PRIMARY OBJECTIVES:
I. To assess the safety of adoptive therapy using ex vivo expanded autologous memory T cells
(central memory T cells [Tcm] or naive and memory T-cells [Tn/mem]) that are enriched and
genetically modified to express a cluster of differentiation (CD)19-specific, hinged
optimized, CD28-costimulatory chimeric antigen receptor (CAR) as well as a truncated human
epidermal growth factor receptor (EGFR) (CD19R[EQ]28zeta/truncated EGFR [EGFRt]+ Tcm or
CD19R[EQ]28zeta/EGFRt+ Tn/mem) shortly following lymphodepletion for adults with
recurrent/progressive/residual CD19 + B-cell lymphoproliferative neoplasms (non-Hodgkin
lymphoma [NHL], chronic lymphocytic leukemia [CLL]/prolymphocytic leukemia [PLL]) and who are
not eligible for or decline City of Hope (COH) Institutional Review Board (IRB) Protocol
Number (No.) 13277.
II. To determine the recommended Phase II dose (RP2D) in the two Tn/mem strata (NHL;
CLL/PLL).
SECONDARY OBJECTIVE:
I. To study antitumor activity of CD19R(EQ)CD28zeta/EGFRt+Tcm or CD19R[EQ]28zeta/EGFRt+
Tn/mem (e.g., detection of CAR+ T cells, B cells, and tumor burden).
OUTLINE: This is a dose-escalation study of autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing
enriched T cells (T-cell infusion). Participants are assigned to 1 of 2 groups based on
disease status.
GROUP I (NON-HODGKIN LYMPHOMA [NHL]):
LYMPHODEPLETING REGIMEN: Patients receive a chemotherapy regimen based on disease type and
extent of disease comprising of cyclophosphamide, bendamustine hydrochloride, fludarabine
phosphate, etoposide.
CELLULAR IMMUNOTHERAPY: Beginning 3-10 days later after lymphodepletion, patients receive
autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes IV over 10-15
minutes on day 0. Patients with relapsed, residual or progressive disease may receive an
optional second infusion of autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched
T-lymphocytes >= 28 days post T cell infusion.
GROUP II (CHRONIC LYMPHOCYTIC LEUKEMIA [CLL] AND/OR PROLYMPHOCYTIC LEUKEMIA [PLL]):
LYMPHODEPLETING REGIMEN: Patients receive a chemotherapy regimen based on disease type and
extent of disease comprising of cyclophosphamide, bendamustine hydrochloride, fludarabine
phosphate, etoposide.
CELLULAR IMMUNOTHERAPY: Beginning 3-10 days later after lymphodepletion, patients receive
autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes IV over 10-15
minutes on day 0. Patients with relapsed, residual or progressive disease may receive an
optional second infusion of autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched
T-lymphocytes >= 28 days post T cell infusion.
After completion of study treatment, patients are followed up at every 2 days for 14 days,
weekly for 1 month, monthly for 1 year, and then yearly for at least 15 years.
Inclusion Criteria:
- SCREENING INCLUSION CRITERIA:
- COH pathology review confirms that research participant's diagnostic material is
consistent with recurrent/progressive/residual B cell lymphoproliferative neoplasms as
listed below AND the research participant is not eligible for or declines COH IRB
Protocol No. 13277; additionally, CD19 positivity must be documented in a pathology
report if the research participant previously received CD19-targeted therapy; however,
it is not a requirement that the CD19 testing be performed by a COH pathologist
- Disease stratum 1 (NHL): Unclassifiable high grade lymphoma, mantle cell
lymphoma, follicular lymphoma, diffuse large B-cell lymphoma (DLBCL) and all its
subtypes, Burkitt lymphoma (BL), marginal zone B-cell lymphoma, hairy cell
leukemia, lymphoplasmacytic lymphoma, B cell lymphoma unclassifiable with
features intermediate between DLBCL and BL, B cell lymphoma unclassifiable with
features intermediate between DLBCL and classical Hodgkin lymphoma, and those
research participants who either declined or were not eligible for COH IRB
Protocol No. 13277, or who collected autologous T cells for COH IRB Protocol No.
13277 but then became ineligible for autologous hematopoietic stem cell
transplant (HSCT) or participants who have relapsed following prior T cell
therapy on either COH IRB Protocol No. 09174 or 12224 may be enrolled on this
study
- Disease stratum 2 (CLL/PLL/SLL): chronic lymphocytic leukemia (CLL), and B-cell
prolymphocytic leukemia (PLL), and small lymphocytic lymphoma (SLL)
- Karnofsky performance status (KPS) of >= 70%
- Life expectancy >= 16 weeks at time of screening
- The effects of CD19R(EQ)28zeta/EGFRt+ TCM or CD19R(EQ)28zeta/EGFRt+ TN/MEM on the
developing fetus are unknown; for this reason, women of child-bearing potential and
men must agree to use adequate contraception (hormonal or barrier method of birth
control or abstinence) prior to study entry and for six months following duration of
study participation; should a woman become pregnant or suspect that she is pregnant
while participating on the trial, she should inform her treating physician immediately
- All subjects must have the ability to understand and the willingness to sign a written
informed consent
- Note: For research participants who do not speak English, a short form consent
may be used with a COH certified interpreter/translator to proceed with screening
and leukapheresis, while the request for a translated full consent is processed;
however, the research participant is allowed to proceed with lymphodepletion and
T cell infusion only after the translated full consent form is signed
- PROTOCOL-SPECIFIC CRITERIA:
- COH pathology review confirms that research participant's diagnostic material is
consistent with a lymphoproliferative B-cell neoplasm
- Documentation of recurrence/progression/residual disease following prior therapy
- Negative serum pregnancy test for women of childbearing potential
- A pretreatment creatinine clearance (CrCl) of >= 60 mL/minute (min), calculated by
Cockcroft Gault
- Patients must have a serum bilirubin =< 2.0 mg/dl
- Patients must have an alanine aminotransferase (ALT) and aspartate aminotransferase
(AST) =< 2.5 times the institutional upper limits of normal
- Ejection fraction measured by echocardiogram or multi gated acquisition scan (MUGA) >
45% (evaluation within 6 weeks of screening does not need to be repeated)
- ELIGIBILITY TO PROCEED WITH PERIPHERAL BLOOD MONONUCLEAR CELL (PBMC) COLLECTION
- Research participant must have appropriate venous access
- Research participant must be at least 2 weeks from having received the last dose of
immunosuppressant medications (e.g. calcineurin inhibitors, methotrexate,
immunosuppressive antibodies, etc)
- The last dose of prior chemotherapy, immunotherapy or radiation must be at least 2
weeks before the leukapheresis procedure
- The last dose of cytotoxic chemotherapeutic agents that are not considered lymphotoxic
must be at least one week before the leukapheresis procedure; oral chemotherapeutic
agents, including lenalidomide and ibrutinib, are allowed if at least 3 half-lives
have elapsed prior to leukapheresis
- The last dose of lymphotoxic chemotherapeutic agents (e.g. cyclophosphamide,
ifosofamide, bendamustine, etc) must be at least 2 weeks before the leukapheresis
procedure
- The last dose of investigational agents must be at least 2 weeks before leukapheresis
procedure unless no response or disease progression is documented on the experimental
therapy and at least 3 half-lives must have elapsed prior to leukapheresis
- Note: exceptions may be made at the discretion of the principal investigator
(PI)/study team
- ELIGIBILITY TO UNDERGO LYMPHODEPLETION:
- Research participant has a released cryopreserved T cell product for T cell infusions
on approximately day 0
- Research participant must be at least 2 weeks out from having received the last dose
of investigational agent
- The last dose of cytotoxic chemotherapeutic agents that are not considered lymphotoxic
must be at least one week before lymphodepletion; oral chemotherapeutic agents,
including lenalidomide and ibrutinib, are allowed if at least 3 half-lives have
elapsed prior to lymphodepletion
- The last dose of lymphotoxic chemotherapeutic agents (e.g. cyclophosphamide,
ifosofamide, bendamustine, etc) must be at least 2 weeks before lymphodepletion
- Toxicity related to prior therapy must either have returned to =< grade 3, baseline,
or deemed irreversible
- KPS >= 70%
- Participants of reproductive potential must agree to use and utilize an adequate
method of contraception throughout treatment and for at least 8 weeks after T cell
infusion
- Absolute neutrophil count (ANC) > 0.75
- Platelets > 50 K without growth factor or transfusion support for a week at least
- Not requiring supplemental oxygen or mechanical ventilation, oxygen saturation 90% or
higher on room air
- Not requiring pressor support, not having symptomatic cardiac arrhythmias
- Preservation of renal function, serum creatinine did NOT increase by more than 2 fold
above the normal range
- Total bilirubin =< 2.0 mg/dL
- Research participant without clinically significant encephalopathy/new focal deficits
- No clinical evidence of uncontrolled active infectious process
- (ELIGIBILITY CRITERIA AT TIME OF INFUSION OF GENETICALLY MODIFIED AUTOLOGOUS T CELLS):
Research participant has completed prescribed lymphodepletion
- (ELIGIBILITY CRITERIA AT TIME OF INFUSION OF GENETICALLY MODIFIED AUTOLOGOUS T CELLS):
Not requiring supplemental oxygen or mechanical ventilation, oxygen saturation 90% or
higher on room air
- (ELIGIBILITY CRITERIA AT TIME OF INFUSION OF GENETICALLY MODIFIED AUTOLOGOUS T CELLS):
Not requiring pressor support, not having symptomatic cardiac arrhythmias
- (ELIGIBILITY CRITERIA AT TIME OF INFUSION OF GENETICALLY MODIFIED AUTOLOGOUS T CELLS):
Preservation of renal function, serum creatinine did NOT increase by more than 2 fold
above the normal range
- (ELIGIBILITY CRITERIA AT TIME OF INFUSION OF GENETICALLY MODIFIED AUTOLOGOUS T CELLS):
Total bilirubin =< 2.0 mg/dL
- (ELIGIBILITY CRITERIA AT TIME OF INFUSION OF GENETICALLY MODIFIED AUTOLOGOUS T CELLS):
Research participant without clinically significant encephalopathy/new focal deficits
- (ELIGIBILITY CRITERIA AT TIME OF INFUSION OF GENETICALLY MODIFIED AUTOLOGOUS T CELLS):
No clinical evidence of uncontrolled active infectious process
Exclusion Criteria:
- SCREENING EXCLUSION CRITERIA:
- Research participants who received memory-enriched CD19R(EQ):CD28:zeta/EGFRt+ on
IRB#13277
- Research participants with any uncontrolled illness including ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, poorly controlled pulmonary disease or psychiatric illness/social
situations that would limit compliance with study requirements
- Research participants with known active hepatitis B or C infection; research
participants who are human immunodeficiency virus (HIV) seropositive based on testing
performed within 4 weeks of screening; research participants with any signs of
symptoms of active infection, positive blood cultures or radiological evidence of
infections
- Research participants with presence of other active malignancy; however, research
participants with history of prior malignancy treated within 2 years with curative
intent and in a complete remission are eligible
- Pregnant and lactating women
- STUDY-SPECIFIC EXCLUSIONS:
- Failure of research participant to understand the basic elements of the protocol
and/or the risks/benefits of participating in this phase I study
- Research participants with precursor B-cell acute lymphoblastic leukemia/lymphoma or
plasma cell dyscrasias
- Any known contraindications to cyclophosphamide, fludarabine, etoposide, bendamustine,
cetuximab or tocilizumab
- Dependence on corticosteroids
- Steroid dependence can be defined as a medical need to be greater than 5 mg of
prednisone (or equivalent doses of other systemic steroids) a day, chronically;
higher doses need to be avoided for at least 3 days prior to leukapheresis and,
again, for at least 3 days prior to T cell infusion and up to at least 3 months
after T cell infusion unless medically indicated to treat a new toxicity
- Note: topical and inhaled corticosteroids in standard doses and physiologic
replacement for subjects with adrenal insufficiency are allowed
- Active autoimmune disease requiring systemic immunosuppressive therapy
- Subjects, who in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study
