Clinical Trials /

CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells in Children and Young Adults With Recurrent or Refractory CD19/CD22-expressing B Cell Malignancies

NCT03448393

Description:

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 30 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. ...

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

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells in Children and Young Adults With Recurrent or Refractory CD19/CD22-expressing B Cell Malignancies
  • Official Title: Phase 1 Dose Escalation Study of CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells in Children and Young Adults With Recurrent or Refractory CD19/CD22-expressing B Cell Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 180059
  • SECONDARY ID: 18-C-0059
  • NCT ID: NCT03448393

Conditions

  • Acute Lymphoid Leukemia
  • B-Cell Leukemia
  • Leukemia, Lymphocytic, B Cell
  • B-Cell Lymphoma
  • Lymphoma, Non-Hodgkin

Interventions

DrugSynonymsArms
CD19/CD22 CAR T-CellsDose escalation
FludarabineDose escalation
CyclophosphamideDose escalation

Purpose

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 30 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 or lymphoma following a cyclophosphamide/fludarabine conditioning
      regimen.

      Eligibility:

      -Patients between 3 years and 30 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 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 (plus or equal to 20%); 1: 3 x 10^5 transduced T cells/kg (plus or
           equal to 20%); 2: 1 x 10^6 transduced T cells/kg; and 3: 3 x 10^6 transduced T cells/kg
           plus or equal to 20%)

        -  Patients will receive a lymphodepleting preparative regimen of fludarabine (25 mg/m2/d x
           3 on Days -4, -3,-2) and cyclophosphamide (900 mg/m2/d x 1 on Day -2) followed by
           infusion of CD19/CD22-CAR T-cells on D0.

        -  Patients will be evaluated sequentially for toxicity, antitumor effects, CAR expansion
           and persistence, as well as research correlatives.
    

Trial Arms

NameTypeDescriptionInterventions
Dose escalationExperimentalCD19/CD22-CARtransduced T cells at escalating doses
  • CD19/CD22 CAR T-Cells
  • Fludarabine
  • Cyclophosphamide
Dose expansionExperimentalCD19/CD22-CARtransduced T cells at MTD or highest dose administered
  • CD19/CD22 CAR T-Cells
  • Fludarabine
  • Cyclophosphamide

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Diagnosis

               -  Patient must have a B cell ALL (inclusive of CML with ALL transformation) 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. Patients who have undergone autologous SCT will be
                  eligible, and patients that have undergone allogeneic SCT will be eligible if, in
                  addition to meeting other eligibility criteria, they have no evidence of GVHD and
                  have been without immunosuppressive agents for at least 30 days. Patients with
                  Philadelphia chromosome + ALL must have failed prior tyrokine kinase inhibitor.

               -  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.

          -  CD22/CD19 Expression

               -  CD19 expression must be detected on greater than 15% of the malignant cells by
                  immunohistochemistry or greater than 90% 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 patient. In general, immunohistochemistry will be used for lymph node
        biopsies, flow cytometry will be used for peripheral blood and bone marrow samples. CD22+ B
        cell malignancy is required and CD22 expression levels will be documented when available,
        but a specific level of expression is not an eligibility requirement; it may be documented
        as positive or negative.

          -  Age:

             --Greater than or equal to 3 years of age (and at least 15 kg) and less than or equal
             to 30 years of age at time of enrollment (> 3 years to < 30 years). NOTE: The first
             patient in each dose cohort must be greater than or equal to 18 years of age.

          -  Clinical Performance

             --Clinical performance status: Patients > 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.

          -  Patients must have normal organ and marrow function as defined below:

               -  leukocytes >750/mcL*

               -  platelets >50,000/mcL*

               -  total bilirubin <2 X ULN (except in the case of subjects with documented Gilbert
                  s disease > 3x ULN)

               -  AST(SGOT)/ALT(SGPT) <10 X institutional upper limit of normal

               -  creatinine within for age and laboratory normal ranges

        OR

          -  creatinine clearance >60 mL/min/1.73 m2 for patients with creatinine levels above
             institutional normal.

          -  Age: less than or equal to 5. Maximun Serum Creatinine (mg/dL): < 0.8

          -  Age: 5 < age less than or equal to 10. Maximum Serum Creatinine (mg/dL):< 1.0

          -  Age: >10. Maximum Serum Creatinine (mg/dL): < 1.2

             * 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.

             -CNS Status:

          -  a. Subjects with leukemia with the following CNS status are eligible only in the
             absence of neurologic symptoms suggestive of CNS leukemia, such as cranial nerve
             palsy:

               -  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.

          -  b. Subjects with lymphoma

               -  Subjects must have no signs or symptoms of CNS disease or detectable evidence of
                  CNS disease on MRI at the time of screening. Subjects who have been previously
                  treated for CNS disease but have no evidence of disease at screening are
                  eligible.

        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.

          -  Contraception:

             --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.

          -  Cardiac function: Left ventricular ejection fraction greater than or equal to 45% or
             fractional shortening greater than or equal to 28%, and no clinically significant ECG
             findings

          -  Pulmonary Function

          -  Baseline oxygen saturation >92% on room air at rest

          -  Patients with respiratory symptoms must have a DLCO/adjusted > 45%. For children who
             are unable to cooperate for PFTs they must not have dyspnea at rest or known
             requirement for supplemental oxygen.

          -  Ability of subject or Legally Authorized Representative (LAR) to understand and the
             willingness to sign a written informed consent document.

        For subjects <18 years old their legal guardian must give informed consent. Pediatric
        subjects will be included in age appropriate discussion and verbal assent will be obtained
        for those > 7 years of age, when appropriate.

        EXCLUSION CRITERIA:

        Subjects meeting any of the following criteria are not eligible for participation in the
        study:

          -  Recurrent or refractory ALL limited to isolated testicular or isolated central nervous
             system (CNS) disease.

          -  Subjects with radiologically-detected CNS lymphoma or CNS 3 disease (presence of
             greater than or equal to 5/micro L WBCs in CSF and cytospin positive for blasts [in
             the absence of a traumatic lumbar puncture] and/or clinical signs of CNS leukemia
             and/or radiographic signs of leptomeningeal disease);

          -  Hyperleukocytosis (greater than or equal to 50,000 blasts/micro L) or rapidly
             progressive disease that in the estimation of the investigator and sponsor would
             compromise ability to complete study therapy;

          -  Pregnant women are excluded from this study because the study agents have the
             potential for teratogenic or abortifacient effects. Because there is an unknown but
             potential risk for adverse events in nursing infants secondary to treatment of the
             mother with the study agents, breastfeeding should be discontinued.

          -  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:

               -  a. There is no time restriction in regard to prior intrathecal chemotherapy
                  provided there is complete recovery from any acute toxic effects of such;

               -  b. Subjects receiving hydroxyurea may be enrolled provided there has been no
                  increase in dose for at least 2 weeks prior to starting apheresis;

               -  c. Patients who are on standard ALL maintenance type chemotherapy (vincristine,
                  6-mercaptopurine, oral methotrexate or tyrosine kinase inhibitors in patients
                  with Ph+ALL) may be enrolled provided that chemotherapy is discontinued at least
                  1 week prior to apheresis.

               -  d. Subjects receiving steroid therapy are allowed provided there has been no
                  increase in dose for at least 1 week prior to starting apheresis; patients on
                  physiologic steroids will not be excluded.

               -  e. 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% in peripheral blood by flow
             cytometry).

          -  Prior monoclonal antibody therapy within 5 half-lives or 7 days prior to apheresis,
             whichever is greater.

          -  HIV/HBV/HCV Infection:

               -  a. 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.)

               -  b. Seropositive for hepatitis C or positive for Hepatitis B surface antigen
                  (HbsAG).

          -  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;

          -  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;

          -  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.

          -  Recruitment Strategies

        The following recruitment strategies will be employed to elicit potential candidates for
        this trial:

          1. Listed on clinical trials.gov;

          2. Listed in PDQ;

          3. In addition, patients treated on other institutional trials who are eligible for
             participation will be offered participation in this study

        Prior to distribution of any recruitment materials, such materials will be submitted to the
        IRB for review.
      
Maximum Eligible Age:30 Years
Minimum Eligible Age:3 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety
Time Frame:End of treatment
Safety Issue:
Description:Safety analyses will consist of tabulations of grades of toxicity by type of toxicity.

Secondary Outcome Measures

Measure:Feasability
Time Frame:28 days post treatment completion
Safety Issue:
Description:Number of patients which can successfully manufacture the targeted dose number
Measure:Overall survival
Time Frame:Death
Safety Issue:
Description:Overall survival (OS) will be determined as the time from the start of the preparative regimen until death
Measure:Progression-free survival
Time Frame:Time of relapse
Safety Issue:
Description:Preparative regimen until the documentation of disease progression or death due to any cause, whichever occurs first.

Details

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

Trial Keywords

  • CD-19 expressing tumor
  • CD-22 Expressing Tumor
  • Adoptive Immunotherapy
  • Philadelphia chromosome (Ph)+ ALL
  • Lymphoma

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