Genetically Engineered Cells (Anti-CD19 CAR-T Cells) for the Treatment of Relapsed or Refractory CD19+ Hematologic Malignancies, The PRODIGY Trial

Inclusion Criteria

• STEP 1: Subjects aged ≥ 18 years
• STEP 1: Histologically confirmed relapsed or refractory CD-19+ malignancy, including: non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL)/Richter’s syndrome. CD-19+ must be confirmed by immunohistochemistry or flow cytometry analysis
• STEP 1: Subjects who have relapsed or refractory disease after failing at least 2 or more prior lines of therapy
• STEP 1: Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• STEP 1: Life expectancy > 12 weeks
• STEP 1: Willing to consent to 15 years of follow-up as part of IRB 110692: Long-Term Evaluation of the Biology and Outcomes of Hematopoietic Stem Cell Transplantation
• STEP 1: Absolute neutrophil count (ANC) ≥ 500/mm^3
• STEP 1: Platelet count ≥ 10,000/mm^3
• STEP 1: Hemoglobin ≥ 8 g/dL
• STEP 1: Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
• STEP 1: Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 3 x institutional ULN
• STEP 1: Serum creatinine ≤ 2 x institutional upper limit of normal (ULN) or estimated glomerular filtration rate (eGFR) > 30 ml/min/1.73m^2
• STEP 1: For subjects of childbearing potential: Negative pregnancy test or evidence of post-menopausal status or evidence of permanent surgical sterilization. The postmenopausal status will be defined as having been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: * Subjects < 50 years of age: ** Amenorrheic for ≥ 12 months following cessation of exogenous hormonal treatments; and ** Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution * Subjects ≥ 50 years of age: ** Amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments; or ** Had radiation-induced menopause with last menses > 1 year ago; or ** Had chemotherapy-induced menopause with last menses > 1 year ago
• STEP 1: Subjects of childbearing potential and subjects with a sexual partner of childbearing potential must agree to use a highly effective method of contraception
• STEP 1: Recovery to baseline or ≤ grade 2 Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 from toxicities related to any prior cancer therapy, unless considered stable by the treating investigator
• STEP 1: Adequate venous access
• STEP 1: Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines
• STEP 2: Confirmation of successful CAR-T manufacturing
• STEP 2: No evidence or suspicion of an infection
• STEP 2: Serum creatinine ≤ 2 x institutional upper limit of normal (ULN) or eGFR > 30 ml/min/1.73m^2
• STEP 2: No worsening of clinical status compared to either the initial eligibility criteria that would, in the opinion of the treating physician, significantly increase the risk from lymphodepleting chemotherapy or exclude them from treatment with study CAR-T therapy
• STEP 3: No worsening of clinical status compared to either the initial eligibility criteria that would, in the opinion of the treating physician, significantly increase the risks from treatment with CAR-T therapy
• STEP 3: Confirmation that washout periods have been followed

Exclusion Criteria

• STEP 1: Autologous or allogeneic stem cell transplant or CAR-T therapy within 6 weeks of planned CAR-T cell infusion
• STEP 1: Subjects with active infection that requires systemic treatment
• STEP 1: History of autoimmune disease (i.e. rheumatoid arthritis, systemic lupus erythematosus) with requirement of immunosuppressive medication within 6 months
• 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 child bearing 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
• STEP 1: Receiving other investigational agents
• STEP 1: Confirmation that washout periods listed have been followed
• STEP 1: Major surgery 4 weeks prior to starting study drug or who have not fully recovered from major surgery
• STEP 1: The diagnosis of another malignancy within ≤ 2 years before study enrollment, except for those considered to be adequately treated with no evidence of disease or symptoms and/or will not require therapy during the study duration (i.e., basal cell or squamous cell skin cancer, carcinoma in situ of the breast, bladder or of the cervix, or low-grade prostate cancer with Gleason score ≤ 6). Patients with transformed disease are allowed
• STEP 1: Known brain metastases or cranial epidural disease * Note: Brain metastases or cranial epidural disease adequately treated with radiotherapy and/or surgery and stable for at least 4 weeks before the first dose of study treatment will be allowed on trial. Subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of the first dose of study treatment
• STEP 1: Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions: * Cardiovascular disorders: ** Congestive heart failure New York Heart Association class III or IV, unstable angina pectoris, serious cardiac arrhythmias ** Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic events, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 3 months before the first dose ** Corrected QT (QTc) prolongation defined as a QT interval corrected using Fredericia equation (QTcF) > 500 ms ** Known congenital long QT ** Left ventricular ejection fraction < 55% ** Uncontrolled hypertension defined as ≥ 140/90 as assessed from the mean of three consecutive blood pressure measurements taken over 10 minutes * Any other condition that would, in the investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, [subjects may not receive the drug through a feeding tube], social/ psychological issues, etc.)
• STEP 1: Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination, radiographic findings, and tuberculosis [TB] testing in line with local practice), hepatitis B (known positive hepatitis B virus [HBV] surface antigen [HBsAg] result), hepatitis C, or seropositive HIV * Note: Subjects with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Subjects positive for hepatitis C (hepatitis C virus [HCV]) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
• STEP 1: Medical, psychiatric, cognitive, or other conditions that may compromise the subject's ability to understand the subject information, give informed consent, comply with the study protocol or complete the study
• STEP 1: Known prior severe hypersensitivity to investigational product (IP) or any component in its formulations (National Cancer Institute [NCI] CTCAE v5.0 grade ≥ 3)
• STEP 1: Subjects taking prohibited medications. Unless otherwise stated, a washout period of prohibited medications for a period of at least five half-lives or as clinically indicated should occur before the start of treatment
• STEP 1: Subjects with history of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure disorders, paresis, aphasia, uncontrolled cerebrovascular disease, severe brain injuries, dementia and Parkinson’s disease