Clinical Trials /

Anti-CD22 Chimeric Receptor T Cells in Pediatric and Young Adults With Recurrent or Refractory CD22-expressing B Cell Malignancies

NCT02315612

Description:

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.

Related Conditions:
  • B-Cell Acute Lymphoblastic Leukemia
  • Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Anti-CD22 Chimeric Receptor T Cells in Pediatric and Young Adults With Recurrent or Refractory CD22-expressing B Cell Malignancies
  • Official Title: Phase I Dose Escalation Study of Anti-CD22 Chimeric Receptor T Cells in Pediatric and Young Adults With Recurrent or Refractory CD22-expressing B Cell Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 150029
  • SECONDARY ID: 15-C-0029
  • NCT ID: NCT02315612

Conditions

  • Follicular Lymphoma
  • ALL
  • NHL
  • Large Cell Lymphoma

Interventions

DrugSynonymsArms
CD22-CARArm 2

Purpose

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.

Detailed Description

      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. Complete

        -  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 3 dose levels (3 x 10(5)
           transduced T cells/kg; 1 x 10(6) transduced T cells/kg; and 3 x 10(6) transduced T
           cells/kg;).If 2/6 patients have DLT at dose level 1, safety will be evaluated in a
           de-escalated dose of 1 x 10(5) dose (or highest level evaluated) is reached, enrollment
           into an expansion cohort of a total of 42 patients at MTD in (21 with and 21 without
           previous CD19 CAR T cells) 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 separately from CAR-na(SqrRoot) ve patients
           as response may be different in these two groups.

        -  Patients will be monitored for toxicity, response and T cell persistence as well as
           other biologic correlates.
    

Trial Arms

NameTypeDescriptionInterventions
1ExperimentalDose escalation of CD22-CAR
  • CD22-CAR
Arm 2ExperimentalDose expansion of CD22-CAR
  • CD22-CAR

Eligibility Criteria

        -INCLUSION CRITERIA:

          1. Patient must have a B cell ALL (inclusive of ALL blast transformation from CML) 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 80% 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 and CSF when feasible.

          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. CNS3 who has failed salvage systemic and intensive IT chemotherapy (and therefore not
             eligible for radiation)

          7. Patients with isolated CNS relapse will be eligible if they have previously been
             treated with cranial radiation (at least 1800 cGy) but only in the absence of
             neurologic symptoms suggestive of bulky CNS disease, such as cranial nerve palsy due

             to active disease.

          8. 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.

          9. Clinical performance status: Patients greater than or equal to 16 years of age:
             Karnofsky greater than or equal to 50%; Patients < 16 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.

         10. 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.

         11. Females of child-bearing potential must have a negative pregnancy test because of the
             potentially dangerous/unknown effects on the fetus.

         12. Cardiac function: Left ventricular ejection fraction greater than or equal to 45% or
             fractional shortening greater than or equal to 28%.

        12. 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.

        13. 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

          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 may be enrolled, provided there has been no
                       increase in dose for at least 1 week 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, or antibody based
                            therapies currently or within 2 weeks 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).

         10. 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).

         11. 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;

         12. 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;

         13. 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)

         14. 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.

         15. 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.
      
Maximum Eligible Age:30 Years
Minimum Eligible Age:3 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Toxicity
Time Frame:End of treatment
Safety Issue:
Description:Number of patients who have grade 3 CRS and above

Secondary Outcome Measures

Measure:Quantitate CAR cell responses
Time Frame:1 month, 3 months and 6 months following CAR infusion
Safety Issue:
Description:Number of patients who have detectable CAR cells

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • CD-22 Expressing Tumor
  • Chimeric Antigen Receptor
  • Adoptive Immunotherapy
  • ALL
  • Lymphoma

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