Phase 1/2 Dose Escalation Study of CD19/CD22 Bicistronic Chimeric Antigen Receptor (CAR) T Cells in Children and Young Adults With Recurrent or Refractory CD19/CD22-expressing B Cell Malignancies

• Status: Not yet recruiting
• Trial end date: 2029-07-01

Summary

Background:

• Despite improvements in therapy, acute lymphoblastic leukemia (ALL) contributes to significant morbidity and mortality for children and young adults with cancer. CD19-CAR and CD22-CAR therapy have proven highly effective in inducing remission in patients with relapsed/refractory disease.

• Immune escape has been observed by several groups following CD19-CAR and CD22- CAR therapy for B-ALL. Investigation of this phenomenon reveals a complex biology responsible for loss or downregulation of CD19 and/or CD22 expression observed in these cases.

• The challenges encountered with currently available CD19- and CD22-directed CAR T cells in B-ALL demonstrates the need for combinatorial treatment strategies simultaneously targeting two antigens, such as CD19 and CD22, to enhance the long-term effectiveness of CARs.

• We have previously treated patients with B-ALL on a phase 1/2 clinical trial using a bivalent CD19/22 CAR T-cell as a first combinatorial treatment strategy. This CAR T-cell construct is well-tolerated and has yielded responses however there has been limited CAR T cell expansion and persistence. Additionally, the previously tested CD19/CD22 bivalent CAR T-cell construct is limited in its ability to target CD22.

• This new CD19/22 targeted construct being tested in this clinical trial has improved dual targeting capability based on preclinical data/evaluation.

Objectives:

• Phase I: Assess the safety of administering escalating doses of autologous CD19/CD22- CAR engineered T cells in children and young adults who are CAR-naive/have received interim hematopoietic stem-cell transplantation (HSCT) or who are CAR-pre-treated with CD19+CD22+ B cell ALL or lymphoma following a cyclophosphamide/fludarabine conditioning regimen.

• Phase II: Determine the efficacy of CD19/CD22 therapy in participants who are CAR- na(SqrRoot) ve/interim HSCT or who are CAR pre-treated.

Eligibility:

-Participants between >= 3 years and <= 35 years of age, with CD19+/CD22+ B cell ALL or lymphoma who have relapsed or have refractory disease after at least one standard chemotherapy regimen and one salvage regimen, with no alternative curative options.

Design:

• Phase I, 3 + 3 dose escalation design across 4 cohorts (B-ALL: A: CAR-naive/interim HSCT vs. B: CAR-pre-treated and B-lymphoma: C: CAR-naive/interim HSCT vs. D: CAR-pre-treated) using the following dose levels: -1: 3 x 10^5 transduced T cells/kg (+/- 20%); 1: 1 x 10^6 transduced T cells/kg (+/- 20%); 2: 3 x 10^6 transduced T cells/kg (+/- 20%); and 3: 1 x 10^7 transduced T cells/kg (+/- 20%). Cohorts will enroll concurrently.

• Participants will be treated based on prior therapy:

• CAR naive participants (including those who have received an interval HSCT after a prior CAR T-cells): Will receive a lymphodepleting preparative regimen of fludarabine (25 mg/m^2/d x 3 on Days -4, -3, -2) and cyclophosphamide (900 mg/m^2/d x 1 on Day -2) followed by infusion of CD19/CD22-CAR T-cells on D0.

• CAR pre-treated participants: Will receive increased lymphodepleting preparative regimen of fludarabine (30 mg/m2/d x 4 on Days -5, -4, -3, -2) and cyclophosphamide (600 mg/m2/d x 2 on Days -3, -2) followed by infusion of CD19/CD22-CAR T-cells on D0.

• Participants will be evaluated sequentially for toxicity, antitumor effects, CAR expansion and persistence, and other biologic correlatives.

• Phase: Phase 1/Phase 2

Details

• Lead Sponsor: National Cancer Institute (NCI)
• Treatments: Cyclophosphamide; Fludarabine