Trial Outcomes & Findings for Anti-CD19 CAR-T Cells With Inducible Caspase 9 Safety Switch for B-cell Lymphoma (NCT NCT03696784)

Between March 12, 2019, and July 31, 2025, 12 participants were enrolled and initiated therapy. No participants were excluded after enrollment and before assignment. All 12 participants completed the 4-week treatment period. After 4th week, seven participants had died, and the remaining five participants continued in follow-up.

Anti-CD19 CAR-T Cells With Inducible Caspase 9 Safety Switch for B-cell Lymphoma

Number of participants with treatment-attributed Grade ≥3 adverse events.Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, v5.0). Treatment-emergent Grade ≥ 3 CRS event that is unresponsive to standard of care interventions and does not decrease to Grade ≤ 2 within 7 days will be reported. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.

Toxicity will be classified and graded as cytokine release syndrome (CRS) according to the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading system. Grade 1 (mild): fever ≥38°C with no hypotension or hypoxia; Grade 2 (moderate): fever ≥38°C with hypotension not requiring vasopressors and/or hypoxia requiring low-flow oxygen (≤6 L/min nasal cannula or blow-by); Grade 3 (severe): fever ≥38°C with hypotension requiring a single vasopressor (± vasopressin) and/or hypoxia requiring high-flow oxygen (\>6 L/min), facemask, nonrebreather, or Venturi mask; Grade 4 (life-threatening): fever ≥38°C with hypotension requiring multiple vasopressors (excluding vasopressin) and/or hypoxia requiring positive pressure ventilation; Grade 5: death. Treatment-emergent Grade ≥ 3 CRS event that is unresponsive to standard of care interventions and does not decrease to Grade ≤ 2 within 7 days will be reported.

Toxicity will be classified and graded according to Immune effector cell-associated neurotoxicity syndrome (ICANS) symptoms will be graded according to the criteria outlined in the protocol on a scale from 1 (mild) to 4 (critical). Cytokine release syndrome (CRS) will be graded according to criteria outlined in the protocol on a scale from 1 (mild) to grade 5 (death). Treatment-emergent Grade ≥ 3 CRS event that is unresponsive to standard of care interventions and does not decrease to Grade ≤ 2 within 7 days will be reported.

The recommended phase 2 dose of iC9-CAR19 cells will be determined based on 3+3 dose finding rules and the tolerability of iC9-CAR19 cells assessed by NCI-CTCAE criteria, CRS grading criteria, and ICANS grading criteria.

Persistence of iC9-CAR19 T cells in vivo will be determined by quantitative polymerase chain reaction (PCR) and flow cytometry in samples of peripheral blood.

ORR: * Revised Lugano criteria CR= no new lesions; normal bone marrow (BM); Target nodes/masses ≤ 1.5 cm; no extra lymphatic sites; and/or PET-CT score of 1-3. * For Primary CNS Lymphoma CR= No contrast enhancement on brain imaging; no corticosteroid dose; normal eye exam; negative cerebrospinal fluid (CSF) cytology. * For Waldenström Macroglobulinemia (WM) CR= normal Immunoglobulin M (IgM)); no monoclonal protein by immunofixation; no histological evidence of BM involvement; resolution of any adenopathy/organomegaly; no signs or symptoms of WM. * International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Revised Criteria Assessment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) CR=Target nodes/nodal masses ≤ 1.5 cm; normal lymphocyte count; platelets \> 100E9/L; Hemoglobin \> 11.0 g/dL; ANC \> 1.5E9/L; no evidence for typical CLL lymphocytes and without nodular lymphoid aggregates on BM biopsy; no constitutional symptoms from CLL/SLL; no hepatosplenomegaly

OS will be measured from the date of administration of iC9-CAR19 T cells to the date of death. Subjects who have not died by the analysis data cut-off date will be censored at their last date of contact.

PFS is day of infusion to date of disease progression (PD) or death due to any cause. * Lugano criteria PD= PET-CT score 4 or 5 with increase in intensity of uptake from baseline and/or New FDG-avid foci consistent with lymphoma * Response Criteria for Primary CNS Lymphoma PD=25% increase in lesion or new site of disease on brain imaging; recurrent/new ocular disease; recurrent/positive CSF cytology * Response Criteria for WM PD= ≥ 25% increase in serum IgM or progression of clinically significant findings due to disease; or symptoms attributable to WM * IWCLL Revised Criteria for Response Assessment of CLL/SLL PD= New enlarged lymph node \> 1.5 cm; new hepato- and/or splenomegaly or organ infiltration; 50% increase from baseline of previous site; 50% increase from baseline of circulating lymphocyte count or CLL cells on marrow biopsy; 50% decrease in platelet count from baseline prior to therapy; Or \> 2 gm g/dL decrease in hemoglobin from baseline

DOR is defined for subjects who experience an objective response as the date of first objective response to the date of disease progression (per the Lugano criteria, Response Criteria for Primary CNS Lymphoma Response Criteria for WM or IWCLL Revised Criteria for Response Assessment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma) or death as a result of any cause. Subjects who do not meet criteria for progression or death by the analysis cut-off date will be censored at their last evaluable disease assessment date.

Patient reported symptoms will be measured using selected symptoms from the NCI Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE). The PRO-CTCAE is a patient-reported outcome measurement system developed to characterize the frequency, severity and interference of symptomatic treatment toxicities. Each of the symptom terms included in the PRO-CTCAE is assessed relative to one or more distinct attributes, including presence/absence, frequency, severity, and/or interference with usual or daily activities. Responses are provided on a 5-point Likert scale: Frequency item: How OFTEN did you have? (Never / Rarely / Occasionally / Frequently / Almost constantly); Severity item: What was the SEVERITY of your at its WORST? (None / Mild / Moderate / Severe / Very severe);Interference item: How much did INTERFERE with your usual or daily activities? (Not at all / A little bit / Somewhat / Quite a bit / Very much)

The Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Short Form 20a v1.0. assesses one's ability to carry out activities that require physical actions, ranging from self-care (activities of daily living) to more complex activities that require a combination of skills, often within a social context. "Physical Function" is inclusive of the term "disability" and includes the full spectrum of physical functioning from severe impairment to exceptional physical abilities. Each question has five response options ranging in value from one to five, resulting in a total score (T-score) from 0 to 100. A higher PROMIS T-score represents more of the concept being measured. For positively-worded concepts like Physical Function, a T-score of 60 is one SD better than average. By comparison, a Physical Function T-score of 40 is one SD worse than average.

The Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health measures assess an individual's physical, mental, and social health. The measures are generic, rather than disease-specific, and often use an "In General" item context as it is intended to globally reflect individuals' assessment of their health. Each question has five response options ranging in value from one to five, which are summed into T-score values for physical and mental health. A higher PROMIS T-score represents more of the concept being measured. Thus, a person who has T- scores of 60 for the Global Physical Health or Global Mental Health scales is one standard deviation better (more healthy) than the general population.