Administration of T Lymphocytes for Prevention of Relapse of Lymphomas

STUDY OBJECTIVES

Primary Objective

- To determine the safety and tolerability and to estimate the MTD of ATLCAR.CD30 post
ASCT in patients with CD30+ lymphoma at high risk for relapse

Secondary Objectives

- To measure the survival of ATLCAR.CD30 in vivo

- To estimate PFS after infusion of ATLCAR.CD30 post ASCT in patients with CD30+ lymphoma
at high risk for relapse

- To determine the overall survival after infusion of ATLCAR.CD30 post ASCT in patients
with CD30+ lymphoma at high risk for relapse

Exploratory Objective

- To measure patient-reported symptom, physical function, and health-related quality of
life at baseline and over time in patients treated with ATLCAR.CD30 cells.

ENDPOINTS

Primary Endpoint

- Toxicity will be classified and graded according to the National Cancer Institute's
Common Terminology Criteria for Adverse Events (CTCAE, version 4.0) and CRS toxicity
will be graded according to the toxicity scale outlined in 11.6 (Appendix F: CRS
Toxicity Grading Scale and Management Guidelines). The MTD will be based on the rate of
dose-limiting toxicity

Secondary (Clinical) Endpoint

- PFS is defined from day of ASCT to relapse (in subjects with a documented complete
response after ASCT) or progression (in subjects with documented stable disease or
partial response after ASCT), or death as a result of any cause as per the Revised
Response Criteria for Malignant Lymphoma.

- Overall survival will be measured from the date of administration of CAR.CD30 transduced
ATL to date of death

- Persistence of CAR.CD30 T cells in vivo will be determined by quantitative PCR and flow
cytometry in peripheral blood samples.

Exploratory Endpoint

- Patient reported symptoms will be measured using selected symptoms from the NCI
PRO-CTCAE. Patient-reported physical function will be measured using the PROMIS Physical
Function Score derived from the PROMIS Physical Function Short Form 20a v1.0.
Patient-reported health-related quality of life will be measured using the PROMIS Global
Health Score derived from the PROMIS Global Health Short Form v1.0-1.1.

OUTLINE

Patients scheduled to undergo an autologous stem cell transplantation (ASCT) for treatment of
lymphoma will be approached for consent to screening and potential enrollment into LCCC1524.
Peripheral blood cells will be collected from consenting patients who meet eligibility for
cell procurement for creation of ATLCAR.CD30 cells prior to ASCT. The ASCT, including
mobilization and collection of PBSCs, administration of myeloablative therapy, reinfusion of
PBSCs and supportive care following transplant will be as per routine standard of care, and
not expected to be impacted by enrollment into LCCC1524. Post ASCT, patients who meet
eligibility criteria for treatment will receive one infusion of ATLCAR.CD30 cells once there
is evidence of hematologic recovery. Research personnel will keep track of any patients who
undergo procurement but do not undergo treatment with ATLCAR.CD30 cells, and the reason for
withholding treatment.

Cell Procurement

Peripheral blood, up to 300 mL total (in up to 3 collections) will be obtained for subjects
for cell procurement. In patients with low (CD3 count as assayed by flow cytometry less than
200/μl) T-cell count 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.

For pediatric patients (patients under 18 years of age), the total amount of blood drawn will
not be more than 3 mL (less than 1 teaspoon per 2.2 lbs. that the child weighs.

ATLCAR.CD30 Cells Administration

Post ASCT, once the patient has started to experience hematologic recovery (defined as ANC
≥500 cells/mm3 for 3 consecutive days, AND platelet count ≥25 cells/mm3 without transfusion
over the preceding 5 days, AND Hg ≥8g/dL without transfusion support over preceding 5 days),
ATLCAR.CD30 cells will be admnistered. This will generally occur between 14 and 20 days
following infusion of autologous stem cells following high-dose chemotherapy.

Duration of Therapy

Therapy in LCCC1524 involves just one infusion of ATLCAR.CD30 cells. Treatment with one
infusion will be administered unless:

- Patient decides to withdraw from study treatment, OR

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

Duration of Follow-Up

Patients will be followed for up to 15 years or until death, whichever occurs first. Patients
removed from study for unacceptable adverse events will be followed until resolution or
stabilization of the adverse event.

Inclusion Criteria:

- Informed consent explained to, understood by and signed by patient/guardian;
patient/guardian given copy of informed consent.

- 3 to 17 years of age for pediatric patients, ≥18 years of age for adults; NOTE:
children will not be allowed to enroll in a dose cohort until a minimum of 2 adult
subjects are enrolled and complete their DLT assessment follow-up at that dose level

- Diagnosis of recurrent HL with a treatment plan that will include high dose
chemotherapy with/without total body irradiation and autologous cell transplantation

- NHL patients with ALK negative CD30+ anaplastic large-cell lymphomas, CD30+ ALCL
regardless of ALK status, with chemotherapy-sensitive relapse, CD30+ high-risk DLBCL,
CD30+ cutaneous T cell lymphoma, or CD30+ mycosis fungoides who are otherwise eligible
for 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 cells); NOTE: CD30 + disease is defined
as requiring documentation of CD30 expression by immunohistochemistry based on the
institutional hematopathology standard.

- Evidence of adequate organ function as defined by:

- The following is required prior to procurement (NOTE: labs do not need to be
redrawn if they have already been performed as part of SOC pre-transplant
work-up; Subject must be eligible to receive ASCT)

- Hgb ≥ 8.0g/dL

- Bilirubin ≤1.5 times the upper limit of normal (ULN)

- AST ≤ 3 times ULN

- Serum creatinine ≤1.5 times ULN

- Cardiac and pulmonary function that is adequate for ASCT

- The following is required prior to infusion of ATLCAR.CD30 cells:

- Absolute neutrophil count (ANC) ≥500 cells/mm3 for 3 consecutive days; Note:
ANC may be measured at the beginning and the end of a time frame expanding
at least 3 days and does not need to be evaluated on each individual day AND

- Platelet count ≥25,000 cells/mm3 without transfusion over preceding 5 days
Note: Platelets may be measured at the beginning and the end of a time frame
expanding at least 5 days and does not need to be evaluated on each
individual day AND

- Hg ≥8g/dL without transfusion support over preceding 5 days Note: Hg may be
measured at the beginning and the end of a time frame expanding at least 3
days and does not need to be evaluated on each individual day

- Bilirubin ≤1.5 times the upper limit of normal (ULN)

- AST ≤ 3 times ULN

- Serum creatinine ≤1.5 times ULN

- Pulse oximetry of > 90% on room air

- Imaging results from within 60 days prior to transplant (used as baseline measure for
documentation of disease status). Note: Results may be obtained at a time point
greater than 30 days from transplant if obtained per the patient's standard of care
and with prior sponsor approval.

- Negative serum pregnancy test within 72 hours prior to procurement and again 72 hours
prior to infusion

- Karnofsky or Lansky score of > 60%

- Considered at high risk for relapse as defined by: The presence of ≥ 1 of the
following: failure to achieve CR post initial treatment; relapsed disease with an
initial remission duration of <12 months; or extranodal involvement at the start of
pre-transplant salvage therapy

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

- Women of childbearing potential (WOCBP) should 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. The male partner of WOCBP subjects enrolled
into the trial should be instructed to use a condom by their female partner enrolled
in the trial.

Exclusion Criteria:

- Received any investigational agents or received any tumor vaccines within the previous
six weeks prior to cell infusion.

- Received anti-CD30 antibody-based therapy within the previous 4 weeks prior to cell
infusion

- History of hypersensitivity reactions to murine protein-containing products

- Pregnant or lactating

- Tumor in a location where enlargement could cause airway obstruction.

- Current use of systemic corticosteroids at doses ≥10mg/day prednisone or its
equivalent; those receiving <10mg/day 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) . Active infection is defined as not being well controlled
on therapy (Note: To meet eligibility subjects are required to be negative for HIV
antibody or HIV viral load, negative for HTLV1 and 2 antibody, negative for Hepatitis
B surface antigen, or negative for HCV antibody or HCV viral load).