Anti-CD19 CAR-T Cells With Inducible Caspase 9 Safety Switch for B-cell Lymphoma

This study is a phase I dose finding trial to determine if chimeric antigen receptor T (CAR-T) cells targeting the CD19 antigen and containing the inducible caspase 9 safety switch can be safely administered to adult subjects with relapsed or refractory B-cell Lymphoma, primary central nervous system lymphoma and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). The safety of iC9-CAR19 cells will be investigated using the 3+3 design. The starting dose of 1 x 106 transduced cells/kg (dose level 1) will enroll at least 3 subjects in the initial cohort. If there are no dose limiting toxicities (DLTs) within 4 weeks of the cell infusion in these 3 subjects, then the next cohort will evaluate 2 x 106 transduced cells/kg. If there is toxicity in 1/3 subjects in the initial cohort, the cohort will be expanded to enroll up to 6 subjects. During iC9-CAR19 T cell dose exploration, rimiducid (0.4 mg/kg), a dimerizing agent that is designed to engage and activate the caspase 9 safety switch to trigger iC9-CAR19 T cell death by apoptosis will be given to subjects who develop grade 4 cytokine release syndrome (CRS) or grade ≥3 CRS that is unresponsive to standard of care interventions, and to subjects who develop grade ≥3 Immune effector cell-associated neurotoxicity syndrome ( ICANS) that does not improve to grade ≤1 within 72 hours with standard of care interventions, and subjects with grade 4 ICANS of any duration that have evidence of cerebral edema and/or generalized convulsive status epilepticus. After the tolerable cell dose (TCD) of iC9-CAR19 T cells has been determined, up to 18 additional adult subjects may be enrolled in an expansion cohort at the TCD. Rimiducid will be given to subjects in the expansion cohort who develop grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS) that does not improve to grade ≤1 within 72 hours with standard of care interventions, and subjects with grade 4 ICANS of any duration that have evidence of cerebral edema and/or generalized convulsive status epilepticus. Subjects in the expansion cohort who experience ≥grade 2 CRS or ICANS that remains ≥grade 2 twenty-four hours after initial standard of care treatment (tocilizumab for CRS or steroids for ICANS) may be part of the rimiducid sub-study. These subjects will receive one of two assigned dose levels of rimiducid with their second standard of care treatment. The percent reduction in CAR T cells will be measured in these subjects. If the subjects' CRS or ICANS is unresponsive to standard treatment and the assigned dose level of rimiducid, subjects with ≥grade3 CRS or ICANS will then be given a full dose (0.4 mg/kg) of rimiducid. If the subject's CRS or ICANS is at grade 2 48 hours after the first dose of rimiducid, they will receive another dose of rimiducid at the assigned dose level.

Cell Procurement Peripheral blood, up to 300 mL (in up to 3 collections) will be obtained from subjects for cell procurement. In subjects with inadequate lymphocyte count in the peripheral blood, a leukapheresis may be performed to isolate sufficient T cells. The parameters for apheresis will be up to 2 blood volumes.

Lymphodepleting Regimen Subjects will receive a "pre-conditioning" cytoreductive regimen of bendamustine 70 mg/m2/day administered IV followed by an IV dose of fludarabine 30 mg/m2/day administered over 3 consecutive days. These agents will be administered per institutional guidelines. Prophylaxis (e.g., hydration, antiemetics, etc.) needed prior to fludarabine and bendamustine chemotherapy will be provided per institutional guidelines. At the discretion of the clinical investigator, subjects with a known history of intolerance to bendamustine may be considered for lymphodepletion with cyclophosphamide 500 mg/m2/day administered by IV followed by an IV dose of fludarabine 30 mg/m2/day administered over 3 consecutive days. These agents will be administered per institutional guidelines.

Administration of iC9-CAR19 T cells Post lymphodepletion, subjects who meet eligibility criteria for cellular therapy will receive iC9-CAR19 T cells within 2 - 14 days after completing the lymphodepleting chemotherapy regimen. Post lymphodepletion iC9-CAR19 will be administered at dose levels specified in the protocol. A recently published trial in refractory DLBCL established that a dose of 2 x 10 6 CAR19+ T cells/kg was safe and associated with significant in vivo expansion and we anticipate similar results with iC9-CAR19+ T cells.

Duration of Therapy Therapy in this study involves 1 infusion of iC9-CAR19 cells.

Duration of Follow-up Subjects who receive a cell infusion will be followed for up to 15 years for replication-competent retrovirus evaluation or until death, whichever occurs first. Subjects who are removed from study and do not receive the cellular therapy product due to unacceptable adverse events will be followed until resolution or stabilization of the adverse event.

Inclusion criteria

for the Study:

Unless otherwise noted, subjects must meet all of the following criteria to participate in all stages of this study:

• Written informed consent and HIPAA authorization for release of personal health information.
• Adults ≥18 years of age.
• Histologically confirmed B-cell NHL, including the following types defined by WHO 2016:

Aggressive Lymphomas:

• DLBCL not otherwise specified (NOS)
• T cell/histiocyte rich large B cell lymphoma; primary cutaneous DLBCL, leg type; EBV-positive DLBCL NOS; DLBCL associated with chronic inflammation; Large B-cell lymphoma with IRF4 rearrangement; Intravascular large B-cell lymphoma; ALK-positive large B-cell lymphoma
• Primary mediastinal (thymic) large B-cell lymphoma
• High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement; high grade B-cell lymphoma, NOS
• B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma
• Transformation of indolent lymphoma or CLL to DLBCL will also be included
• Burkitt lymphoma
• Primary CNS lymphoma

Indolent Lymphomas:

• Follicular lymphoma
• Splenic marginal zone lymphoma
• Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue
• Nodal marginal zone lymphoma
• Waldenstrom's macroglobulinemia (Lymphoplasmacytic lymphoma)
• Mantle cell lymphoma
• CLL/SLL by International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria
• Subjects with CNS involvement of lymphoma are eligible.

--For aggressive lymphomas, must have relapsed or refractory disease after having received at least 2 prior lines of systemic therapy, including, at a minimum:

• An anti-CD20 monoclonal antibody
• An anthracycline containing chemotherapy regimen (if eligible)
• An autologous stem cell transplant (if eligible)
• Subjects with primary CNS lymphoma must have failed at least 1 prior line of therapy that included high dose methotrexate.
• For indolent lymphomas, subjects must have received at least 2 prior lines of therapy for their lymphoma
• Subjects with specifically relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma must have received at least 2 prior therapy regimens which can include, but not limited to:

• A combination of an anti-CD20 monoclonal antibody and an alkylating agent, OR
• A Bruton's Tyrosine Kinase Inhibitor, OR
• A BCL-2 inhibitor in combination with an anti-CD20 monoclonal antibody.
• Subjects with prior or concurrent malignancies of the same or different tumor type whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational drug are eligible for enrollment at the discretion of the clinical investigator.
• Subjects relapsed after allogeneic stem cell transplant will be eligible if they meet other inclusion criteria and have no active graft vs host disease (GVHD)
• Measurable or assessable disease by Lugano criteria, response criteria for primary CNS lymphoma, or WM criteria, or IWCLL criteria. Subjects with bone marrow-only involvement are eligible.
• Karnofsky score of > 60%
• Women of childbearing potential (WOCBP) must be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study, and for 6 months after the study is concluded. WOCBP are those who have not been surgically sterilized or have not been free from menses for > 1 year. The two birth control methods can be composed of: two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. WOCBP subjects will also be instructed to tell their male partners to use a condom.

Exclusion criteria

for the Study:

Subjects meeting any of the following exclusion criteria will not be able to participate in this study (procurement, lymphodepletion, and cell infusion):

• Subject is pregnant or lactating.
• Tumor in a location where enlargement could cause airway obstruction.
• Current use of systemic corticosteroids at doses ≥10mg prednisone daily or its equivalent; those receiving <10mg daily may be enrolled at the discretion of investigator. Patients with primary CNS lymphoma can receive higher doses of steroids per the investigator's discretion.
• Active infection with HIV, HTLV, HBV, and HCV (can be pending at the time of cell procurement; only those samples confirming lack of active infection will be used to generate transduced cells) defined as not being well controlled on therapy. Subjects are required to have negative HIV antibody, negative HTLV1 and HTLV2 antibodies, negative Hepatitis B surface antigen, and negative HCV antibody or viral load. In addition, subjects with positive Hepatitis B core antibody will have Hepatitis B viral load tested and subjects with positive Hepatitis B viral load will also be excluded.
• Subject must either have core antibody negative HBV (results can be pending at the time of cell procurement) OR if a subject is hepatitis B core antibody positive they must have their hepatitis B viral load checked. These subjects will be excluded if their viral load is positive at baseline. Subjects who are core antibody positive and viral load negative at baseline will be considered eligible.
• A history of intolerance to fludarabine. Note: subjects with history of intolerance to bendamustine may be considered for enrollment at the discretion of the clinical investigator if they are candidates for lymphodepletion with cyclophosphamide and fludarabine.

Eligibility criteria to be met prior to procurement:

• Subjects must sign a consent to undergo cell procurement.
• Life expectancy ≥ 12 weeks.
• Evidence of adequate organ function as defined by:

The following is required within 7 days prior to procurement:

• Bilirubin ≤1.5 times the upper limit of normal (ULN). Subjects with Gilbert's syndrome may be enrolled despite a total bilirubin level >1.5 mg/dL if their conjugated bilirubin is <1.5× ULN)
• AST ≤ 3 times ULN
• Creatinine Clearance (CrCl) >30mL/min per Cockcroft and Gault
• Pulse oximetry of >90% on room air

• Left ventricular ejection fraction (LVEF) ≥35% as measured by ECHO, with no additional evidence of decompensated heart failure.
• In patients with disease assessed by imaging, imaging results from within 90 days prior to procurement to assess the presence of active disease. If disease is not measurable by imaging, evidence of active disease within 90 days of procurement via bone marrow biopsy or SPEP/immunofixation.
• Negative serum pregnancy test within 72 hours prior to procurement or documentation that the subject is post-menopausal. Post-menopausal status must be confirmed with documentation of absence of menses for >1 year, or documentation of surgical menopause involving bilateral oophorectomy.

Eligibility criteria to be met prior to lymphodepletion:

• Written informed consent to enroll in the CAR T-cell therapy trial must be obtained prior to lymphodepletion.
• Imaging results from within 7 days prior to lymphodepletion. Imaging must occur at least 3 weeks after most recent therapy (used as baseline measure for documentation of progression before the lymphodepletion) to document measurable or assessable disease. Imaging does not need to be repeated if it is within 7 days prior to lymphodepletion. For WM, imaging does not need to be repeated prior to lymphodepletion if no evidence of disease at screening.
• Evidence of adequate organ function as defined by:

The following are required within 72 hours prior to lymphodepletion:

• Adequate bone marrow function (ANC ≥1.0 x 10^9/L and platelets ≥50 x 10^9/L) unless related to lymphoma involvement. Subjects cannot have received platelet transfusion within 7 days of lymphodepletion.
• Bilirubin ≤1.5 times the upper limit of normal (ULN). Subjects with Gilbert's syndrome may be enrolled despite a total bilirubin level >1.5 mg/dL if their conjugated bilirubin is <1.5× ULN)
• AST ≤ 3 times ULN
• Creatinine Clearance (CrCl) >30mL/min per Cockcroft and Gault
• Pulse oximetry of > 90% on room air
• Negative serum pregnancy test within 72 hours prior to lymphodepletion or documentation that the subject is post-menopausal. Post-menopausal status must be confirmed with documentation of absence of menses for > 1 year, or documentation of surgical menopause involving bilateral oophorectomy.
• In subjects with CLL/SLL or lymphoma with bone marrow only involvement, a bone marrow biopsy within 28 days prior to lymphodepletion.
• Subjects that have received therapy with murine antibodies must have documentation of absence of human anti-mouse antibodies (HAMA) prior to lymphodepletion. Subjects who have received prior therapy with murine antibodies must have documentation of absence of HAMA within 8 weeks of lymphodepletion or after their most recent murine antibody therapy (whichever is shortest). For subjects that receive murine monoclonal antibodies or murine-human chimeric monoclonal antibodies between procurement and lymphodepletion, HAMA testing should be performed within 4 weeks prior to lymphodepletion and after the last monoclonal antibody dose.
• Available autologous transduced activated T cells product meets the certificate of analysis.
• Has not received any investigational agents or received any tumor vaccines within the previous six weeks prior to lymphodepletion.
• Subject is not taking a prohibited or contraindicated medication prior to lymphodepletion. Contraindicated medications should be discontinued at least two weeks prior to the scheduled lymphodepletion or by at least 5 half-lives of the contraindicated medication, whichever is shorter.
• Subject is not taking strong inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin) as these may increase plasma concentrations of bendamustine, and decrease plasma concentrations of its metabolites. See http://medicine.iupui.edu/clinpharm/ddis/ for an updated list of strong inhibitors of CYP1A2. (This applies to subjects who receive bendamustine for lymphodepletion (required) up through 72 hours after the last dose of bendamustine).
• Subject has not received chemotherapy within the previous 3 weeks prior to lymphodepletion.

Eligibility criteria to be met prior to cell infusion after lymphodepletion:

• No evidence of uncontrolled infection or sepsis.
• Negative serum pregnancy within 7 days of cell infusion (does not need to be repeated if pre-lymphodepletion pregnancy test is within window).