CD5CAR-NK is a first-in-human, pilot, dose-escalation, and single-site study to evaluate the safety of CD5CAR-CBNK in patients with invasive mold diseases (IMD). The study population consists of patients aged ≥18 years with refractory mold infections. The number of patients treated will be 10. This is a dose-escalation study including 3 cohorts.
CD5CAR-NK is a first-in-human, pilot, dose-escalation, and single-site study to evaluate the safety of CD5CAR-CBNK in patients with invasive mold diseases (IMD). The study population consists of patients aged ≥18 years with refractory mold infections. The number of patients treated will be 10. This is a dose-escalation study including 3 cohorts. The dose escalation scheme will follow the following scheme: Cohort 1(3 patients) The sentinel patient of cohort 1 will receive 10 x106 CAR+ cells of CD5CAR-CBNK at day 0. Intra-patient safety will be reviewed daily following the first dose. The second dose (day+3) and third (day+6) will only be administered after a safety review from clinicians that confirms the absence of dose-limiting toxicities (DLTs). Cohort 1 is planned to include 3 evaluable patients. If a patient does not receive the full planned dosing schedule (all 3 doses), additional patients will be enrolled until at least 3 patients have completed the full prescribed treatment for this cohort. Escalation to Cohort 2 will only occur once safety data from 3 fully-treated patients have been reviewed. The first subject in each cohort will be dosed and undergo a safety observation period between administrations. The second subject will be dosed 7 days after the first subject completes treatment and after review of safety data. The third subject will be dosed 3 days after the last dose of the second subject, subject to confirmation of acceptable safety. Cohort 2 (3 patients) The sentinel patient of cohort 2 will receive 10 x106 CAR+ cells of CD5CAR-CBNK at days 0,3 and 6 followed by 25 x106 CAR+ cells at days 9 and 12. Intra-patient safety will be reviewed daily following the first 25 million dose. The dose at day +12 will only be administered after a safety review from clinicians that confirms the absence of dose-limiting toxicities (DLTs). Cohort 3 (4 patients) The sentinel patient of cohort 3 will receive 10 x106 CAR+ cells of CD5CAR-CBNK at days 0,3 and 6 followed by 25 x106 CAR+ cells at days 9 and 12, and additionally 50 x106 CAR+ cells at days 15 and 18. In this occasion, intra-patient safety will be reviewed daily following the first 50 million dose. The dose at day +18 will only be administered after a safety review from clinicians that confirms the absence of dose-limiting toxicities (DLTs).
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
10
Allogeneic natural killer (NK) cells derived from umbilical cord blood (CB) units, genetically modified to express a chimeric antigen receptor (CAR) based on the CD5 receptor (CD5CAR).
Hospital Clinic Barcelona
Barcelona, Barcelona, Spain
Evaluate the safety of allogeneic CD5CAR-CBNK cells in patients with refractory mold infection.
Number and proportion of patients with grade 3-4 treatment-related adverse events according to the Common Toxicity Criteria (CTCAE) version 5.0
Time frame: 28 days following the first infusion
Evaluate the safety and tolerability of CD5CAR-CBNK cells.
Incidence of all grade \>3 adverse events (AEs) as per CTCAE version 5.0.
Time frame: at 6 and 12 weeks
Evaluate the safety and tolerability of CD5CAR-CBNK cells.
Number and percentage of patients with Adverse Events of Special Interest (AESI) throughout the study duration. The following AEs will be considered as AESI: i. Cytokine release syndrome (CRS) ii. Immune effector cell-associated neurotoxicity syndrome (ICANS) iii. Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis (IEC-HS) iv. Prolonged cytopenia.
Time frame: at 6 and 12 weeks
Evaluate the safety and tolerability of CD5CAR-CBNK cells.
Procedure-related mortality rate (PRM), defined as any death not related to the underlying disease or fungal infection.
Time frame: During the first year after first administration
Evaluate the safety and tolerability of CD5CAR-CBNK cells.
Number and proportion of patients with grade 3-4 treatment-related adverse events according to the Common Toxicity Criteria (CTCAE) version 5.0
Time frame: During the first year after first administration
Evaluate the safety and tolerability of CD5CAR-CBNK cells.
Number and percentage of patients with Serious Adverse Events (SAEs) according to CTCAE version 5.0.
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Time frame: During the first year after first administration
Assess the efficacy of CD5CAR-CBNK cells.
Response rate
Time frame: at day 15, day 28, 6 and 12 weeks.
Assess the efficacy of CD5CAR-CBNK cells.
Overall Survival (OS)
Time frame: at day 28, 6 and 12 weeks from the first CD5CAR-CBNK cell infusion and from study inclusion.
Assess the efficacy of CD5CAR-CBNK cells.
Survival rate
Time frame: at day 28, 6 and 12 weeks from the first CD5CAR-CBNK cell infusion and from study inclusion.
Assess the efficacy of CD5CAR-CBNK cells.
Overall response rate (ORR)
Time frame: at day 28, 6 and 12 weeks from the CD5CAR-CBNK cell infusion and inclusion of the patient.
Assess the efficacy of CD5CAR-CBNK cells.
Time to response calculated from the day of infusion to the date when the patient first meets the criteria for partial or complete response.
Time frame: During the first year after first administration
Assess the efficacy of CD5CAR-CBNK cells.
Duration of response: defined as the time between first response and loss of response.
Time frame: During the first year after first administration
Assess the efficacy of CD5CAR-CBNK cells.
Event-free survival (EFS) calculated from CD5CAR-CBNK cell infusion and study inclusion to the date of first occurrence of any of the following events: (i) Fungal disease progression (radiological or clinical). (ii) Loss of response or fungal recurrence (iii) Severe therapy-related toxicity. (iv) Death for any cause.
Time frame: During the first year after first administration
To quantify persistence and kinetics of allogeneic CD5CAR-CBNK cells in blood after administration.
Number of circulating CD5CAR-CBNK cells in peripheral blood
Time frame: During the first year after first administration
To quantify persistence and kinetics of allogeneic CD5CAR-CBNK cells in blood after administration.
Changes in serum pro-inflammatory and anti-inflammatory cytokines
Time frame: During the first year after first administration
To quantify persistence and kinetics of allogeneic CD5CAR-CBNK cells in blood after administration.
CD5 expression
Time frame: During the first year after first administration
To quantify persistence and kinetics of allogeneic CD5CAR-CBNK cells in blood after administration.
Percentage of transduction, T-cell, NK-cell and B-cell subsets, and exhaustion and senescence population
Time frame: During the first year after first administration