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

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ClinicalTrials.gov Identifier: NCT03448393
Recruitment Status : Recruiting
First Posted : February 28, 2018
Last Update Posted : January 4, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Acute Lymphoid Leukemia B-Cell Leukemia Leukemia, Lymphocytic, B Cell B-Cell Lymphoma Lymphoma, Non-Hodgkin Biological: CD19/CD22 CAR T-Cells Drug: Fludarabine Drug: Cyclophosphamide Phase 1

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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 87 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : March 26, 2018
Estimated Primary Completion Date : December 1, 2021
Estimated Study Completion Date : December 1, 2032


Arm Intervention/treatment
Experimental: Dose escalation
CD19/CD22-CARtransduced T cells at escalating doses
Biological: CD19/CD22 CAR T-Cells
CD19/CD22 cells will be infused on Day 0 after induction chemotherapy regimen.

Drug: Fludarabine
Fludarabine is administered as an IV infusion in an appropriate solution over 30 minutes. To prevent undue toxicity the dose will be based on BSA (25 mg/m2/dose)

Drug: Cyclophosphamide
Cyclophosphamide will be diluted in an appropriate solution and infused over one hour. The dose will be based on the patient s body weight, at 900 mg/m2/dose after fludarabine infusion on Day -2.

Experimental: Dose expansion
CD19/CD22-CARtransduced T cells at MTD or highest dose administered
Biological: CD19/CD22 CAR T-Cells
CD19/CD22 cells will be infused on Day 0 after induction chemotherapy regimen.

Drug: Fludarabine
Fludarabine is administered as an IV infusion in an appropriate solution over 30 minutes. To prevent undue toxicity the dose will be based on BSA (25 mg/m2/dose)

Drug: Cyclophosphamide
Cyclophosphamide will be diluted in an appropriate solution and infused over one hour. The dose will be based on the patient s body weight, at 900 mg/m2/dose after fludarabine infusion on Day -2.




Primary Outcome Measures :
  1. Safety [ Time Frame: End of treatment ]
    Safety analyses will consist of tabulations of grades of toxicity by type of toxicity.


Secondary Outcome Measures :
  1. Feasability [ Time Frame: 28 days post treatment completion ]
    Number of patients which can successfully manufacture the targeted dose number

  2. Overall survival [ Time Frame: Death ]
    Overall survival (OS) will be determined as the time from the start of the preparative regimen until death

  3. Progression-free survival [ Time Frame: Time of relapse ]
    Preparative regimen until the documentation of disease progression or death due to any cause, whichever occurs first.



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Ages Eligible for Study:   3 Years to 30 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03448393


Contacts
Contact: Leah E Hoffman, R.N. (240) 858-3828 leah.hoffman@nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Nirali N Shah, M.D. National Cancer Institute (NCI)

Additional Information:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03448393     History of Changes
Other Study ID Numbers: 180059
18-C-0059
First Posted: February 28, 2018    Key Record Dates
Last Update Posted: January 4, 2019
Last Verified: January 2, 2019

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
CD-19 expressing tumor
CD-22 Expressing Tumor
Adoptive Immunotherapy
Philadelphia chromosome (Ph)+ ALL
Lymphoma

Additional relevant MeSH terms:
Lymphoma
Leukemia
Lymphoma, B-Cell
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, B-Cell
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Fludarabine phosphate
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites