Non Hodgkin Lymphoma Clinical Trial
huJCAR014 CAR-T Cells in Treating Adult Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma or Acute Lymphoblastic Leukemia
This phase I trial studies the side effects of huJCAR014 in treating patients with relapsed or refractory B-cell non-Hodgkin lymphoma or acute lymphoblastic leukemia. huJCAR014 CAR-T cells are made in the laboratory by genetically modifying a patient's T cells and may specifically kill cancer cells that have a molecule CD19 on their surfaces.
In Stage 1, dose-finding studies will be conducted in 3 cohorts:
Aggressive B cell NHL
Low burden ALL
High burden ALL
In Stage 2, studies may be conducted in one or more cohorts to collect further safety, PK, and efficacy information at the huJCAR014 dose level(s) selected in Stage 1 for the applicable cohort(s). There are two separate cohorts for stage 2:
Cohort 2A, CAR-naïve (n=10): patients who have never received CD19 CAR-T cell therapy.
Cohort 2B, CAR-exposed (n=27): patients who have previously failed CD19 CAR-T cell therapy.
OUTLINE: This is a dose-escalation study of huJCAR014.
Patients undergo leukapheresis. Beginning 1-2 weeks after leukapheresis, patients undergo lymphodepleting chemotherapy comprising either cyclophosphamide intravenously (IV) daily for 1 day and fludarabine IV daily for 3 days or cyclophosphamide and fludarabine IV daily for 3 days. Alternative lymphodepleting chemotherapy regimens maybe used if patient's clinical situation or other logistical factors dictate otherwise. Within 36-96 hours after completion of lymphodepleting chemotherapy, patients receive huJCAR014 IV over 20-30 minutes on day 0.
After completion of study treatment, patients are followed up every 30 days for the first 3 months, every 3 months for up to 12 months, and then yearly for 15 years.
Male or female >= 18 years of age at the time of screening consent
INCLUSION CRITERIA FOR SCREENING
Diagnosis of R/R B-cell NHL or ALL as defined below:
Relapsed or refractory B-cell NHL meeting all of the following criteria:
Diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS); high grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements; LBCL transformed from any indolent histology; or primary mediastinal B-cell lymphoma (PMBCL)
Prior treatment with an anthracycline and rituximab or another CD20-targeted agent (unless the disease is CD20-negative); transformed DLBCL (tDLBCL) must have failed treatment for DLBCL
At least one of the following:
Refractory disease after frontline chemo-immunotherapy
Not eligible for autologous hematopoietic stem cell transplant (auto-HSCT)
Relapsed or refractory disease after at least 2 lines of therapy or after auto-HSCT
Relapsed or refractory disease after allogeneic hematopoietic stem cell transplant (allo-HSCT)
Relapsed or refractory B-cell ALL (patients with Burkitt's lymphoma/leukemia are not eligible)
All B-ALL patients must have detectable disease by morphology, flow cytometry, cytogenetic analysis (e.g. polymerase chain reaction [PCR], fluorescence in situ hybridization [FISH], karyotyping) or imaging (e.g. positron emission tomography [PET]/computed tomography [CT]) or a high likelihood of active disease
Refractory: failure to achieve complete response (CR) (minimal residual disease [MRD]-negative) at the end of induction
Relapsed: recurrence of disease after achieving CR
Evidence of CD19 expression by immunohistochemistry or flow cytometry on any prior or current tumor specimen or high likelihood of CD19 expression based on disease histology
INCLUSION CRITERIA FOR LEUKAPHERESIS AND PRE-THERAPY EVALUATION
Screening evaluation appropriate for leukapheresis and T-cell collection
Adequate vascular access available or planned for leukapheresis procedure (either peripheral line or surgically placed line)
Documentation of CD19 expression on any prior or current tumor biopsy; patients who have received previous CD19-targeted therapy must have CD19-positive disease confirmed on a biopsy since completing the prior CD19-targeted therapy
Internal review of histology
Stage 2; cohort 2B (CAR-exposed) only:
Relapsed disease after achieving CR at the discretion of the principal investigator (PI) or designee, in response after prior CD19-targeted non-huJCAR014 CAR T-cell therapy OR
Persistent disease after achieving PR at the discretion of the PI or designee, after prior CD19-targeted non-huJCAR014 CAR T-cell therapy. Patients who are less than 3 months from prior CD19-targeted non-huJCAR014 CAR T-cell therapy must have persistent disease on biopsy or imaging (e.g. PET-CT or CT) evidence of disease progression
INCLUSION CRITERIA FOR LYMPHODEPLETING CHEMOTHERAPY AND huJCAR014 TREATMENT
Successful collection of T cells for huJCAR014 manufacturing
Detectable disease by imaging (for example PET +/- CT, magnetic resonance imaging [MRI]) and/or pathology evaluation
Karnofsky performance status >= 60%
Assessed by the investigator to have adequate bone marrow function to receive lymphodepleting conditioning chemotherapy
Serum creatinine =< 1.5 x age-adjusted upper limit of normal (ULN) or calculated creatinine clearance (Cockcroft and Gault) > 30 mL/min/1.73 m^2
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 5 x ULN and total bilirubin < 2.0 mg/dL unless due to malignancy or Gilbert's syndrome in the opinion of the PI or designee
Common Terminology Criteria for Adverse Events (CTCAE) grade =< 1 dyspnea and oxygen saturation (SaO2) >= 92% on room air
Left ventricular ejection fraction (LVEF) >= 40% as assessed by echocardiogram (ECHO) or multiple uptake gated acquisition (MUGA) scan performed within 1 month before starting lymphodepleting chemotherapy
Women of childbearing potential (defined as all women physiologically capable of becoming pregnant) must agree to both of the following:
Use highly effective methods of contraception for at least 6 months after the last dose of huJCAR014, and
Have a negative serum pregnancy test performed within 28 days before starting lymphodepleting chemotherapy
Males who have partners of childbearing potential must agree to use an effective barrier contraceptive method for at least 6 months after the last dose of huJCAR014
EXCLUSION CRITERIA FOR SCREENING
For patients in stage 1 only, prior treatment with any CD19 CAR T-cell therapy is excluded
Known active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection
Pregnant or breastfeeding women
Any known contraindication to leukapheresis
Any known and irreversible contraindication to huJCAR014 therapy
Medical, psychological, familial, sociological, or geographical condition that does not permit compliance with the protocol as judged by the PI or designee, or unwillingness or inability to follow protocol procedures
EXCLUSION CRITERIA FOR LEUKAPHERESIS AND PRE-THERAPY EVALUATION
History or presence of clinically relevant central nervous system (CNS) pathology that, in the opinion of the PI or designee, is a contraindication to lymphodepleting chemotherapy or huJCAR014 infusion
History of another primary malignancy that has not been in remission for at least 2 years with the following exceptions: nonmelanoma skin cancer, curatively treated localized prostate cancer, cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on Pap smear, or other malignancy considered by the investigator to have a low risk of relapse or progression
Active autoimmune disease requiring immunosuppressive therapy, unless considered by the PI or designee to be eligible
Presence of active acute or chronic graft versus host disease (GVHD)
Use of any of the following:
Cytotoxic or lymphotoxic agents (including prednisone > 5 mg/day or equivalent corticosteroid) within 1 week prior to leukapheresis; physiologic corticosteroid replacement, and topical or inhaled corticosteroids are not excluded
GVHD therapies within 4 weeks prior to leukapheresis (e.g., calcineurin inhibitors, methotrexate or other chemotherapeutics, mycophenolate, rapamycin, thalidomide, immunosuppressive antibodies such as anti-TNF, anti-IL-6, or anti-IL-6R)
Experimental agents within 4 weeks prior to leukapheresis unless progression is documented on therapy and at least 3 half-lives have elapsed prior to leukapheresis
Radiation encompassing all sites of known tumor within 6 weeks prior to leukapheresis, unless there is evidence of active disease after radiation by imaging, biopsy or clinical evaluation
Allo-HSCT within 60 days prior to leukapheresis or donor lymphocyte infusion (DLI) within 6 weeks prior to leukapheresis
Treatment with cladribine within 3 months prior to leukapheresis
Treatment with alemtuzumab within 3 months prior to leukapheresis
EXCLUSION CRITERIA FOR LYMPHODEPLETING CHEMOTHERAPY AND huJCAR014 TREATMENT
Uncontrolled and serious infection
Presence of active acute or chronic GVHD
DLI within 6 weeks prior to lymphodepletion chemotherapy
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