Study of CAR-T Cells Expressing CD30 and CCR4 for r/r CD30+ HL and NHL

This study is a single center, open-label Phase I clinical trial designed to determine the
safety of escalating doses of autologous activated T lymphocytes (ATLs) expressing the
chimeric antigen receptor specific for the CD30 antigen and the CCR4 chemokine receptor
(ATLCAR.CD30.CCR4) in subjects with relapsed/refractory CD30+ Hodgkin (HL) and Non-Hodgkin
lymphoma (NHL). Subjects will receive either ATLCAR.CD30.CCR4 or two ATL products
simultaneously: one ATL product in which T cells co-express CAR.CD30 and CCR4
(ATLCAR.CD30.CCR4) and one ATL product encoding only the CAR.CD30 (ATLCAR.CD30). The dose for
ATLCAR.CD30 will be fixed at the highest dose level as this product has been shown to be safe
in phase I trials with and without lymphodepletion. Six dose levels of ATLCAR.CD30.CCR4 will
be tested. Prior to receiving the infusions, subjects will undergo lymphodepletion with
bendamustine and fludarabine, The 3+3 design will be used for estimating the maximum
tolerated dose (MTD) of ATLCAR.CD30.CCR4 cell infusions. Secondary endpoints include
evaluation of persistence of ATLCAR.CD30.CCR4 vs. ATLCAR.CD30 in the peripheral blood,
accumulation of ATLCAR.CD30.CCR4 vs. ATLCAR.CD30 in tumor biopsies, and progression free
survival (PFS). The study will enroll up to a maximum of 44 subjects.

OUTLINE

Cell Procurement

Up to 300 mL total of peripheral blood will be obtained (in up to 3 collections) from
subjects for cell procurement. In subjects with a low absolute lymphocyte count (< 0.5 x
109/L) in the peripheral blood, a leukapheresis may be performed to isolate sufficient T
cells. The parameters for pheresis will be up to 2 blood volumes.

Cell Administration

ATLCAR.CD30.CCR4 with or without ATLCAR.CD30 cells will be given to eligible subjects 2-14
days (preferably 2-4 days) after lymphodepletion with fludarabine and bendamustine. The dose
of cells will vary, depending on the cohort enrolled. The cells will be administered by a
licensed provider (oncology nurse or physician) via intravenous injection over 1-10 minutes
through either a peripheral or a central line. The expected volume will be 1-50cc. Subjects
in the dose expansion part of the study who received the highest safe dose level of
ATLCAR.CD30 and ATLCAR.CD30.CCR4 may receive a second infusion of ATLCAR.CD30 and
ATLCAR.CD30.CCR4 if cells are available equal to the dose administered for the first cell
infusion (or a lower dose).

Duration of Therapy

Therapy in LCCC1606-ATL involves one to two infusion(s) of ATLCAR.CD30.CCR4 with or without
ATLCAR.CD30 cells. Treatment with one infusion will be administered unless:

- Subject decides to withdraw from study treatment, OR

- General or specific changes in the subject's condition render the subject unacceptable
for further treatment in the judgment of the investigator.

Duration of Follow-up

Subjects who receive a cell infusion will be followed for up to 15 years for replication
competent retrovirus (RCR) 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.
Subjects who have progressive disease or initiate another cancer therapy after receiving a
cell infusion(s) will still be required to complete abbreviated follow up procedures.

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

- Written informed consent and HIPAA authorization for release of personal health
information. Subjects must sign a consent to undergo cell procurement. Written
informed consent to enroll in the CAR T-cell therapy trial must be obtained prior to
lymphodepletion.

- Adults ≥18 years of age.

- Diagnosis of recurrent HL or NHL in subjects who have failed ≥2 prior treatment
regimens.

- These prior treatment regimens must include brentuximab vedotin.

- If the subject has Hodgkin Lymphoma, the subject must have either failed
autologous transplant or must not be eligible for autologous transplant.

- For CD30+ Non-Hodgkin Lymphoma, the subject must have failed an anthracycline
containing regimen.

- Subjects relapsed after autologous or allogeneic stem cell transplant are
eligible for this study.

- CD30+ disease (result can be pending at the time of cell procurement, but must be
confirmed prior to treatment with ATLCAR.CD30.CCR4 and ATLCAR.CD30 cells); NOTE: CD30+
disease requires documented CD30 expression by immunohistochemistry based on the
institutional hematopathology standard.

- Karnofsky score of > 60%

- Willing to undergo biopsy following the cell infusion. A biopsy may be required (i.e.,
considered mandatory) in subjects receiving both cellular products if the investigator
determines the tumor site is easily accessible (e.g., palpable tumor). If the
investigator feels that the biopsy would be difficult to obtain or poses a high degree
of risk to the subject, it may be deferred.

- 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 - Subjects meeting any of the following exclusion criteria will not be
able to participate in this study:

- 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 human immunodeficiency virus (HIV), human T-lymphotropic virus
(HTLV), hepatitis B virus (HBV), hepatitis C virus (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 or negative HIV viral load,
negative HTLV1 and 2 antibody, 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.

- Subject is not a good candidate for treatment with ATLCAR.CD30.CCR4 with and without
ATLCAR.CD30 per investigator's discretion.

Eligibility Criteria to Be Met Prior to Procurement:

-Evidence of adequate organ function as defined by:

The following is required prior to procurement:

- Hgb ≥ 8.0g/dL (transfusion independent for 2 weeks prior to enrollment)

- 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)

- Aspartate aminotransferase (AST) ≤ 3 times ULN

- Serum creatinine ≤1.5 times ULN.

- Creatinine Clearance (CrCl) >60mL/min per Cockcroft and Gault

- Pulse oximetry of >90% on room air

- Imaging results from within 120 days prior to procurement to assess presence of
active disease (no tumor imaging is required prior to procurement for
participants with cutaneous lymphoma).

- 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.

- Subject has no clinical indication of rapidly progressing disease in opinion of
treating physician.

- Subject has adequate cardiac function, defined as:

- No ECG evidence of acute ischemia

- No ECG evidence of active, clinically significant conduction system
abnormalities

- Prior to study entry, any ECG abnormality at screening not felt to put the
subject at risk has to be documented by the investigator as not medically
significant

- No uncontrolled angina or severe ventricular arrhythmias

- No clinically significant pericardial disease

- No history of myocardial infarction within the last 6 months prior to
infusion

- No Class 3 or higher New York Heart Association Congestive Heart Failure

Eligibility Criteria to Be Met Prior to Lymphodepletion:

- Imaging results from within 7 days prior to lymphodepletion to assess presence of
active disease. Patients who have received bridging chemotherapy must have imaging
performed at least 3 weeks after most recent therapy (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 prior to lymphodepletion:

- Adequate bone marrow function (ANC>1000 cells/mm3 and platelets >75,000/mm3). 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

- Serum creatinine ≤1.5 times ULN.

- Creatinine Clearance (CrCl) >60mL/min per Cockcroft and Gault

- Pulse oximetry of > 90% on room air

- 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.

- Subjects must have autologous transduced activated T-cells that meet the
Certificate of Analysis (CofA) acceptance criteria.

- Has not received any investigational agents or received any tumor vaccines within
the previous six weeks prior to lymphodepletion.

- Has not received anti-CD30 antibody-based therapy within the previous 4 weeks
prior to lymphodepletion.

- Has not received chemotherapy or radiation therapy within the previous 3 weeks
prior to lymphodepletion.

- Subjects cannot be on strong inhibitors of CYP1A2 (e.g., fluvoxamine,
ciprofloxacin) as these may increase plasma concentrations of bendamustine, and
decrease plasma concentrations of its metabolites. (This applies to subjects who
receive bendamustine for lymphodepletion (required) up through 72 hours after the
last dose of bendamustine).

- Subjects who are HBV core antibody positive and HBV viral load negative prior to
lymphodepletion must have initiated anti-HBV prophylaxis prior to
lymphodepletion.

Eligibility Criteria to Be Met Prior to Cell Infusion after Lymphodepletion:

- No evidence of uncontrolled infection or sepsis.

- Evidence of adequate organ function as defined by:

1. Bilirubin ≤2 times the upper limit of normal (ULN)

2. AST ≤3 times ULN

3. Alanine aminotransferase (ALT) ≤3 times ULN

4. Creatinine Clearance (CrCl) >60mL/min per Cockcroft and Gault (see Section 11.13)

5. Pulse oximetry of >90% on room air