNBC PATIENTS: Hemoglobin >= 9 g/dL

Exclusion Criteria

• Patient has received any of the following treatments prior to leukapheresis: cytotoxic chemotherapy or radiation therapy within 14 days; an antineoplastic monoclonal antibody within prior 4 weeks; prior targeted therapy 14 days or 5 half-lives from the last dose whichever is shorter; or prior systemic inhibitory/stimulatory immune checkpoint molecule therapy (eg, ipilimumab, nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists) within 3 half-lives; or has not recovered from (i.e., >= grade 1) adverse event (AE) caused by prior treatment. Exceptions include hydroxyurea, single agent vincristine or steroids for uncontrolled ALL
• Burkitt lymphoma is excluded
• Prior allogeneic hematopoietic stem cell transplantation (HSCT) or donor lymphocyte infusion within 6 months prior to enrollment, current acute graft versus host disease grade 2-4 by Glucksberg criteria or severity B-D by International Bone Marrow Transplant Registry (IBMTR) index or history of severe (grade 3-4) acute graft versus host disease
• Patients with a history of immunodeficiency (except for acquired hypogammablobulinea), patients with active autoimmune disease requiring systemic immunosuppressive therapy (i.e., > 15 mg of prednisone daily or equivalent), or patients who have received any other form of immunosuppressive therapy within 7 days prior to leukapheresis
• Patients with a history of autoimmune disease resulting in end-organ injury are not eligible unless attributable to primary disease which is target of this study
• Patient requires treatment with warfarin
• Patients who have contraindication to the lymphodepletion chemotherapy regimen
• Patient received a live vaccine administration within 4 weeks prior to leukapheresis
• Patient is currently participating in another investigation treatment study, or has participated in a study of an investigational agent within 4 weeks prior to leukapheresis
• Patients with clinically significant pulmonary dysfunction, as determined by medical history and physical exam should undergo pulmonary function testing; those with a forced expiratory volume in 1 second (FEV1) of =< 65% or diffuse capacity lung for carbon monoxide (DLCO; corrected) < 40% will be excluded
• Patients with history of other active malignancy within 1 year prior to enrollment. Patients with adequately resected basal or squamous cell carcinoma of the skin, non-melanoma skin cancer or carcinoma in situ (e.g., skin, cervix, bladder, breast), superficial bladder cancer, asymptomatic localized low grade prostate cancer for which watch-and-wait approach is standard of care, or any other cancer that has been in remission are eligible
• History of concomitant genetic syndrome associated with bone marrow failure such as Fanconi anemia, Kostmann syndrome, Shwachman-Diamond syndrome
• Known human immunodeficiency virus (HIV) seropositivity or active hepatitis B or C infection. A history of hepatitis B or C is permitted if the viral load is undetectable by quantitative assay (i.e., polymerase chain reaction [PCR] or comparable)
• Ongoing uncontrolled serious infection, clinically significant cardiac disease (i.e., symptomatic congestive heart failure, myocardial infarction, cardiac angioplasty or stenting, unstable angina pectoris, uncontrolled cardiac arrhythmia), poorly controlled pulmonary disease (no clinically significant pleural effusion), or psychiatric illness/social situations that would limit compliance with study requirements within 12 months prior to enrollment
• History of any central nervous system (CNS) disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, any autoimmune disease with CNS involvement, posterior reversible encephalopathy syndrome, or cerebral edema
• History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months prior to enrollment
• CNS lymphoma, untreated CNS metastases, leptomeningeal disease and/or carcinomatous meningitis; patients with a history of brain metastases that are previously treated, stable, and off systemic steroids for over 30 days prior to screening are eligible
• Patients that have not recovered from major acute infections and/or recent surgical procedures
• Toxicities due to prior therapy must be stable and recovered to =< grade 1 (except for clinically non-significant toxicities such as alopecia)
• Patients, who in the opinion of the investigator, may not be able to comply with the monitoring requirements of the study