Anti-CD19 CAR-T Cells With Inducible Caspase 9 Safety Switch for B-cell Lymphoma
Anti-CD19 CAR-T Cells With Inducible Caspase 9 Safety Switch for B-cell Lymphoma
This research study combines 2 different ways of fighting disease: antibodies and T cells.
 Both antibodies and T cells have been used to treat patients with cancers, and both have
 shown promise, but neither alone has been sufficient to cure most patients. This study
 combines both T cells and antibodies to create a more effective treatment. The treatment
 being researched is called autologous T lymphocyte chimeric antigen receptor cells targeted
 against the CD19 antigen (ATLCAR.CD19) administration.

 Prior studies have shown that a new gene can be put into T cells and will increase their
 ability to recognize and kill cancer cells. The new gene that is put in the T cells in this
 study makes a piece of an antibody called anti-CD19. This antibody sticks to leukemia cells
 because they have a substance on the outside of the cells called CD19. For this study, the
 anti-CD19 antibody has been changed so that instead of floating free in the blood part of it
 is now joined to the T cells. When an antibody is joined to a T cell in this way it is called
 a chimeric receptor. These CD19 chimeric (combination) receptor-activated T cells seem to
 kill some of the tumor, but they do not last very long in the body and so their chances of
 fighting the cancer are unknown.

 Preliminary results have shown that subjects receiving this treatment have experienced
 unwanted side effects including cytokine release syndrome and neurotoxocity. In this study,
 to help reduce cytokine release syndrome and/or neurotoxicity symptoms, the ATLCAR.CD19 cells
 have a safety switch that, when active, can cause the cells to become dormant. These modified
 ATLCAR.CD19 cells with the safety switch are referred to as iC9-CAR19 cells. If the subject
 experiences moderate to severe cytokine release syndrome and or neurotoxicity as a result of
 being given iC9-CAR19 cells, the subject can be given a dose of a second study drug, AP1903,
 if standard interventions fail to alleviate the symptoms of cytokine release syndrome and/or
 neurotoxicity. AP1903 activates the iC9-CAR19 safety switch, reducing the number of the
 iC9-CAR19 cells in the blood. The ultimate goal is to determine what dose of AP1903 can be
 given that reduces the severity of the cytokine release syndrome and/or neurotoxicity, but
 still allows the remaining iC9-CAR19 cells to effectively fight the lymphoma.

 The primary purpose of this study is to determine whether receiving iC9-CAR19 cells is safe
 and tolerable in patients with relapsed/refractory 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. 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, AP1903 (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 CAR-T-cell-related encephalopathy syndrome (CRES) or grade 2
 CRES 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 that remains
 ≥grade 2 twenty four hours after an initial dose of tocilizumab may be part of the sub-study
 of rimiducid. These subjects will receive one of two assigned dose levels of rimiducid with
 their second tocilizumab infusion. The percent reduction in CAR T cells will be measured in
 these subjects. If the subjects' CRS is unresponsive to tocilizumab and the assigned dose
 level of rimiducid, subjects with ≥grade 3 CRS will then be given a full dose (0.4 mg/kg) of
 rimiducid.

 Cell Procurement

 Peripheral blood, up to 300 mL (in up to 3 collections) will be obtained from subjects for
 cell procurement. In subjects with low T-cell count (CD3 count as assayed by flow cytometry
 less than 200/μL) in the peripheral blood, a leukopheresis may be performed to isolate
 sufficient T cells. The parameters for pheresis 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. We will administer iC9-CAR19 post lymphodepletion at dose levels
 specified in the table in section 4.1. A recently published trial in refractory DLBCL
 established that a dose of 2 x 106 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; Lymphomatoid
 granulomatosis; 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

 Indolent Lymphomas:

 -  Follicular lymphoma

 -  Splenic marginal zone lymphoma

 -  Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue

 -  Nodal marginal zone lymphoma

 -  Mantle cell lymphoma

 -  Subjects with CNS disease will not be excluded as long it has been stable for 3 months

 --For aggressive lymphomas, relapsed or refractory disease, defined as one of the
 following:

 -  Residual disease after primary therapy and not eligible for autologous stem cell
 transplant (ASCT)

 -  Relapsed or persistent disease after prior ASCT

 -  Beyond 1st complete remission with relapsed or persistent disease and not eligible or
 appropriate for conventional allogeneic or ASCT

 -  For indolent lymphomas, subjects must have received at least 2 prior lines of
 therapy for their lymphoma

 -  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

 -  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 discretion of investigator.

 -  Active infection with HIV, HTLV, HBV, 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.

 -  Known additional malignancy that is active and/or progressive requiring treatment;
 exceptions include basal cell or squamous cell skin cancer, in situ cervical or
 bladder cancer, or other cancer for which the subject has been disease-free for at
 least five years.

 -  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 (See Section 12.3)

 -  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.

 -  Imaging results from within 90 days prior to procurement to assess presence of
 active disease.

 -  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.

 -  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 109/L and platelets ≥75 x 109/L). 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.

 -  Subjects that have received therapy with murine antibodies must have
 documentation of absence of human anti-mouse antibodies (HAMA) prior to
 lymphodepletion.

 -  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).