CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells in Children and Young Adults With Recurrent or Refractory CD19/CD22-expressing B Cell Malignancies
- Conditions
- B-Cell LymphomaAcute Lymphocytic LeukemiaB-Cell LeukemiaB-Non Hodgkin LymphomaLymphoma, Non-HodgkinLeukemia, Lymphocytic, B CellAcute Lymphoid LeukemiaB-NHLAcute Lymphoblastic LeukemiaB-All
- Interventions
- Registration Number
- NCT03448393
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
Background:
B-cell leukemias and lymphomas are cancers that are often difficult to treat. The primary objective of this study is to determine the ability to take a patient's own cells (T lymphocytes) and grow them in the laboratory with the CD19/CD22-CAR receptor gene through a process called 'lentiviral transduction (also considered gene therapy) and growing them to large numbers to use as a treatment for hematologic cancers in children and young adults.. Researchers want to see if giving modified CD19/CD22-CAR T cells to people with these cancers can attack cancer cells. In addition, the safety of giving these gene modified cells to humans will be tested at different cell doses. Additional objectives are to determine if this therapy can cause regression of B cell cancers and to measure if the gene modified cells survive in patients blood.
Objective:
To study the safety and effects of giving CD19/CD22-CAR T cells to children and young adults with B-cell cancer.
Eligibility:
People ages 3-39 with certain cancers that have not been cured by standard therapy. Their cancer tissue must express the CD19 protein.
Design:
A sample of participants blood or bone marrow will be sent to NIH and tested for leukemia.
Participants will be screened with:
Medical history
Physical exam
Urine and blood tests (including for HIV)
Heart and eye tests
Neurologic assessment and symptom checklist.
Scans, bone marrow biopsy, and/or spinal tap
Some participants will have lung tests.
Participants will repeat these tests throughout the study and follow-up.
Participants will have leukapheresis. Blood will be drawn from a plastic tube (IV) or needle in one arm then go through a machine that removes lymphocytes. The remaining blood will be returned to the participant s other arm.
Participants will stay in the hospital about 2 weeks. There they will get:
Two chemotherapy drugs by IV
Their changed cells by IV
Standard drugs for side effects
Participants will have frequent follow-up visits for 1 year, then 5 visits for the next 4 years. Then they will answer questions and have blood tests every year for 15 years.
...
- Detailed Description
Background:
* Acute lymphoblastic leukemia (ALL) accounts for approximately 25% of childhood cancer. Survival rates have improved, but outcomes for some subgroups, including infants and young adults remain poor, and survival for patients who relapse is \< 50%, despite allogeneic stem cell transplant following second remission.
* CD19 immune escape has been observed by several groups following CD19-CAR therapy for B-ALL. Investigation of this phenomenon reveals a complex biology responsible for loss or downregulation of CD19 expression observed in these cases.
* Sequential therapy using CD22-CARs to treat CD19 dim/lo escape is associated with rapid development of resistance due to CD22 downregulation. This trial will test whether simultaneous targeting of CD19 and CD22 using a novel bivalent CD19/22-CAR is safe and feasible.
Objectives:
-Assess the safety of administering escalating doses of autologous CD19/CD22-CAR engineered T cells that meet established release specifications in children and young adults with CD19+CD22+ B cell ALL, isolated CNS ALL, or lymphoma following a cyclophosphamide/fludarabine conditioning regimen.
Eligibility:
-Participants between \>= 3 years and \<= 39 years of age, with CD19+/CD22+ B cell ALL, isolated CNS 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 who meet standard Phase I eligibility criteria.
Design:
* Phase I, 3 + 3 dose escalation design using the following dose levels: -1: 1 x 10\^5 transduced T cells/kg (+/- 20%); 1: 3 x 10\^5 transduced T cells/kg (+/- 20%); 2: 1 x 10\^6 transduced T cells/kg; and 3: 3 x 10\^6 transduced T cells/kg (+/- 20%); 4: 1 x 10\^7 transduced T cells/kg (+/- 20%).
* Participants 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. Participants who are CAR pretreated (with exception for those with an interval HSCT) 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. If fludarabine is unavailable, pentostatin may be given as an alternative.
* Patients will be evaluated sequentially for toxicity, antitumor effects, CAR expansion and
persistence, as well as research correlatives.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 150
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Dose expansion Cyclophosphamide CD19/CD22-CAR-transduced T cells at MTD or highest dose administered Dose escalation CD19/CD22 CAR T-Cells CD19/CD22-CAR-transduced T cells at escalating doses Dose expansion Fludarabine CD19/CD22-CAR-transduced T cells at MTD or highest dose administered Dose escalation Fludarabine CD19/CD22-CAR-transduced T cells at escalating doses Dose escalation Cyclophosphamide CD19/CD22-CAR-transduced T cells at escalating doses Dose expansion CD19/CD22 CAR T-Cells CD19/CD22-CAR-transduced T cells at MTD or highest dose administered
- Primary Outcome Measures
Name Time Method Safety End of treatment Safety analyses will consist of tabulations of grades of toxicity by type of toxicity.
- Secondary Outcome Measures
Name Time Method Feasability 28 days post treatment completion Number of patients which can successfully manufacture the targeted dose number
Progression-free survival Time of relapse Preparative regimen until the documentation of disease progression or death due to any cause, whichever occurs first.
Overall survival Death Overall survival (OS) will be determined as the time from the start of the preparative regimen until death
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States