CD19/CD22 Bicistronic Chimeric Antigen Receptor (CAR) T Cells in Children and Young Adults With Recurrent or Refractory CD19/CD22-expressing B Cell Malignancies
Purpose
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....
Conditions
- B-NHL
- B-Non Hodgkin Lymphoma
- Acute Lymphocytic Leukemia
- Acute Lymphoblastic Leukemia
- B-precursor ALL
- B-All
- Lymphoma, Non-Hodgkin
- Leukemia, Lymphocytic, B Cell
- B-Cell Lymphoma
- B-Cell Leukemia
- Acute Lymphoid Leukemia
Eligibility
- Eligible Ages
- Between 3 Years and 39 Years
- Eligible Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Diagnosis - Participant must: - Have pathology confirmed B cell ALL (not isolated to the testis or CNS), CML with ALL transformation, or high-grade lymphoma (e.g., Burkitt's lymphoma, B-lymphoblastic lymphoma, diffuse large B-cell lymphoma, inclusive of low-grade lymphoma that has transformed to high grade disease); and - Have relapsed or been refractory after at least one standard chemotherapy regimen and at least one salvage treatment. Participants with Philadelphia chromosome + ALL must have failed prior tyrosine kinase inhibitor; and - Be ineligible for allogeneic stem cell transplant (SCT), have refused SCT, or have recurred after SCT; and - Have no evidence of graft-versus- host disease (GVHD) and have been without immunosuppressive agents for at least 30 days prior to apheresis, if undergone prior allogeneic SCT; and - Be unable to access (in a timely manner), ineligible for, or have relapsed/failed after or not responded to a commercially available CD19 CAR T-cell construct; and - Have evidence of at least minimal residual disease or PET-avid disease (lymphoma) at the time of enrollment. - CD22/CD19 expression - CD19 must be detected on >15% of the malignant cells by immunohistochemistry or > 80% by flow cytometry. - CD22 positivity must be confirmed. - Age >= 3 years of age and <=39 years of age at time of enrollment. - Clinical Performance status: Participants >= 16 years of age: Karnofsky >= 50%; Participants < 16 years of age: Lansky scale >= 50%. - Participants must have adequate organ and marrow function as defined below: - leukocytes >= 750/mcL* - platelets >= 50,000/mcL* - total bilirubin <=2 X ULN (except in the case of participants with documented Gilbert's disease > 3x ULN) - AST(SGOT)/ALT(SGPT) <=10 X institutional upper limit of normal - creatinine <= the maximum for age listed in the table below OR - measured creatinine clearance >=60 mL/min/1.73 m^2 for participants with creatinine levels above the max listed below per age. - Age (Years) <= 5 / Maximum Serum Creatinine (mg/dL) <= 0.8 - Age (Years) 6 to <= 10 / Maximum Serum Creatinine (mg/dL) <= 1.0 - Age (Years) >10 / Maximum Serum Creatinine (mg/dL) <= 1.2 - a participant will not be excluded because of pancytopenia >= Grade 3 if it is due to underlying bone marrow involvement by leukemia - Central nervous system (CNS) Status - Participants with leukemia with CNS 1 and 2 disease are eligible in the absence of
Exclusion Criteria
- Participants of child-bearing or child-fathering potential must be willing to practice effective birth control from the time of enrollment until 12 months following completion of study treatment for women and for 4 months following completion of study treatment for men. - Participants who are breastfeeding or plan to breastfeed must agree to discontinue/postpone breastfeeding while on study therapy and until 1 month after the administration of CAR. - Cardiac function: Left ventricular ejection fraction >= 45% or fractional shortening >=28% - Pulmonary Function - Baseline oxygen saturation >92% on room air at rest - Ability of participant or Legally Authorized Representative (LAR) to understand and the willingness to sign a written informed consent document. - Ability and willingness of participant or Legally Authorized Representative (LAR) to co- enroll on 15-C-0028: Follow-up Evaluation for Gene-Therapy Related Delayed Adverse Events after Participation in Pediatric Oncology Branch Clinical Trials. EXCLUSION CRITERIA: Participants meeting any of the following criteria are not eligible for participation in the study: - Participants with CNS3 disease, progressing neurologic signs* of CNS disease, radiologically detected active CNS lymphoma (*resolving manifestation or persistent and/or irreversible findings from prior CNS involvement (e.g., blindness) is not exclusionary) - Hyperleukocytosis (>= 50,000 blasts/microL) - Positive serum or urine beta-HCG pregnancy test performed at screening. - Participants will be excluded based on prior therapy if they fail to meet following washout criteria: - Therapy: Systemic Chemotherapy, anti-neoplastic agents, antibody- based therapies - Washout*: >=2 weeks - Exceptions: 6 weeks for clofarabine or nitrosoureas; No washout for prior intrathecal chemotherapy, steroid therapy, hydroxyurea (no dose increases within prior 2 weeks) or ALL maintenance-type chemotherapy (vincristine, 6-mercaptopurine, oral methotrexate, or a tyrosine kinase inhibitor for participants with Ph+ ALL) provided there is recovery from any acute toxic effects - Therapy: Radiation - Washout*: >=3 weeks - Exceptions: No time restriction with radiation therapy if the volume of bone marrow treated is less than 10% and the participant has measurable/evaluable disease outside the radiation window - Therapy: Allogeneic Stem Cell Transplant - Washout*: >= 100 days since SCT; >= 30 days since completion of immunosuppression; >= 6 weeks since donor lymphocyte infusion (DLI) - Exceptions: Cannot have evidence of active graft-versus-host disease (GVHD) - Therapy: CAR T-Cell Therapy or other Adoptive Cell Therapy - Washout*: > 30 days post infusion - Washout: Time between therapy and apheresis - Positive HIV antibodies consistent with active HIV. - Positive hepatitis C antibodies or positive Hepatitis B surface antigen (HbsAG) indicative of current/active HCV/HBV. - Active second malignancy other than in situ carcinoma of the cervix, unless the tumor was treated with curative intent at least two years previously and participant is in remission. - History of severe, immediate hypersensitivity reaction attributed to compounds of similar chemical or biologic composition to any agents used in study or in the manufacturing of the cells. - Uncontrolled, symptomatic, intercurrent illness or social situations that would limit compliance with study requirements or in the opinion of the PI would pose an unacceptable risk to the participant.
Study Design
- Phase
- Phase 1/Phase 2
- Study Type
- Interventional
- Allocation
- Non-Randomized
- Intervention Model
- Parallel Assignment
- Primary Purpose
- Treatment
- Masking
- None (Open Label)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Experimental 1/Phase I Dose Escalation-with standard LD - CLOSED |
CD19/CD22-CAR-transduced T cells at escalating dose + standard LD |
|
|
Experimental 1b/Phase 1 Dose Escalation - low disease burden |
CD19/CD22-CAR-transduced T cells |
|
|
Experimental 2/Phase I Dose Escalation- with intensified LD - CLOSED |
CD19/CD22-CAR-transduced T cells + standard LD |
|
|
Experimental 2b/Phase 1 Dose Escalation - high disease burden |
CD19/CD22-CAR-transduced T cells |
|
|
Experimental 3/Phase II Dose Expansion- with low disease burden |
CD19/CD22-CAR-transduced T cells at MTD/or highest dose administered with LD |
|
|
Experimental 4/Phase II Dose Expansion- with high disease burden |
CD19/CD22-CAR-transduced T cells at MTD/or highest dose administered with LD regimen #2 |
|
|
No Intervention A/Pre-treatment |
All participants enrolled on the study prior to treatment initiation. |
|
Recruiting Locations
Bethesda, Maryland 20892
For more information at the NIH Clinical Center contact National Cancer Institute Referral Office
888-624-1937
More Details
- Status
- Recruiting
- Sponsor
- National Cancer Institute (NCI)
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.