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T Cells Expressing a Fully-human AntiCD19 Chimeric Antigen Receptor for Treating B-cell Malignancies

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ClinicalTrials.gov Identifier: NCT02659943
Recruitment Status : Recruiting
First Posted : January 21, 2016
Last Update Posted : July 6, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

The immune system fights infection and can affect cancer cells. T cells are white blood cells that are a major part of the immune system. T cells can destroy tumors. Researchers want to try to manipulate the immune system to better recognize and kill tumor cells.

Objective:

To test the safety of giving T cells expressing a novel fully-human anti-CD19 chimeric antigen receptor (CAR) to people with advanced B-cell cancer.

Eligibility:

People ages 18 73 with a B-cell cancer that has not been controlled by other therapies.

Design:

Participants will be screened with:

Physical exam

Blood and urine tests

Heart tests

Bone marrow sample taken

Scans in machines that take pictures

Participants will have apheresis. Blood is removed through a needle in an arm. T cells are removed. The rest of the blood is returned through a needle in the other arm.

The cells will be changed in a laboratory.

Participants will get 2 chemotherapy drugs over 3 days.

Two days later, participants will check into the hospital. They will get an intravenous (IV) catheter in an arm or chest vein. They will get the T cells through the IV in 1 infusion.

After this, participants will stay in the hospital for at least 9 days and stay nearby for 2 weeks. Then they will have blood tests and see a doctor.

Participants will have visits 6 visits for 1 year after the infusion. Some may have more follow-up visits.

Participants may samples taken of spinal fluid, bone marrow, and tumors.


Condition or disease Intervention/treatment Phase
Lymphoma, B-Cell Lymphoma, Non-hodgkins Biological: Anti-CD19-CAR T cells Drug: Cyclophosphamide Drug: Fludarabine Phase 1

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 64 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: T Cells Expressing a Fully-Human Anti-CD19 Chimeric Antigen Receptor for Treating B-cell Malignancies
Study Start Date : January 20, 2016
Estimated Primary Completion Date : December 1, 2020
Estimated Study Completion Date : December 1, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cohort 1
Dose escalation for patients who never had an alloHSCT
Biological: Anti-CD19-CAR T cells
Dose-escalation trial starting dose: 0.66x106 CAR+ T cells/kg(weight based dosing)(up to a maximum dose of 18x10^6 CAR+ T cells/kg) infuse on day 0

Drug: Cyclophosphamide
300 mg/m2 IV infusion over 30 minutes on days -5, -4 and -3

Drug: Fludarabine
30 mg/m2 IV infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4,and -3

Experimental: Cohort 2
Closed: Dose escalation for patients who have had an alloHSCT
Biological: Anti-CD19-CAR T cells
Dose-escalation trial starting dose: 0.66x106 CAR+ T cells/kg(weight based dosing)(up to a maximum dose of 18x10^6 CAR+ T cells/kg) infuse on day 0

Drug: Cyclophosphamide
300 mg/m2 IV infusion over 30 minutes on days -5, -4 and -3

Drug: Fludarabine
30 mg/m2 IV infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4,and -3




Primary Outcome Measures :
  1. Determine the safety and feasibility of administering T cells expressing a novel fully-human anti-CD19 chimeric antigen receptor (CAR) [ Time Frame: 4-5 weeks after first dose ]
    List of adverse event frequency



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Ages Eligible for Study:   18 Years to 73 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Malignancy criteria:

    • Patients with the following malignancies are potentially eligible: any B-cell lymphoma, and chronic lymphocytic leukemia (CLL). Patients with indolent malignancies that have transformed to diffuse large B-cell lymphoma are eligible.
    • Clear CD19 expression must be uniformly detected on 75% or more of malignant cells from either bone marrow or a leukemia or lymphoma mass by flow cytometry or immunohistochemistry. These assays must be performed at the National Institutes of Health. It is preferable but not required that the specimen used for CD19 determination comes from a sample that was obtained after the patient s most recent treatment. If paraffin embedded unstained samples of bone marrow involved with malignancy or a lymphoma mass are available, these can be shipped to the NIH for CD19 staining; otherwise, new biopsies will need to be performed for determination of CD19 expression.
    • DLBCL patients must have received at least two prior chemotherapy-containing regimens at least one of which must have contained doxorubicin and a monoclonal antibody. Follicular lymphoma patients must have received at least 2 prior regimens including at least 1 regimen with chemotherapy. All other lymphoma and leukemia patients must have had at least 1 prior chemotherapy-containing regimen. All patients with CLL or small lymphocytic lymphoma must have had prior treatment with ibrutinib or another signal transduction inhibitor.
    • Patients must have measurable malignancy as defined by at least one of the criteria below.

      • Lymphoma or leukemia masses that are measurable (minimum 1.5 cm in largest diameter) by CT scan is required for all diagnoses except CLL. All masses must be less than 10 cm in the largest diameter.
      • For a lymphoma mass to count as measurable malignancy, it must have abnormally increased metabolic activity when assessed by positron emission tomography (PET) scan.
      • For CLL and lymphoma with only bone marrow involvement no mass is necessary, but if a mass is not present, bone marrow malignancy must be detectable by flow cytometry in lymphoma and CLL.
  • Other inclusion criteria:

    • Greater than or equal to 18 years of age and less than or equal to age 73.
    • Able to understand and sign the Informed Consent Document.
    • Clinical performance status of ECOG 0-1
    • Room air oxygen saturation of 92% or greater
    • Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for four months after receiving the preparative regimen.
    • Women of child bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the preparative chemotherapy on the fetus. Women of child-bearing potential are defined as all women except women who are post-menopausal

or who have had a hysterectomy. Postmenopausal will be defined as women over the age of 55 who have not had a menstrual period in at least 1 year.

  • Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune -competence and thus are less responsive to the experimental treatment and more susceptible to its toxicities.)
  • Patients with a known history of hepatitis B or hepatitis C are not eligible due to the risk of re-activation of hepatitis after prolonged B-cell depletion due to anti-CD19 CAR T cells.
  • Seronegative for hepatitis B antigen, positive hepatitis B tests can be further evaluated by confirmatory tests, and if confirmatory tests are negative, the patient can be enrolled. Patients with a known history of hepatitis B are not eligible.
  • Seronegative for hepatitis C antibody unless antigen negative. If hepatitis C antibody test is positive, then patients must be tested for the presence of RNA by RT-PCR and be HCV RNA negative. Patients with a known history of hepatitis C are not eligible.
  • Absolute neutrophil count greater than or equal to 1000/mm(3) without the support of filgrastim or other growth factors.
  • Platelet count greater than or equal to 45,000/mm(3) without transfusion support
  • Hemoglobin greater than 8.0 g/dl.
  • Less than 5% malignant cells in the peripheral blood leukocytes
  • Serum ALT and AST less or equal to 3 times the upper limit of the institutional normal unless liver involvement by malignancy is demonstrated.
  • Serum creatinine less than or equal to 1.4 mg/dL.
  • Total bilirubin less than or equal to 2.0 mg/dl.
  • At least 14 days must have elapsed since any prior systemic therapy prior to apheresis and prior to the initiation of chemotherapy (including systemic corticosteroids at any dose). Because this protocol requires collection of autologous blood cells by leukapheresis

in order to prepare CAR T cells, systemic anti-malignancy therapy including systemic corticosteroid therapy of any dose are not allowed within 14 days prior to the required leukapheresis. NOTE: Because of the long half-life and potential to affect CAR T cells, 60 days must elapse from the time of administration of anti-PD-1 or anti-PD-L1 antibodies or other agents that in the opinion of the PI can stimulate immune activity and infusion of CAR T cells.

  • Normal cardiac ejection fraction (greater than or equal to 55% by echocardiography) and no evidence of hemodynamically significant pericardial effusion as determined by an echocardiogram within 4 weeks of the start of the treatment protocol.
  • Patients must not take corticosteroids including prednisone, dexamethasone or any other corticosteroid for 14 days before apheresis and CAR T-cell infusion. Patients must also not take corticosteroids at doses higher than 5 mg/day of prednisone or equivalent at any

time after the CAR T cell infusion.

--Patients who have been treated on other protocols of genetically-modified T cells at the NIH only are potentially eligible under these conditions:

---At least 6 months have elapsed since the last genetically-modified T-cell therapy that the patient received and there is no evidence of replication-competent retroviruses (evidence must be provided from prior NIH gene-therapy protocol Principal Investigator) and persisting genetically-modified T cells are not detectable in the patient s blood (evidence must be provided by prior NIH gene-therapy protocol Principal Investigator).

EXCLUSION CRITERIA:

  • Patients that require urgent therapy due to tumor mass effects or spinal cord compression.
  • Patients that have active hemolytic anemia.
  • Patients with second malignancies in addition to their B-cell malignancy are not eligible if the second malignancy has required treatment (including maintenance therapy) within the past 4 years or is not in complete remission. There are two exceptions to this

criterion: successfully treated non-metastatic basal cell or squamous cell skin carcinoma.

  • Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant.
  • Active uncontrolled systemic infections (defined as infections causing fevers and infections requiring intravenous antibiotics when intravenous antibiotics have been administered for less than 72 hours), active coagulation disorders or other major uncontrolled medical illnesses of the cardiovascular, respiratory, endocrine, renal, gastrointestinal, genitourinary or immune system, history of myocardial infarction, history of ventricular tachycardia or ventricular fibrillation, active cardiac arrhythmias (active atrial fibrillation is not allowed, resolved atrial fibrillation not requiring current treatment is allowed (anticoagulants count as current treatment) ), active obstructive or restrictive pulmonary disease, active autoimmune diseases such as rheumatoid arthritis.
  • Patients will not be seen for screening appointments or enrolled on the protocol if they have been hospitalized within the 7 days prior to the screening appointment or the date of protocol enrollment.
  • Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
  • Systemic corticosteroid steroid therapy of any dose is not allowed within 14 days prior to the required leukapheresis, or the initiation of the conditioning chemotherapy regimen. Corticosteroid creams, ointments, and eye drops are allowed.
  • History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  • Patients with current CNS involvement by malignancy (either by imaging or cerebrospinal fluid involvement or biopsy-proven).

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): NCT02659943


Contacts
Contact: Brenna Hansen (301) 435-5605 hansenb3@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike 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: James N Kochenderfer, M.D. National Cancer Institute (NCI)

Additional Information:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02659943     History of Changes
Other Study ID Numbers: 160054
16-C-0054
First Posted: January 21, 2016    Key Record Dates
Last Update Posted: July 6, 2018
Last Verified: April 3, 2018

Studies a U.S. FDA-regulated Drug Product: Yes

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Gene Therapy
Adoptive T Cell Therapy
Allogeneic Stem Cell Transplantation
T-cell infusion
Residual Malignancy

Additional relevant MeSH terms:
Lymphoma
Neoplasms
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
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