CART19 to Treat B-Cell Leukemia or Lymphoma That Are Resistant or Refractory to Chemotherapy

Pilot Study of Redirected Autologous T-cells Engineered to Contain Anti-CD19 Attached to TCR and 4-1BB Signaling Domains in Patient With Chemotherapy Resistant or Refractory CD19+ Leukemia and Lymphoma

This is a Pilot/Phase I, single arm, single center, open label study to determine the safety, efficacy and cellular kinetics of CART19 (CTL019) in chemotherapy resistant or refractory CD19+ leukemia and lymphoma subjects. The study consists of three Phases:

1) a Screening Phase, followed by 2) an Intervention/Treatment Phase consisting of apheresis, lymphodepleting chemotherapy (determined by the Investigator and based on subject's disease burden and histology, as well as on the prior chemotherapy history received), infusions of CTL019, tumor collection by bone marrow aspiration or lymph node biopsy (optional, depending on availability), and 3) a Follow-up Phase.

The suitability of subjects' T cells for CTL019 manufacturing was determined at study entry.

Subjects with adequate T cells were leukapheresed to obtain large numbers of peripheral blood mononuclear cells for CTL019 manufacturing. The T cells were purified from the peripheral blood mononuclear cells, transduced with TCR-ζ/4-1BB lentiviral vector, expanded in vitro and then frozen for future administration. The number of subjects who had inadequate T cell collections, expansion or manufacturing compared to the number of subjects who had T cells successfully manufactured is a primary measure of feasibility of this study.

Unless contraindicated and medically not advisable based on previous chemotherapy, subjects were given conditioning chemotherapy prior to CTL019 infusion. The chemotherapy was completed 1 to 4 days before the planned infusion of the first dose of CTL019.

Up to 20 evaluable subjects with CD19+ leukemia or lymphoma were planned to be dosed with CTL019. A single dose of CTL019 (consisting of approximately 5x10^9 total cells, with a minimal acceptable dose for infusion of 1.5x10^7 CTL019 cells) was to be given to subjects as fractions (10%, 30% and 60% of the total dose) on Day 0, 1 and 2. A second 100% dose of CTL019 was initially permitted to be given on Day 11 to 14 to subjects, providing they had adequate tolerance to the first dose and sufficient CTL019 was manufactured.

Primary objectives:

1. To evaluate the safety and feasibility of a single target dose of 5 times 10e9 total cells, acceptable range of 1.5 times 10e7 to 5 times 10e9 total cells comprised of autologous CART-19 cells that express the TCR zeta and 4-1 BB costimulatory domain.

Secondary objectives:

1. Proof of mechanism: determine if 2nd generation CAR expressing 4-1BB costimulation domains have improved persistence in patients.
2. Proof of concept: determine the effects of CART-19 on CD19 expression in vivo.
3. Proof of bioactivity: Evaluate changes in systemic soluble immune factors in patients
4. Proof of bioactivity: Evaluate impact of CART19 treatment on tumor burden
5. Explore whether CART-19 cells retain anti-tumor activity in vivo.
6. Determine if host immunity develops against CART-19.
7. Characterize the relative subsets of CART-19 T cells (Tcm, Tem, and Treg).
8. Describe survival and response rates

Inclusion

• Male and female subjects with CD19+ B cell malignancies in patients with no available curative treatment options (such as autologous or allogeneic SCT) who have limited prognosis (several months to < 2 year survival) with currently available therapies will be enrolled
• CD19+ leukemia or lymphoma
• ALL in CR2 or CR3 and not eligible for allogeneic SCT because of age, comorbid disease, or lack of available family member or unrelated donor
• Follicular lymphoma, previously identified as CD19+:
• At least 2 prior combination chemotherapy regimens (not including single agent monoclonal antibody (Rituxan) therapy
• Stage III-IV disease
• Less than 1 year between last chemotherapy and progression (i.e. most recent progression free interval < 1 year)
• Disease responding or stable after most recent therapy (chemotherapy, MoAb, etc)
• CLL:
• At least 2 prior chemotherapy regimens (not including single agent monoclonal antibody (Rituxan) therapy. Patients with high risk disease manifested by deletion chromosome 17p will be eligible if they fail to achieve a CR to initial therapy or progress within 2 years of 1 prior
• Less than 2 years between last chemotherapy and progression (i.e. most recent progression free interval < 2 years)
• Not eligible or appropriate for conventional allogeneic SCT
• Patients who achieve only a partial response to FCR as initial therapy will be eligible.
• Mantle cell lymphoma:
• Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate for conventional allogeneic or autologous SCT
• Disease responding or stable after most recent therapy (chemotherapy, MoAb, etc...)
• Relapsed after prior autologous SCT
• B-cell prolymphocytic leukemia (PLL) with relapsed or residual disease after at least 1 prior therapy and not eligible for allogeneic SCT
• Diffuse large cell lymphoma, previously identified as CD19+:
• Residual disease after primary therapy and not eligible for autologous SCT
• Relapsed after prior autologous SCT
• Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate of conventional allogeneic or autologous SCT
• Expected survival > 12 weeks
• Creatinine < 2.5 mg/dl
• ALT/AST < 3x normal
• Bilirubin < 2.0 mg/dl
• Any relapse after prior autologous SCT will make patient eligible regardless of other prior therapy
• Adequate venous access for apheresis, and no other contraindications for leukapheresis
• Voluntary informed consent is given

Exclusion

• Pregnant or lactating women
• The safety of this therapy on unborn children is not known
• Female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion
• Uncontrolled active infection
• Active hepatitis B or hepatitis C infection
• Concurrent use of systemic steroids. Recent or current use of inhaled steroids is not exclusionary
• Previously treatment with any gene therapy products
• Feasibility assessment during screening demonstrates < 30% transduction of target lymphocytes, or insufficient expansion (< 5-fold) in response to CD3/CD28 costimulation
• Any uncontrolled active medical disorder that would preclude participation as outlined
• HIV infection