huJCAR014 CAR-T Cells in Treating Adult Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma or Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVES:

I. To evaluate preliminary safety of huJCAR014 in adult patients with CD19+ relapsed or
refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (NHL) and acute lymphoblastic
leukemia (ALL).

SECONDARY OBJECTIVES:

I. To characterize the pharmacokinetic (PK) profile of huJCAR014 in CD19+ R/R aggressive
B-cell NHL and ALL.

II. To assess the antitumor activity of huJCAR014 in CD19+ R/R aggressive NHL and ALL.

III. To estimate the progression free survival (PFS) and overall survival (OS) in patients
with CD19+ R/R aggressive NHL and ALL treated with huJCAR014.

EXPLORATORY OBJECTIVES:

I. To assess the cellular and humoral immune responses to huJCAR014.

II. To assess the pharmacodynamic effects of huJCAR014.

III. To assess the effect of huJCAR014 product attributes on safety, PK, and antitumor
activity.

IV. To assess the effect of tumor and tumor microenvironment on huJCAR014 PK and biomarkers.

OUTLINE: This is a dose-escalation study of huJCAR014.

Patients undergo leukapheresis. Beginning 1-2 weeks after leukapheresis, patients undergo
lymphodepleting chemotherapy comprising either cyclophosphamide intravenously (IV) daily for
1 day and fludarabine IV daily for 3 days or cyclophosphamide and fludarabine IV daily for 3
days. Within 36-96 hours after completion of lymphodepleting chemotherapy, patients receive
huJCAR014 IV over 20-30 minutes on day 0.

After completion of study treatment, patients are followed up every 30 days for the first 3
months, every 3 months for up to 12 months, and then yearly for 15 years.

Inclusion Criteria:

CRITERIA FOR SCREENING

- Ability to understand and provide informed consent

- Diagnosis of R/R B-cell NHL or ALL as defined below:

- Relapsed or refractory B-cell NHL meeting all of the following criteria:

- Diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS); high
grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements; LBCL
transformed from any indolent histology; or primary mediastinal B-cell
lymphoma (PMBCL)

- Prior treatment with an anthracycline and rituximab or another CD20-targeted
agent (unless the disease is CD20-negative); transformed DLBCL (tDLBCL) must
have failed treatment for DLBCL

- At least one of the following:

- Refractory disease after frontline chemo-immunotherapy

- Not eligible for autologous hematopoietic stem cell transplant
(auto-HSCT)

- Relapsed or refractory disease after at least 2 lines of therapy or
after auto-HSCT

- Relapsed or refractory disease after allogeneic hematopoietic stem cell
transplant (allo-HSCT)

- Relapsed or refractory B-cell ALL (patients with Burkitt's lymphoma/leukemia are
not eligible)

- All B-ALL patients must have detectable disease by morphology, flow cytometry,
cytogenetic analysis (e.g. polymerase chain reaction [PCR], fluorescence in situ
hybridization [FISH], karyotyping) or imaging (e.g. positron emission tomography
[PET]/computed tomography [CT]) or a high likelihood of active disease

- Refractory: failure to achieve complete response (CR) (minimal residual
disease [MRD]-negative) at the end of induction

- Relapsed: recurrence of disease after achieving CR

- Evidence of CD19 expression by immunohistochemistry or flow cytometry on any prior or
current tumor specimen or high likelihood of CD19 expression based on disease
histology

CRITERIA FOR LEUKAPHERESIS AND PRE-THERAPY EVALUATION

- Screening evaluation appropriate for leukapheresis and T-cell collection

- Adequate vascular access available or planned for leukapheresis procedure (either
peripheral line or surgically placed line)

- Documentation of CD19 expression on any prior or current tumor biopsy; patients who
have received previous CD19-targeted therapy must have CD19-positive disease confirmed
on a biopsy since completing the prior CD19-targeted therapy

- Internal review of histology

CRITERIA FOR LYMPHODEPLETING CHEMOTHERAPY AND huJCAR014 TREATMENT

- Successful collection of T cells for huJCAR014 manufacturing

- Detectable disease by imaging (for example PET +/- CT, magnetic resonance imaging
[MRI]) and/or pathology evaluation

- Karnofsky performance status >= 60%

- Assessed by the investigator to have adequate bone marrow function to receive
lymphodepleting conditioning chemotherapy

- Serum creatinine =< 1.5 x age-adjusted upper limit of normal (ULN) or calculated
creatinine clearance (Cockcroft and Gault) > 30 mL/min/1.73 m^2

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 5 x ULN and
total bilirubin < 2.0 mg/dL unless due to malignancy or Gilbert's syndrome in the
opinion of the PI or designee

- Common Terminology Criteria for Adverse Events (CTCAE) grade =< 1 dyspnea and oxygen
saturation (SaO2) >= 92% on room air

- Left ventricular ejection fraction (LVEF) >= 40% as assessed by echocardiogram (ECHO)
or multiple uptake gated acquisition (MUGA) scan performed within 1 month before
starting lymphodepleting chemotherapy

- Women of childbearing potential (defined as all women physiologically capable of
becoming pregnant) must agree to both of the following:

- Use highly effective methods of contraception for at least 6 months after the
last dose of huJCAR014, and

- Have a negative serum pregnancy test performed within 28 days before starting
lymphodepleting chemotherapy

- Males who have partners of childbearing potential must agree to use an effective
barrier contraceptive method for at least 6 months after the last dose of huJCAR014

Exclusion Criteria:

CRITERIA FOR SCREENING

- For patients in stage 1 only, prior treatment with any CD19 CAR T-cell therapy is
excluded

- Known active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection

- Pregnant or breastfeeding women

- Any known contraindication to leukapheresis

- Any known and irreversible contraindication to huJCAR014 therapy

- Medical, psychological, familial, sociological, or geographical condition that does
not permit compliance with the protocol as judged by the PI or designee, or
unwillingness or inability to follow protocol procedures

CRITERIA FOR LEUKAPHERESIS AND PRE-THERAPY EVALUATION

- History or presence of clinically relevant central nervous system (CNS) pathology
that, in the opinion of the PI or designee, is a contraindication to lymphodepleting
chemotherapy or huJCAR014 infusion

- History of another primary malignancy that has not been in remission for at least 2
years with the following exceptions: nonmelanoma skin cancer, curatively treated
localized prostate cancer, cervical carcinoma in situ on biopsy or a squamous
intraepithelial lesion on pap smear, or other malignancy considered by the
investigator to have a low risk of relapse or progression

- Active autoimmune disease requiring immunosuppressive therapy, unless considered by
the PI or designee to be eligible

- Presence of active acute or chronic graft versus host disease (GVHD)

- Use of any of the following:

- Cytotoxic or lymphotoxic agents (including prednisone > 5 mg/day or equivalent
corticosteroid) within 1 week prior to leukapheresis; physiologic corticosteroid
replacement, and topical or inhaled corticosteroids are not excluded

- GVHD therapies within 4 weeks prior to leukapheresis (e.g., calcineurin
inhibitors, methotrexate or other chemotherapeutics, mycophenolate, rapamycin,
thalidomide, immunosuppressive antibodies such as anti-TNF, anti-IL-6, or
anti-IL-6R)

- Experimental agents within 4 weeks prior to leukapheresis unless progression is
documented on therapy and at least 3 half-lives have elapsed prior to
leukapheresis

- Radiation within 6 weeks prior to leukapheresis unless there is progressive
disease in irradiated lesions or there are additional non-irradiated, positron
emission tomography (PET)-positive lesions

- Allo-HSCT within 60 days prior to leukapheresis or donor lymphocyte infusion
(DLI) within 6 weeks prior to leukapheresis

- Treatment with cladribine within 3 months prior to leukapheresis

- Treatment with alemtuzumab within 3 months prior to leukapheresis

CRITERIA FOR LYMPHODEPLETING CHEMOTHERAPY AND huJCAR014 TREATMENT

- Uncontrolled and serious infection

- Presence of active acute or chronic GVHD

- DLI within 6 weeks prior to lymphodepletion chemotherapy