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T Cells Expressing Fully-human Anti-CD19 and Anti-CD20 Chimeric Antigen Receptors for Treating B-cell Malignancies and Hodgkin Lymphoma

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ClinicalTrials.gov Identifier: NCT04160195
Recruitment Status : Not yet recruiting
First Posted : November 11, 2019
Last Update Posted : December 6, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

CD19 and CD20 are often found on certain cancer cells. Researchers think that a person s T cells can be modified in a lab to kill cells that have CD19 and CD20 on the surface.

Objective:

To see if it is safe to give anti-CD19 and anti-CD20 CAR T cells to people with a B cell cancer or Hodgkin lymphoma.

Eligibility:

People ages 18 and older with a B cell cancer or Hodgkin lymphoma that has not been controlled with standard therapies

Design:

Participants will be screened under protocol 01C0129 with:

Medical history

Physical exam

Blood and heart tests

Bone marrow biopsy: A needle is inserted into the participant s hip bone to remove a small amount of marrow.

Scans

Participants will have apheresis: Blood will be removed through a vein. The blood with circulate through a machine that removes the T cells. The rest of the blood will be returned to the participant.

Once a day for 3 days before they get the T cells, participants will receive chemotherapy through a vein.

Participants will receive the T cells through a vein. They will stay in the hospital for at least 9 days.

Participants may have a lumbar puncture: A needle will remove fluid from the spinal cord.

Participants may have a tumor biopsy.

Participants will repeat the screening tests throughout the study.

Participants will have follow-up visits 2 weeks after infusion; monthly for 4 months; at 6, 9, and 12 months; every 6 months for 3 years; and then annually for 5 years. Participants will then be contacted annually for 15 years.


Condition or disease Intervention/treatment Phase
Lymphoma, B-Cell Lymphoma, Non-hodgkins Chronic Lymphocytic Leukemia B-Cell Chronic Lymphocytic Leukemia Biological: Anti-CD19-CAR and Anti-CD20-CAR T cells Drug: Cyclophosphamide Drug: Fludarabine Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 88 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 and Anti-CD20 Chimeric Antigen Receptors for Treating B-cell Malignancies
Estimated Study Start Date : December 11, 2019
Estimated Primary Completion Date : December 30, 2023
Estimated Study Completion Date : December 30, 2024


Arm Intervention/treatment
Active Comparator: 1/Conditioning chemotherapy plus CAR T-cells dose escalation
All patients will be receiving escalating dose of Anti-CD19 and anti-CD20 CAR T cells/kg + conditioning chemotherapy
Biological: Anti-CD19-CAR and Anti-CD20-CAR T cells
Dose-escalation trial starting dose: 0.66 x106 CAR+ T cells/kg (weight based dosing one time)(up to a maximum dose of 10x106 CAR+ T cells/kg based on cohort) infuse on day 0

Drug: Cyclophosphamide
500 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

Active Comparator: 2/Conditioning chemotherapy plus CAR T-cells expansion phase
MTD dose of Anti- CD19 and anti- CD20 CAR T cells/kg + Conditioning chemotherapy
Biological: Anti-CD19-CAR and Anti-CD20-CAR T cells
Dose-escalation trial starting dose: 0.66 x106 CAR+ T cells/kg (weight based dosing one time)(up to a maximum dose of 10x106 CAR+ T cells/kg based on cohort) infuse on day 0

Drug: Cyclophosphamide
500 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 and anti-CD20 CAR [ Time Frame: 4-5 weeks after first dose ]
    List of adverse event frequency



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

MALIGNANCY CRITERIA:

  • Patients must have any B-cell lymphoma, or CLL/SLL, Gray-zone lymphoma, nodular lymphocyte-predominant Hodgkin lymphoma, or classical Hodgkin lymphoma with any CD19 or CD20 expression on Reed-Sternberg cells. Lower grade lymphomas or CLL transformed to DLBCL are potentially eligible as is primary mediastinal B-cell lymphoma and all other subtypes of DLBCL. Burkitt and mantle cell lymphoma are potentially eligible.
  • For classical Hodgkin lymphoma only, a biopsy from any time from any institution that shows any CD19 or CD20 expression on Reed-Sternberg cells is adequate for eligibility. CD19 or CD20 expression on the Reed-Sternberg cells that is weak or only present on some Reed-Sternberg cells by immunohistochemistry is compatible with protocol eligibility.
  • For all lymphoma types except for classical Hodgkin lymphoma, either CD19 or CD20 expression must be uniform . Uniform CD19 or CD20 expression is defined as no obvious lymphoma population lacking antigen expression is present. Antigen expression can be assessed by either immunohistochemistry or flow cytometry.
  • Only when insufficient biopsy material is available to allow CD19 and CD20 expression assessment at the NIH, CD19 and/or CD20 staining performed at another institution can be used
  • 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 B-cell 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.and venetoclax.
  • Hodgkin lymphoma patients must have:

    • had at least 3 prior lines of therapy.
    • documented progression of lymphoma while on checkpoint inhibitor therapy or failure to respond to checkpoint inhibitor therapy, or intolerance to checkpoint inhibitor therapy.
    • had at least 1 prior cytotoxic chemotherapy-containing regimen.
    • had prior exposure to brentuximab vedotin.
    • had undergone autologous stem cell transplant or been transplant ineligible or refused autologous transplantation
  • Eligibility will be expanded to include CD19 and CD20-negative classical Hodgkin lymphoma if any 2 patients with classical Hodgkin lymphoma and CD19/CD20 expression on RS cells have durations of response 6 months or greater (responses could be PRs or CRs) or a CR of 3 months or greater.
  • All 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 or equal to 10.0 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. CLL masses do not need to have increased activity on 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. Note that leukemia cells must make up 1% or less of peripheral blood lymphocytes in CLL patients for these patients to be eligible.

OTHER INCLUSION CRITERIA:

  • Greater than or equal to 18 years of age.
  • 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 sexes must be willing to practice birth control from the time of enrollment on this study and for four months after receiving the protocol treatment.
  • A patient with a negative blood PCR test for hepatitis B DNA test can be enrolled. If hepatitis B DNA (PCR) testing is not available, patients with a negative hepatitis B surface antigen and negative hepatitis B core antibody can be enrolled.
  • Patients must be tested for the presence of Hepatitis C antigen by PCR and be HCV RNA negative in order to be eligible. Only if Hepatitis C PCR testing is not available in a timely manner, patients who are Hepatitis C antibody-negative can be enrolled.
  • 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 50,000/mm^3 without transfusion support
  • Hemoglobin greater than 8.0 g/dl.
  • For CLL only, less than or equal to 1% malignant cells in the peripheral blood lymphocytes must be documented by flow cytometry of blood within 2 weeks of protocol enrollment.
  • 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 1.5 mg/dl.
  • Total bilirubin less than or equal to 2.0 mg/dl.
  • Normal cardiac ejection fraction (greater than or equal to 50% by echocardiography) and no evidence of hemodynamically significant pericardial effusion as determined by an echocardiogram within 4 weeks of treatment start.
  • 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 must be able to understand and be willing to sign a written informed consent.
  • Patients who have either been previously treated on protocols of genetically-modified T cells on a clinical trial at the NCI or received T cells modified with the MSGV or MSGV1 gamma-retroviral vectors at any institution are potentially eligible under these conditions:
  • At least 3 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 protocol Principal Investigator), and persisting genetically-modified T cells are either not detectable in the patient s blood or detectable at levels less than or equal to 0.2% of blood T cells as measured by flow cytometry using the Kip-1 antibody in the flow cytometry lab of the NCI Laboratory of Pathology (Maryalice Stetler-Stevenson s lab).

EXCLUSION CRITERIA:

  • Patients that require urgent therapy due to tumor mass effects or spinal cord compression.
  • Patients must not have received any anti-CD20 or anti-CD19 antibody products in the past 30 days prior to CAR T-cell infusion.
  • Prior 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 interfere with infusion of CAR-T cells within 8 weeks of enrollment
  • Patients that have active hemolytic anemia.
  • HIV-positive patients are excluded because HIV causes complicated immune deficiency and study treatment can pose more risks for these patients.
  • 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 3 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.

Pregnant women are excluded from this study because study therapy can cause fetal harm. Because there is potential risk for adverse events in nursing infants secondary to treatment of the mother with study therapy, breastfeeding should be discontinued if the mother is treated with study drugs.

  • 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.
  • Hospitalization within the 7 days prior to enrollment.
  • Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
  • Prior allogeneic stem cell transplant
  • Systemic corticosteroid steroid therapy of any dose greater than 5 mg/day or more of prednisone or equivalent 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 on systemic anticoagulant therapy except aspirin.
  • Active central nervous system metastases or cerebrospinal fluid malignancy. Patients with known brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.

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): NCT04160195


Contacts
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Contact: Ashley E Carpenter (240) 858-3190 carpentera@mail.nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Not yet recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact NCI/Surgery Branch Recruitment Center    866-820-4505    irc@nih.gov   
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: James N Kochenderfer, M.D. National Cancer Institute (NCI)

Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04160195     History of Changes
Other Study ID Numbers: 200008
20-C-0008
First Posted: November 11, 2019    Key Record Dates
Last Update Posted: December 6, 2019
Last Verified: November 7, 2019

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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) ):
Autologous T Cells Infusion
Hu1928-Hu20BB
Hodgkin Reed-Sternberg Cells
Adoptive T Cell Therapy
Gene Therapy
Additional relevant MeSH terms:
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Lymphoma
Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Cyclophosphamide
Fludarabine
Rituximab
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological