Bethesda, Maryland 20892


Background: - One type of cancer therapy takes blood cells from a person, changes them in a lab, then gives the cells back to the person. In this study, researchers are using an anti-CD22 gene, a virus, and an immune receptor to change the cells. Objective: - To see if giving anti-CD22 Chimeric Antigen Receptor (CAR) cells to young people with certain cancers is safe and effective. Eligibility: - People ages 1-30 with a leukemia or lymphoma that has not been cured by standard therapy. Design: - Participants will be screened to ensure their cancer cells express the CD22 protein. They will also have medical history, physical exam, blood and urine tests, heart tests, scans, and x-rays. They may give spinal fluid or have bone marrow tests. - Participants may have eye and neurologic exams. - Participants will get a central venous catheter or a catheter in a large vein. - Participants will have white blood cells removed. Blood is removed through a needle in an arm. White blood cells are removed. The rest of the blood is returned by needle in the other arm. - The cells will be changed in a laboratory. - Participants will get two IV chemotherapy drugs over 4 days. Some will stay in the hospital for this. - All participants will be in the hospital to get anti-CD22 CAR cells through IV. They will stay until any bad side effects are gone. - Participants will have many blood tests. They may repeat some screening exams. - Participants will have monthly visits for 2-3 months, then every 3-6 months. They may repeat some screening exams. - Participants will have follow-up for 15 years.

Study summary:

Background: - Adoptive cellular therapy with T cells genetically modified using viral-basedvectors to express chimeric antigen receptors targeting the CD19 molecule have demonstrated dramatic clinical responses in patients with acute lymphoblastic leukemia (ALL). However, not all patients respond and CD19-negative escape has been observed following CD19 CAR therapy, as well as anti-CD19/CD3 bispecific antibody therapy. Thus, additional targets are needed. - CD22 is a B-lineage-restricted, transmembrane phosphoglycoprotein of the Ig superfamily that is widely expressed on B-cell malignancies including 96% to 100% of pediatric Bprecursor ALL. Therefore, CD22 represents a promising target. Encouraging responses targeting CD22 with an antibody based immunoconjugate have been seen in patients, including children, with recurrent and refractory ALL. This will be the first in human testing of anti-CD22 CAR adoptive cell therapy. Objectives: - To determine the feasibility of producing anti-CD22 CAR cells meeting established release criteria. - To assess the safety of administering escalating doses of anti-CD22-CAR engineered T cells in children and young adults with recurrent or refractory CD22- expressing B cell malignancies following a cyclophosphamide/fludarabine preparative regimen. Eligibility: - Patients 1-30 years of age, at least 15 kg, with CD22-expressing B-cell malignancies that have recurred after or not responded to one or more standard regimens and deemed incurable by standard therapy. Patients with a history of allogeneic hematopoietic transplantation (SCT) who meet all eligibility criteria are eligible to participate. Patients previously treated with anti-CD19 CAR engineered T cells are also eligible. Design: - PBMC will be obtained by leukapheresis, CD3+ cells enriched and cultured in the presence of anti-CD3/-CD28 beads followed by lentiviral vector supernatant containing the anti-CD22 (M971BBz) CAR. - On Day -4 (cell infusion is Day 0), patients will begin induction chemotherapy comprising fludarabine 25 mg/m2 on Days -4, -3 and -2 and cyclophosphamide 900 mg/m2 on day 2. - The CD22-CAR cells will be infused on Day 0, with up to a 72h delay allowed for infusion of fresh cells or a 7 day delay if cells are cryopreserved, if needed for resolution of clinical toxicities, to generate adequate cell numbers, or to facilitate scheduling. - A phase I cell dose escalation scheme will be performed using 4 dose levels (3 x 105 transduced T cells/kg; 1 x 106 transduced T cells/kg; 3 x 106 transduced T cells/kg; and 1 x 107 transduced T cells/kg ( 20%)). If 2/6 patients have DLT at dose level 1, safety will be evaluated in a de-escalated dose of 1 x 105 transduced T cells/kg ( 20%)). Once the maximum tolerated dose (or highest level evaluated) is reached, enrollment into an expansion cohort of a total of 17 patients at MTD in two strata will proceed to provide additional information regarding the feasibility, safety and efficacy of this treatment. Patients who have previously received CD19 CAR T cells will be evaluated as a separate stratum from CARna(SqrRoot) ve patients as response may be different in these two groups.


-INCLUSION CRITERIA 1. Patient must have a B cell ALL or lymphoma and must have relapsed or refractory disease after at least one standard chemotherapy regimen and one salvage regimen. In view of the PI and the primary oncologist, there must be no available alternative curative therapies and subjects must be either ineligible for allogeneic stem cell transplant (SCT), have refused SCT, recurred after SCT, or have disease activity that prohibits SCT at the time of enrollment. 2. CD22 expression must be detected on greater than 15% of the malignant cells by immunohistochemistry or greater than 30% by flow cytometry. The choice of whether to use flow cytometry or immunohistochemistry will be determined by what is the most easily available tissue sample in each patent. In general, immunohistochemistry will be used for lymph node biopsies, flow cytometry will be used for peripheral blood and bone marrow samples. 3. Patients must have measurable or evaluable disease at the time of enrollment, which may include any evidence of disease including minimal residual disease detected by flow cytometry, cytogenetics, or polymerase chain reaction (PCR) analysis. 4. Greater than or equal to 1 year of age (and at least 15 kg) and less than or equal to 30 years of age at time of enrollment. NOTE: The first 3 patients in the first dose cohort must be greater than or equal to 16 years of age, while the first 2 patients in subsequent dose cohorts must be greater than or equal to 16 years of age. 5. Subjects with the following CNS status are eligible: - CNS 1, defined as absence of blasts in cerebral spinal fluid (CSF) on cytospin preparation, regardless of the number of WBCs; - CNS 2, defined as presence of < 5/uL WBCs in CSF and cytospin positive for blasts, or > 5/uL WBCs but negative by Steinherz/Bleyer algorithm: - CNS 2a: < 10/uL RBCs; < 5/uL WBCs and cytospin positive for blasts; - CNS 2b: greater than or equal to 10/uL RBCs; < 5/uL WBCs and cytospin positive for blasts; - CNS 2c: greater than or equal to 10/uL RBCs; greater than or equal to 5/uL WBCs and cytospin positive for blasts but negative by Steinherz/Bleyer algorithm. 6. Patients, parents/guardian(s), legally authorized representative (LAR), or durable power of attorney must be able to give consent and sign the informed consent document. Pediatric subjects will be included in age appropriate discussion and verbal assent will be obtained for those > 7 years of age, when appropriate. 7. Clinical performance status: Patients > 10 years of age: Karnofsky greater than or equal to 50%; Patients less than or equal to 10 years of age: Lansky scale greater than or equal to 50%. Subjects who are unable to walk because of paralysis, but who are upright in a wheelchair will be considered ambulatory for the purpose of calculating the performance score. 8. Patients of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four months after receiving the preparative regimen. 9. Females of child-bearing potential must have a negative pregnancy test because of the potentially dangerous/unknown effects on the fetus. 10. Cardiac function: Left ventricular ejection fraction greater than or equal to 45% or fractional shortening greater than or equal to 28%. 11. Patients with history of allogeneic stem cell transplantation are eligible if at least 100 days post-transplant, if there is no evidence of active GVHD and no longer taking immunosuppressive agents for at least 30 days prior to enrollment. 12. Patients previously treated with anti-CD19 CAR or other adoptive cell therapies will be eligible if all other eligibility criteria are met but will be evaluated as a separate strata from CAR-naive patients in the expansion phase. Circulating CAR T cells must be <5%. EXCLUSION CRITERIA Subjects meeting any of the following criteria are not eligible for participation in the study: 1. Recurrent or refractory ALL limited to isolated testicular or isolated central nervous system (CNS) disease. 2. Hepatic function: Inadequate liver function defined as total bilirubin > 2 x upper limit of normal (ULN) (except in the case of subjects with documented Gilbert s disease > 3 x ULN) or transaminase (ALT and AST) > 5 x ULN based on age- and laboratory specific normal ranges; 3. Renal function: Greater than age-adjusted normal serum creatinine or a creatinine clearance < 60 mL/min/1.73 m^2. - Less than or equal to 5 years old, maximum serum creatinine:0.8 mg/dL - Less than 5 years old, less than or equal to 10 years old, maximum serum creatinine:1.0 mg/dL - Greater than 10 years old, maximum serum creatinine:1.2 mg/dL 4. Hematologic function: - Absolute neutrophil count (ANC) < 750/uL, or platelet count < 50,000/uL, if these cytopenias are not judged by the investigator to be due to underlying disease (i.e. potentially reversible with anti-neoplastic therapy); - A subject will not be excluded because of pancytopenia greater than or equal to Grade 3 if it is due to disease, based on the results of bone marrow studies. 5. Subjects with radiologically-detected CNS lymphoma or CNS 3 disease (presence of greater than or equal 5 /uL WBCs in CSF and cytospin positive for blasts [in the absence of a traumatic lumbar puncture] and/or clinical signs of CNS leukemia); 6. Hyperleukocytosis (greater than or equal 50,000 blasts/uL) or rapidly progressive disease that in the estimation of the investigator and sponsor would compromise ability to complete study therapy; 7. Pregnant or breast-feeding females; 8. Recent prior therapy: 9. Systemic chemotherapy less than or equal to 2 weeks (6 weeks for clofarabine or nitrosoureas) or radiation therapy less than or equal to 3 weeks prior to apheresis; - Exceptions: 1. There is no time restriction in regard to prior intrathecal chemotherapy provided there is complete recovery from any acute toxic effects of such; 2. Subjects receiving hydroxyurea may be enrolled provided there has been no increase in dose for at least 2 weeks prior to starting apheresis; 3. Patients who are on standard ALL maintenance type chemotherapy (vincristine, 6- mercaptopurine or oral methotrexate or a tyrosine kinase inhibitor for patients with Ph+ ALL) may be enrolled provided that chemotherapy is discontinued at least 1 week prior to apheresis. 4. Subjects receiving steroids are allowed provided there has been no increase in dose for at least 2 weeks prior to starting apheresis; 5. For radiation therapy: Radiation therapy must have been completed at least 3 weeks prior to enrollment, with the exception that there is no time restriction if the volume of bone marrow treated is less than 10% and also the subject has measurable/evaluable disease outside the radiation port. --Other anti-neoplastic investigational agents currently or within 30 days prior to apheresis (i.e. start of protocol therapy); -- Subjects must have recovered from the acute side effects of their prior therapy, such that eligibility criteria are met. Cytopenias deemed to be disease-related and not therapy-related are exempt from this exclusion. - Prior CAR therapy within 30 days prior to apheresis or prior CAR therapy at any time with evidence for persistence of CAR T cells in blood samples (circulating levels of genetically modified cells of greater than or equal to 5% by flow cytometry). - Prior monoclonal antibody therapy within 5 half-lives or 30 days prior to apheresis, whichever is greater. 9. HIV/HBV/HCV Infection: 1. Seropositive for HIV antibody. (Patients with HIV are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy in the future should study results indicate effectiveness.) 2. Seropositive for hepatitis C or positive for Hepatitis B surface antigen (HbsAG). 10. Uncontrolled, symptomatic, intercurrent illness including but not limited to infection, congestive heart failure, unstable angina pectoris, cardiac arrhythmia, psychiatric 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 subject; 11. Second malignancy other than in situ carcinoma of the cervix, unless the tumor was treated with curative intent at least two years previously and subject is in remission; 12. 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 (i.e. gentamicin) 13. Severely impaired lung function defined as spirometry and DLCO that is 50% of the normal predicted value corrected for hemoglobin and alveolar volume and/or oxygen saturation that is 92% or less on room air while at rest. For patients who do not have respiratory symptoms (e.g. dyspnea at rest, known requirement for supplemental oxygen therapy), pulmonary function tests are not required. For children who are unable to cooperate for PFTs, the criterion is: No evidence of dyspnea at rest, no exercise intolerance and no requirement for supplemental oxygen therapy. 14. Active macrophage activation syndrome (MAS) as evidenced by laboratory abnormalities (e.g. elevated ferritin,, elevated triglycerides), hemophagocytosis on the bone marrow sample, and/or clinical indications.



Primary Contact:

Principal Investigator
Nirali N Shah, M.D.
National Cancer Institute (NCI)

Bonnie D Yates, C.R.N.P.
Phone: (240) 760-6970

Backup Contact:

Nirali N Shah, M.D.
Phone: (240) 760-6970

Location Contact:

Bethesda, Maryland 20892
United States

For more information at the NIH Clinical Center contact National Cancer Institute Referral Office
Phone: 888-624-1937

Site Status: Recruiting

Data Source:

Date Processed: November 20, 2017

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