Trials / Recruiting

RecruitingNCT05442515

CD19/CD22 Bicistronic Chimeric Antigen Receptor (CAR) T Cells in Children and Young Adults With Recurrent or Refractory CD19/CD22-expressing B Cell Malignancies

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: Recruiting
Phase: Phase 1 / Phase 2
Study type: Interventional
Enrollment: 126 (estimated)

Sponsor: National Cancer Institute (NCI) · NIH
Sex: All
Age: 3 Years – 39 Years
Healthy volunteers: Not accepted

Summary

Background: Acute lymphoblastic leukemia (ALL) is the most common cancer in children. About 90% of children and young adults who are treated for ALL can now be cured. But if the disease comes back, the survival rate drops to less than 50%. Better treatments are needed for ALL relapses. Objective: To test chimeric antigen receptor (CAR) therapy. CARs are genetically modified cells created from each patient s own blood cells. his trial will use a new type of CAR T-cell that is targeting both CD19 and CD22 at the same time. CD19 and CD22 are proteins found on the surface of most types of ALL. Eligibility: People aged 3 to 39 with ALL or related B-cell lymphoma that has not been cured by standard therapy. Design: Participants will be screened. This will include: Physical exam Blood and urine tests Tests of their lung and heart function Imaging scans Bone marrow biopsy. A large needle will be inserted into the body to draw some tissues from the interior of a bone. Lumbar puncture. A needle will be inserted into the lower back to draw fluid from the area around the spinal cord. Participants will undergo apheresis. Their blood will circulate through a machine that separates blood into different parts. The portion containing T cells will be collected; the remaining cells and fluids will be returned to the body. The T cells will be changed in a laboratory to make them better at fighting cancer cells. Participants will receive chemotherapy starting 4 or 5 days before the CAR treatment. Participants will be admitted to the hospital. Their own modified T cells will be returned to their body. Participants will visit the clinic 2 times a week for 28 days after treatment. Follow-up will continue for 15 years....

Detailed description

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 with B cell ALL (stratified by disease burden) or lymphoma following a cyclophosphamide/fludarabine conditioning regimen. * Phase II: Determine the efficacy of CD19/CD22 therapy in participants stratified by disease burden. Eligibility: -Participants between \>= 3 years and \<= 39 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 3 cohorts (B-ALL/B-cell lymphoblastic lymphoma: A: low-disease burden (\<25 % marrow blasts without extramedullary disease) vs. B: high-disease burden (\>= 25 % marrow blasts or with EMD): C: B-cell non-Hodgkin lymphoma using the following dose levels: -2: 1 x 10\^5 transduced T cells/kg (+/- 20%); -1: 3 x 10\^5 transduced T cells/kg (+/- 20%); 1: 1 x 10\^6 transduced T cells/kg (+/- 20%); and 2: 3x 10\^6 transduced T cells/kg (+/- 20%). Cohorts will enroll concurrently. * Participants will be treated based on disease burden and will receive 1 of 2 lymphodepleting preparative regimens: * Lymphodepleting preparative regimen # 1: Fludarabine (30 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. * Lymphodepleting preparative regimen #2: 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. * Determination for use of LD regimen #1 versus #2 will be based on pre-treatment absolute lymphocyte count, pre-existing cytopenias, receipt of prior CAR T-cell therapy, high disease burden and assessment of infection risk. * Participants will be evaluated sequentially for toxicity, antitumor effects, CAR expansion and persistence, and other biologic correlatives.

Conditions

Interventions

Type	Name	Description
BIOLOGICAL	CD19/CD22-CAR-transduced T cells	CD19/CD22-CAR-transduced T cells on D0 after lymphodepleting preparative regimen
DRUG	cyclophosphamide	Cyclophosphamide will be diluted in an appropriate solution and infused over one hour. The dose will be based on the patient s body weight, at 900 mg/m2/dose after fludarabine infusion.
DRUG	fludarabine	Fludarabine is administered as an IV infusion in an appropriate solution over 30 minutes. To prevent undue toxicity the dose will be based on BSA (25 mg/m2/dose).

Timeline

Start date: 2022-12-28
Primary completion: 2027-07-01
Completion: 2029-07-01
First posted: 2022-07-05
Last updated: 2026-03-12

Locations

1 site across 1 country: United States

Regulatory

FDA-regulated drug study

Source: ClinicalTrials.gov record NCT05442515. Inclusion in this directory is not an endorsement.