Acute Lymphoblastic Leukemia Clinical Trial
Official title:
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
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....
Status | Recruiting |
Enrollment | 116 |
Est. completion date | July 1, 2029 |
Est. primary completion date | July 1, 2027 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 3 Years to 39 Years |
Eligibility | - 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, neurologic signs of CNS disease, radiologically detected active CNS lymphoma - 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 - Exceptions: For patients previously treated with CAR T-cells without interim HSCT (cohorts B1 and D1) cannot have circulating CAR T cells (or genetically modified cells) >5% by flow cytometry in peripheral blood - 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. |
Country | Name | City | State |
---|---|---|---|
United States | National Institutes of Health Clinical Center | Bethesda | Maryland |
Lead Sponsor | Collaborator |
---|---|
National Cancer Institute (NCI) |
United States,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Efficacy | Determine the efficacy of CD19/CD22 therapy in participants stratified by disease burden. | Monthly until 3 months post CAR T infusion and then at 6 months and every 6 months after that, for 2 years post-infusion for each participant, up to 2 years after the entry date of the last participant. | |
Primary | Safety | Assess the safety of administering escalating doses of autologous CD19/CD22-CAR engineered T cells in children and young adult with B cell ALL (stratified by disease burden) or lymphoma following a cyclophosphamide/fludarabine LD. | 30 days post CAR T infusion | |
Secondary | Feasibility | Determine the feasibility of producing CD19/CD22-CAR T cells meeting the established release criteria. | Up to two years after the last participant has entered. | |
Secondary | Adverse Events | Phase II: Assess the safety of CD19/CD22 therapy in participants based on underlying disease burden. | 30 days post CAR T infusion | |
Secondary | Persistence and expansion | Evaluate persistence and expansion of C19/CD22-CAR T cells in children and young adults with CD19+CD22+ B-ALL or lymphoma | Up to two years after the last participant has entered. | |
Secondary | Progression free survival (PFS) and Overall survival (OS) | Evaluate PFS and OS in participants, separately by phase II cohort | Up to two years after the last participant has entered. | |
Secondary | Overall response rate | Phase I: Evaluate the ability of CD19/CD22-CAR T cells to mediate clinical activity in children and young adults with CD19+CD22+ B cell ALL or lymphoma. | Monthly until 3 months post infusion and then at 6 months and every 6 months after that, for 2 years post-infusion for each participant, for up to two years from the entry date of the last participant | |
Secondary | Assess response and toxicity (CRS grade) | Assess overall response rate and CRS grades (toxicity) in participants who received subsequent infusion | Up to two years after last participant has entered |
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