This study will assess safety and feasibility of infusing genetically modified autologous T
cells transduced to express a chimeric antigen receptor targeting the B cell surface antigen
Cluster of Differentiation 19 (CD19)
This is an open-label, pilot, phase 1 study to determine the safety profile of anti-CD19
CAR-T cell infusion in participants with R/R B-cell NHL. The dose-finding cohorts in this
study will evaluate and define the safe dose of anti-CD19 CAR-T cells. Using a "3+3" design,
participants will be enrolled sequentially to each dose level. A dose expansion will then
occur at the maximum tolerated dose (MTD) and dose levels that have not exceeded the MTD.
Up to 36 participants will be enrolled and treated. Each subject will provide consent and be
evaluated for study eligibility. Eligible subjects will undergo apheresis with collection of
autologous peripheral blood mononuclear cells that will be used to generate CAR-T cells. The
CAR T cells will be produced using the Miltenyi Prodigy and an FDA compliant Lentigen CD19
targeted lentiviral vector. After successful generation of the anti-CD19 CAR-T cells (drug
product (DP)), subjects will undergo lymphodepleting chemotherapy with fludarabine and
cyclophosphamide followed by 2-5 days of rest. A single infusion of anti-CD19 CAR-T cells at
the starting dose of 5 x 105 cells/kg will be given on Day=0. Following treatment with DP,
subjects will be followed on this study for 12 months for safety, disease status, and
survival. For long term follow-up, participants will be followed for 15 years.
For participants whose dose does not meet the target dose, enrollment into a conforming
product low-dose cohort, at minimum dose level - 1 and that has not exceeded the MTD will
occur. This conforming product low-dose cohort will be evaluated for toxicity and efficacy of
those lower dose levels as part of the primary safety and secondary objectives.
For participants whose CAR-T product does not meet the pre-specified release criteria,
enrollment into a non-conforming product cohort, at a minimum dose level - 1 and that has not
exceeded the MTD will occur. This non-conforming product cohort will be evaluated for
toxicity and efficacy of the non-conforming product cohort as part of the exploratory
objectives
PRIMARY OBJECTIVES
1. To evaluate the safety of administering chimeric antigen receptor T cells targeting
CD-19 to patients with relapsed or refractory CD19+ B-cell nonHodgkin lymphoma (NHL).
2. To determine the recommended phase 2 dose (RP2D) for this cellular therapy.
SECONDARY OBJECTIVES
1. To assess the safety and toxicity of cell collection and infusion of CAR-T cells
targeting CD19 in patients with relapsed or refractory CD19+ B cell NHL.
2. To describe the efficacy of chimeric antigen receptor T cells targeting CD-19 in
patients with relapsed or refractory CD19+ B cell NHL.
3. To evaluate the feasibility of CD19 CAR T cell manufacturing for patients with relapsed
or refractory CD19+ B cell NHL of local manufacturing and ability to produce adequate
quantities of vector positive T-cells
Inclusion Criteria:
1. Patients must have a diagnosis of relapsed or refractory B-cell NHL:
- DLBCL, Mantle Cell, Follicular Lymphoma, Lymphoplasmacytic lymphoma, Small
Lymphocytic Lymphoma, Primary Mediastinal B-Cell Lymphoma, Burkitt Lymphoma,
transformed lymphoma.
- Subjects with small lymphocytic lymphoma (SLL) must have progressed after at
least 2 prior therapies and prior treatment with or intolerance of both
ibrutinib and venetoclax.
- Subjects with DLBCL, primary mediastinal B- Cell lymphoma, Burkitt lymphoma
and transformed lymphoma must have relapsed or failed to respond to >= 2
prior lines of multiagent chemoimmunotherapy with prior exposure to both an
anti-CD20 antibody agent and an anthracycline.
- Subjects with indolent lymphomas (follicular lymphoma and lymphoplasmacytic
lymphoma) must have relapsed after or been refractory to >=2 prior lines of
multi-agent chemoimmunotherapy including prior exposure to rituximab and at
least 2 other chemotherapy agents.
- For subjects with Mantle cell lymphoma, previous lines of therapy may
include multiagent chemotherapy including alkylating agent or anthracycline
and anti CD20 antibody therapy and Bruton's tyrosine kinase (BTK) inhibitor
therapy.
- Positron Emission Tomography (PET) -positive disease according to
"Recommendations for Initial Evaluation, Staging, and Response Assessment of
Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification"
- At least one of the following:
- Primary refractory or early relapse (first remission < 12 months) and not
eligible for stem cell transplant
- Relapsed or refractory disease after two or more lines of systemic therapy
- No significant circulating disease, defined as an elevated total lymphocyte count
above the ULN due to the presence of malignant cells.
2. CD19 positive by either immunohistochemistry or flow cytometry analysis on any biopsy.
If prior anti-CD19 therapy has been administered, CD19 positivity has to be
re-established on the most recent biopsy.
3. Age >=18 years at the time of consent
4. Absolute lymphocyte count > 100/ (microliter)
5. Eastern Cooperative Oncology Group (ECOG) performance status < 2
6. Adequate organ function, defined as:
- Adequate bone marrow function for apheresis and lymphodepleting chemotherapy
- Hemoglobin (Hgb) >8 grams per deciliter (gm/dl) (transfusions allowed)
- Platelets >50,000/microliter (uL) (transfusions allowed)
- Absolute Neutrophil Count (ANC) > 500/uL
- Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < 3 x
institutional upper limit of normal (ULN) and Total bilirubin < 1.5 mg/dl x
institutional ULN, except with Gilbert's syndrome
- Serum Creatinine < 2 x the institutional ULN
- Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) >
40% as assessed by echocardiogram or multiple uptake gated acquisition (MUGA)
7. Adequate vascular access for leukapheresis procedure (either peripheral line or
surgically placed line).
8. Women of childbearing potential (defined as all women physiologically capable of
becoming pregnant) must have a negative serum or urine pregnancy test AND agree to use
highly effective methods of contraception for 1 year after the last dose of antiCD19
CAR-T cells
9. Males who have partners of childbearing potential must agree to use an effective
barrier contraceptive method
10. Ability to understand a written informed consent document, and the willingness to sign
it.
Exclusion Criteria:
1. Autologous transplant within 6 weeks of planned CAR-T cell infusion
2. Recipient of prior CAR-T cell therapy targeting CD19 outside of this protocol
3. Active other malignancy, other than non-melanoma skin cancer, carcinoma in situ (e.g.,
cervix, bladder, or breast).
4. HIV seropositivity
5. Serologic status reflecting active hepatitis B or C infection. Patients that are
positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or
hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to
enrollment. (PCR positive patients will be excluded.)
6. Subjects with uncontrolled intercurrent illness including, but not limited to ongoing
or active infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, pulmonary abnormalities or psychiatric illness/social situations
that would limit compliance with study requirements.
7. Pregnant or breastfeeding women are excluded from this study because CAR-T cell
therapy may be associated with the potential for teratogenic or abortifacient effects.
Because there is an unknown, but potential risk for adverse events in nursing infants
secondary to treatment of the mother with CAR-T cells, breastfeeding should be
discontinued. These potential risks may also apply to other agents used in this study.
NOTE: Women of childbearing potential must have a negative serum or urine pregnancy
test.
8. Patients with history of clinically relevant central nervous system (CNS) pathology
such as epilepsy, seizure disorders, paresis, aphasia, uncontrolled cerebrovascular
disease, severe brain injuries, dementia and Parkinson's disease.
9. History of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus
erythematosus) with requirement of immunosuppressive medication within 6 months.
10. Body weight <40 kilograms(kg)
Eligibility for Infusion of Investigational Product:
Subjects will undergo an evaluation of eligibility on day 1 prior to infusion of anti-CD19
CAR-T cell product. This eligibility criterion will include the inclusion and exclusion
criteria required for enrollment with the following exceptions and additions:
1. No significant laboratory abnormalities. Laboratory result abnormalities that are
considered not clinically significant by the principal investigator AND are not the
result of a demonstrated active infection or an active central nervous system
condition.
2. ECOG performance status < 2
3. No evidence of uncontrolled intercurrent illness including, but not limited to ongoing
or active infection, inflammatory response, symptomatic congestive heart failure,
unstable angina pectoris, cardiac arrhythmia, pulmonary abnormalities or psychiatric
illness/social situations.
4. No new neurologic symptoms suggestive of an active central nervous system condition,
or uncontrolled CNS involvement by lymphoma.
5. No corticosteroid use within 7 days prior to infusion (with exception of agents used
for prevention of emesis during lymphodepletive chemotherapy).
