Autologous CD19-28z CAR Expressing T-lymphocytes in Treating Patients with Relapsed or Refractory CD19+ Blood Cancer
This phase I trial studies the side effects and best dose of autologous CD19-28z CAR expressing T-lymphocytes in treating patients with blood cancer that has come back after a period of improvement or that does not respond to treatment. T cells are removed from the patient, altered in the laboratory by inserting a new gene, then given back to the patient. Autologous CD19-28z CAR expressing T-lymphocytes may allow T cells to then recognize and kill blood cancer cells.
Inclusion Criteria
- Patients must have CD19+ B cell malignancy with relapsed or refractory disease, defined as below: * Patients with chronic lymphocytic leukemia (CLL): ** Refractory to or relapsed after at least 2 prior chemo or chemoimmunotherapy (e.g. fludarabine, cyclophosphamide, rituximab [FCR], bendamustine plus rituximab [BR]) requiring further treatment, or ** Refractory to or relapsed after at least 1 prior biologic agent (e.g. ibrutinib, idelalisib, venetoclax, except a single agent anti-CD20 monoclonal antibody) requiring further treatment * Patients with indolent non-Hodgkin lymphoma (iNHL) (follicular lymphoma [FL], marginal zone lymphoma [MZL], Waldenstrom macroglobulinemia [WM]): ** Refractory or relapsed after at least 2 lines of chemoimmunotherapy (including at least one course of anti-CD20 antibody), or ** Refractory or relapsed after at least 1 prior biologic agent (e.g. lenalidomide, ibrutinib, idelalisib) ** Patients must have measurable disease (for WM patients, measurable disease is demonstrable monoclonal paraprotein and bone marrow involvement) * Patients with diffuse large B cell lymphoma (DLBCL), transformed B cell lymphoma, or high grade B cell lymphoma: ** Refractory to or relapsed after 1 or more prior chemoimmunotherapies with at least one containing an anthracycline and CD20 directed therapy ** Transplant ineligible ** Biopsy proven relapsed disease * Patients with acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) in lymphoid blast crisis or Burkitt‘s lymphoma: ** Refractory to at least 1 prior induction chemotherapy, or ** Relapsed after at least 1 prior multiagent systemic chemotherapy that included induction and consolidation ** Patients with Philadelphia chromosome-positive ALL must have failed a second generation tyrosine kinase inhibitor
- Creatinine =< 2.0 mg/100 ml
- Direct bilirubin =< 2.0 mg/100 ml
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x upper limit of normal (ULN)
- Adequate pulmonary function as assessed by >= 92% oxygen saturation on room air by pulse oximetry
Exclusion Criteria
- Karnofsky performance status < 70
- Pregnant or lactating women; women and men of childbearing age should use effective contraception while on this study and continue for 1 year after all treatment is finished
- Impaired cardiac function (left ventricular ejection fraction [LVEF] < 40%) as assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan
- Patients with active known autoimmune disease are ineligible
- Patients with following cardiac conditions will be excluded: * New York Heart Association (NYHA) stage III or IV congestive heart failure * Myocardial infarction =< 6 months prior to enrollment * History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration =< 6 months prior to enrollment * History of severe non-ischemic cardiomyopathy with ejection fraction (EF) =< 20%
- Patients with human immunodeficiency virus (HIV) or active hepatitis B or hepatitis C infection are ineligible
- Patients with uncontrolled systemic fungal, bacterial, viral or other infection are ineligible
- Patients with any concurrent active malignancies as defined by malignancies requiring any therapy other than expectant observation or hormonal therapy, with the exception of squamous and basal cell carcinoma of skin
- Patients with history or presence of clinically significant neurological disorders such as epilepsy, generalized seizure disorder, severe brain injuries are ineligible
- Any other issue which, in the opinion of the treating physician, would make the patient ineligible for the study
Additional locations may be listed on ClinicalTrials.gov for NCT03085173.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVE:
I. To determine the toxicity and maximum tolerated dose (MTD) of autologous CD19-28z chimeric antigen receptor (CAR) expressing T-lymphocytes (EGFRt/19-28z/4-1BBL CAR T cells) in patients with relapsed or treatment-refractory CD19+ hematologic malignancies.
SECONDARY OBJECTIVES:
I. To assess the anti-tumor efficacy of EGFRt/19-28z/4-1BBL CAR T cells.
II. To assess the in vivo persistence of EGFRt/19-28z/4-1BBL CAR T cells.
EXPLORATORY OBJECTIVES:
I. To assess the change in cellular and cytokine tumor microenvironment following CAR T cell infusions.
II. To assess the impact of infused CAR T cells on the endogenous anti-tumor immune response.
III. To assess development of B cell aplasia.
IV. To assess the level of minimal residual disease (MRD) following modified T cell infusions.
OUTLINE: This is a dose-escalation study.
Beginning 2-7 days after chemotherapy, patients receive autologous CD19-28z CAR expressing T-lymphocytes intravenously (IV) over 1-3 days. Patients who have obtained clinical benefit and experience no hematologic grade 4 toxicities may receive additional autologous CD19-28z CAR expressing T-lymphocytes at the treating physician’s discretion.
After completion of study treatment, patients are followed up at 12 weeks, monthly for 6 months, periodically for 5 years, and then annually for 10 years.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
Principal InvestigatorJae Park
- Primary ID16-1570
- Secondary IDsNCI-2017-00534
- ClinicalTrials.gov IDNCT03085173