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A Phase I/II Study to Evaluate the Safety of Cellular Immunotherapy Using Autologous T cells Engineered to Express a CD20-Specific Chimeric Antigen Receptor for Patients with Relapsed or Refractory B-cell Non-Hodgkin Lymphomas

Complete title: A Phase I/II Study to Evaluate the Safety of Cellular Immunotherapy Using Autologous T cells Engineered to Express a CD20-Specific Chimeric Antigen Receptor for Patients with Relapsed or Refractory B-cell Non-Hodgkin Lymphomas

Research Study Number 9738
Principal Investigator Mazyar Shadman
Phase I/II

Research Study Description

The purpose of this research is to find the best dose of genetically modified T-cells, to study the safety of this treatment, and to see how well it works in treating patients with B cell non-Hodgkin lymphoma that has come back or did not respond to previous treatment.

Eligibility Criteria (must meet the following to participate in this study)

Ages Eligible for Study: 18 Years and older (Adult, Senior)

Sexes Eligible for Study: All

- Patients must have B-cell non-Hodgkin lymphoma, including mantle cell, follicular, lymphoplasmacytic, marginal zone, transformed indolent B cell lymphoma (including transformed chromic lymphoid leukemia [CLL]), or diffuse large B cell lymphoma that has relapsed after a response to at least one prior therapy regimen or is refractory to prior therapy; patients with de novo diffuse large B-cell lymphoma (DLBCL) must meet one of the following criteria:

-- * Biopsy-proven refractory disease after a frontline regimen containing both an anthracycline and rituximab or other anti-CD20 antibody (i.e. "primary refractory"), where any disease recurring within 6 months of completion of the regimen is considered refractory

-- * Relapsed or refractory disease after at least one of the following:

--- ** At least 2 lines of therapy (including at least one with an anthracycline and anti-CD20 antibody)

--- ** Autologous stem cell transplant

--- ** Allogeneic stem cell transplant

- Patients of any gender, race or ethnicity

- Patients must be capable of understanding and providing a written informed consent

- Negative serum pregnancy test within 2 weeks of planned lymphodepletion chemotherapy for women of childbearing potential, defined as those who have not been surgically sterilized or who have not been free of menses for at least 1 year

- Fertile male and female patients must be willing to use an effective contraceptive method before, during, and for at least 4 months after the CAR T cell infusion

- Patients must have a Karnofsky performance status of >= 60%

- Confirmation of diagnosis by internal pathology review of initial or subsequent biopsy or other pathologic material at Fred Hutchinson Cancer Research Center (FHCRC)/Seattle Cancer Care Alliance (SCCA)

- Evidence of CD20 expression by immunohistochemistry or flow cytometry on the tumor specimen obtained with the biopsy performed with screening

- Serum creatinine =< 2.5

- Total bilirubin =< 3.0 mg/dL

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 5 x the upper limit of normal

- Adequate pulmonary function, defined as = grade 1 dyspnea and saturated oxygen (SaO2) >= 92% on room air; if pulmonary function test (PFT)s are performed based on the clinical judgment of the treating physician, patients with forced expiratory volume in 1 second (FEV1) >= 50% of predicted and carbon monoxide diffusing capability (DLCO) (corrected) of >= 40% of predicted will be eligible

- Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) of >= 50% as assessed by echocardiogram or multigated acquisition (MUGA) scan, or LVEF of 45-49% and clearance by a cardiologist

- Measurable disease that can be accurately measured in at least one dimension as >= 2.0 cm with computed tomography (CT), ultrasound, or magnetic resonance imaging (MRI) techniques; extranodal disease that is measurable by fludeoxyglucose F-18 (FDG)-positron emission tomography (PET) imaging only will also be allowed; note that if an excisional biopsy was performed that removed the sole site of measurable disease, the patient will not be eligible for leukapheresis and generation of CAR T cell product

- Have a CAR T cell product generated that meets the release criteria required for infusion as specified in the investigational new drug (IND) application, appropriate for the type of cell product (fresh versus [vs.] cryopreserved)

- Absence of uncontrolled active infection (bacterial, fungal, viral, mycobacterial) not responding to treatment with antibiotics, antiviral agents, or antifungal agents

- Not requiring ongoing systemic corticosteroid therapy

Other eligibility criteria may apply.

Exclusions (conditions that would prevent participation in this study)

- Active autoimmune disease requiring systemic immunosuppressive therapy

- Patients requiring corticosteroid therapy at a dose of 15 mg or more per day of prednisone or the equivalent; pulsed corticosteroid dose for disease control is acceptable

- Patients who are human immunodeficiency virus (HIV) seropositive

- Women who are pregnant or breastfeeding

- Significant cardiovascular diseases within the past 6 months including uncontrolled congestive heart failure (> New York Heart Association [NYHA] class II), myocardial infarction, unstable angina, or uncontrolled arrhythmia

- Symptomatic hypotension, or oral or intravenous treatment (including hydration) for low blood pressure within 5 days before the enrollment day

- History of severe immediate hypersensitivity reaction to cyclophosphamide or fludarabine

- History or presence of clinically relevant non-lymphoma central nervous system pathology, including seizures that are uncontrolled on anticonvulsant therapy (>= 1 seizure in the last year), paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson disease, cerebellar disease, or psychosis

- Treatment with other investigational agents within 30 days of planned lymphodepletion chemotherapy

- Treatment with any anti-CD19 or anti-CD20 antibody or antibody-drug conjugate therapy within 4 weeks of signing the consent for leukapheresis, chemotherapy, and T cell infusion (Consent A)

- Previous treatment with CD19-targeted CAR T cells

- Known active central nervous system metastases and/or lymphomatous meningitis; subjects with previously treated central nervous system (CNS) disease may participate provided: 1) any CNS-directed treatment was completed at least 1 month prior to planned leukapheresis, 2) imaging studies and cerebrospinal fluid (CSF) evaluation show no evidence of disease progression, and 3) any neurologic symptoms have returned to baseline

- Presence of active acute or chronic graft versus host disease (GVHD)

- Uncontrolled active infection (bacterial, fungal, viral, mycobacterial) not responding to treatment with intravenous antibiotics, antiviral or antifungal agents

- Patients with concurrent known additional malignancy that is progressing or requires active treatment; exceptions include squamous or basal cell carcinoma of the skin and low grade prostate carcinoma (Gleason grade =< 6)

- Patients with blood or platelet transfusion within 1 week prior to signing Consent A, or with platelets < 50,000/mm^3, neutrophils < 750/mm^3, or hemoglobin < 8.5 g/dL, unless the cytopenias are considered by the treating physician to be largely due to marrow involvement by lymphoma

Other exclusion criteria may apply.

Research Study Number 9738
Contact Seattle Cancer Care Alliance Intake Office
Telephone 800-804-8824 / 206-606-1024

Keywords: Hematologic Malignancies; Leukemia; Lymphoma; Lymphoproliferative Disorders; Lymphoma, Non-Hodgkin (NHL); Leukemia, Lymphoid; Immunoproliferative Disorders; Waldenstrom Macroglobulinemia; Lymphoma, Mantle-Cell; Cardiovascular Diseases; Lymphoma, B-Cell; Lymphoma, Follicular; Leukemia, B-Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasms, Plasma Cell; Paraproteinemias; Lymphoma, Large B-Cell, Diffuse; Immune System Diseases; Hemorrhagic Disorders; Hematologic Diseases; Lymphoma, B-Cell, Marginal Zone

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Please remember:

  • Talk to your health care providers first before making decisions about your health care.
  • Whether you are eligible for a research study depends on many things. There are specific requirements to be in research studies. These requirements are different for each study.

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