This phase I/II trial will investigate a new CD19 directed CAR-T therapy manufactured locally with the goals to expedite infusion to wider patient inclusion that includes those who were previously excluded, such as pediatric patients with B-cell NHL and patients in primary relapse.
Pediatric patients with refractory or multiply relapsed leukemia and lymphoma do poorly with traditional chemotherapy and have overall survival rates below 20%-50% depending on a variety of disease and patient related characteristics. Approximately 10-20% of pediatric patients with pre B-ALL will relapse (1) and relapsed pre B-ALL is a leading cause of cancer death in children (2). Site of relapse and timing of first relapse from initial therapy are important factors that impact the survival rates after first relapse (3). The 5-year survival for pre B-ALL pediatric patients with early relapse is 25-50% (2). Pediatric patients who experience a late relapse have excellent survival rates with chemotherapy alone, however if they have MRD positivity after reinduction, this drops their survival rates down to 50-60% (4). The FDA approval of CD19-directed CAR-T cell therapy has increased treatment options for patients with refractory disease or those in second relapse. However, many patients, including those in first relapse do not fit the current criteria to receive this treatment. As well, regardless of the number of prior relapses, some patients in second relapse cannot tolerate the extended delay and ongoing therapy that is necessary for the commercial manufacturing of these cells at the commercial level. This phase I/II trial will investigate a new CD19-directed CAR-T therapy manufactured locally with the goal of expediting the infusion to patients who were previously excluded, such as pediatric patients with relapsed B-cell NHL and patients in their initial (or greater) leukemic relapse. We hypothesize that CD19-directed CAR-T cells manufactured using the Miltenyi CliniMACs Prodigy System (UCD19 CAR-T) will be safe, well-tolerated, and show preliminary efficacy in pediatric patients with relapsed and/or refractory B-ALL or B-NHL. No controls will be used beyond historical comparisons.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
45
The CD19 CAR used in this study consists of three main components: the variable regions of the anti-CD19 monoclonal antibody FMC63 71, linked to the TNFRSF-19-derived transmembrane domain, the 4-1BB costimulatory molecule, and the signaling domain of the CD3-zeta molecule. The DNA encoding this receptor was cloned into a lentiviral vector (LV) backbone.
Children's Hospital Colorado
Aurora, Colorado, United States
RECRUITINGDetermine the safety and tolerability of UCD19 CAR-T infusion in pediatric patients with B-ALL or B-NHL
DLTs of UCD19 CAR-T will be assessed at each of the dose levels in a standard 3+3 dose-escalation design with a determination of recommended Phase 2 dose (RP2D).
Time frame: Post UCD19 infusion to Day 28
Determine the preliminary efficacy of UCD19 CAR-T cells in pediatric patients with B-ALL or B-NHL
Following determination of UCD19 CAR-T RP2D, there will be a cohort expansion to determine preliminary efficacy and biological activity by assessment of CR status.
Time frame: Day 28 (for B-ALL) and Day 90 (for B-NHL) post UCD19 infusion
Determine the preliminary efficacy of UCD19 CAR-T cells in pediatric patients with B-ALL during the expansion phase
Rate of patients who have morphologic remission post infusion for B-ALL as assessed by bone marrow morphology.
Time frame: Day 60
Determine the preliminary efficacy of UCD19 CAR-T cells in pediatric patients with B-ALL during the expansion phase
Rate of patients with radiographic remission post infusion for B-NHL
Time frame: Day 90
Determine the preliminary efficacy of UCD19 CAR-T cells in pediatric patients with B-ALL during the expansion phase
Rate of efficacy as assessed by bone marrow minimal residual disease assessment by flow cytometric analysis and next generation sequencing for B-ALL patients
Time frame: Months 1, 2, 3, 6, and 12
Determine the preliminary efficacy of UCD19 CAR-T cells in pediatric patients with B-ALL during the expansion phase
Median duration of remission as assessed by bone marrow minimal residual disease assessment by flow cytometric analysis and next generation sequencing for B-ALL patients
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Time frame: Months 1, 2, 3, 6, and 12
Determine the preliminary efficacy of UCD19 CAR-T infusion in pediatric patients after first relapse with B-ALL during the expansion phase
Rate of event free survival (EFS) post UCD19 CAR-T cell infusion for B-ALL patients in first relapse.
Time frame: At Months 6 and 12
Determine the preliminary efficacy of UCD19 CAR-T infusion in pediatric patients after first relapse with B-ALL during the expansion phase
Median duration of B-cell aplasia will be assessed by flow cytometry post UCD19 CAR-T cell infusion.
Time frame: At Months 1, 2 , 3, 6 and 12-months
Determine the preliminary efficacy of UCD19 CAR-T infusion in pediatric patients after first relapse with B-ALL during the expansion phase
Incidence of patients who require stem cell transplantation (SCT) within 12-months post UCD19 CAR-T cell infusion.
Time frame: Up to 12 months post infusion
Determine the preliminary efficacy of UCD19 CAR-T infusion in pediatric patients after first relapse with B-ALL during the expansion phase
Incidence of patients who require cranial radiation within 12-months post UCD19 CAR-T cell infusion.
Time frame: Up to 12 months post infusion
Determine the preliminary efficacy of UCD19 CAR-T infusion in pediatric patients after first relapse with B-ALL during the expansion phase
Incidence of clinically significant infections (defined as those that require treatment) will be collected over the first year of treatment.
Time frame: Up to 12 months post infusion