Study on CD30 CAR Therapy for Relapsed or Hard-to-Treat CD30+ Hodgkin and Non-Hodgkin Lymphoma

Inclusion Criteria Prior to Cell Procurement

Informed consent explained to, understood by and signed by the subject or legal guardian for pediatric subjects; subject and/or legal guradian given a copy of informed consent form for procurement

Ages 3 to 17 years of age for pediatric subjects (weight must be ≥10kg), and for adults ages ≥18 years of age

Diagnosis of recurrent HL or NHL in subjects who have failed >2 prior treatment regimens. 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 cells). NOTE: CD30+ disease requires documented CD30 expression by immunohistochemistry based on the institutional hematopathology standard.

Karnofsky or Lansky score of >60% (Karnofsky for ≥16 years old and Lansky for <16 years old)

Evidence of adequate organ function as defined by:

• Hemoglobin ≥ 8.0 g/dL (transfusion independent for 2 weeks prior to enrollment)
• Total bilirubin ≤ 1.5 × ULN, unless attributed to Gilbert's Syndrome
• AST ≤ 3 × ULN
• Serum creatinine ≤ 1.5 × ULN
• For subjects <18 years old use the following table for serum creatinine requirements:

Maximum Serum Creatinine (mg/dL) Age (years) Male Female 3 to <6 ≤0.8 ≤0.8 6 to <10 ≤1.0 ≤1.0 10 to <13 ≤1.2 ≤1.2 13 to <16 ≤1.5 ≤1.4 ≥16 and <18 ≤1.7 ≤1.4

Negative serum pregnancy test in females within 72 hours prior to procurement or documentation that the subject is post-menopausal or premenarchal.

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.

• Postmenopausal status must be confirmed with documentation of absence of menses for >1 year.

Exclusion Criteria Prior to Cell Procurement

Pregnant or lactating

Tumor in a location where enlargement could cause airway obstruction

Must not have an Active infection with human immunodeficiency virus (HIV), Hepatitis B Virus (HBV))or, Hepatitis C virus (HCV) (can be pending at the time of cell procurement; only subjects meeting the criteria as so described will be infused). Note: To meet eligibility subjects are required to have negative HIV antibody, negative for Hepatitis B surface antigen and negative for HCV antibody or viral load.

Inclusion Criteria Prior to Lymphodepletion

Informed consent explained to, understood by and signed by the subject or legal guardian for pediatric subjects; subject and/or legal guradian given a copy of informed consent form.

CD30+ disease (result can be pending at the time of cell procurement, but must be confirmed prior to lymphodepletion); Note: CD30+ disease requires documented CD30 expression by immunohistochemistry based on the institutional hematopathology standard.

Prior to administration of lymphodepletion:

• Absolute neutrophil count (ANC) is > 1.0 × 10^9/L
• Platelet count > 75 × 10^9/L
• For Grade 4 neutropenia, Grade ≥3 febrile neutropenia, or Grade 4 thrombocytopenia, hold bendamustine until toxicity resolve to Grade ≤2

For WOCBP negative serum pregnancy test within 72 hours prior to lymphodepletion.

Imaging results from within 7 days (30 days in subjects with cutaneous T cell lymphoma) prior to lymphodepletion. Subjects 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).

Karnofsky or Lansky score of >60% (Karnofsky for pediatric subjects ≥16 years old and Lansky for <16 years old).

Available autologous transduced activated T cells that meet the Certificate of Analysis (CofA) 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.

Exclusion Criteria Prior to Lymphodepletion

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.

Received chemotherapy within the previous 3 weeks prior to lymphodepletion.

Subject has rapidly progressive disease, per treating oncologist's discretion.

Subject is not a good candidate for CAR T cell therapy, per treating oncologist's discretion.

Pregnant or lactating.

Tumor in a location where enlargement could cause airway obstruction.

Current use of systemic corticosteroids at doses equivalent of ≥10mg prednisone daily or its equivalent; those receiving <10mg daily may be enrolled at discretion of investigator. Inhaled steroids are allowed.

For pediatric subjects, physiologic replacement hydrocortisone at doses 6-12 mg/m2/day is allowed. Equivalently dosed alternative steroids are allowed at discretion of investigator, though not to exceed 10mg prednisone per day. Inhaled steroids are allowed.

Subjects on 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. Details are given in the protocol.(This applies to subjects who receive bendamustine for lymphodepletion (required) up through 72 hours after the last dose of bendamustine.)

Active infection with HIV, HBV or HCV (can be pending at the time of cell procurement; only subjects meeting the criteria as so described will be infused. Subjects are required to have negative HIV antibody or negative for Hepatitis B surface antigen and negative HCV antibody or viral load.

Hepatitis B: Subjects who are positive for Hepatitis B Surface Antigen are excluded. Subjects who are Hepatitis B Surface Antigen negative but hepatitis B core Antibody positive 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 if the subject has initiated an anti-HBV prophylaxis regimen prior to lymphodepletion.

Inclusion Criteria Prior to Infusion of ATLCAR.CD30 Cells

Evidence of adequate organ function as defined by:

• Total bilirubin ≤1.5 × ULN, unless attributed to Gilbert's Syndrome
• AST ≤3 × ULN
• Serum creatinine ≤1.5 × ULN
• Pulse oximetry of >90% on room air
• For subjects <18 years old use following table for serum creatinine requirements:

Maximum Serum Creatinine (mg/dL) Age (years) Male Female 3 to <6 ≤0.8 ≤0.8 6 to <10 ≤1.0 ≤1.0 10 to <13 ≤1.2 ≤1.2 13 to <16 ≤1.5 ≤1.4 ≥16 and <18 ≤1.7 ≤1.4

Karnofsky or Lansky score of >60% (Karnofsky for ≥16 years old and Lansky for <16 years old)

Available autologous transduced activated T cells that meet the Certificate of Analysis (CofA) 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.

Exclusion Criteria Prior to Infusion of ATLCAR.CD30 Cells

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.

Tumor in a location where enlargement could cause airway obstruction.

Subject has rapidly progressive disease, per treating oncologist's discretion.

Subject is not a good candidate for CAR T cell therapy, per treating oncologist's discretion.

Current use of systemic corticosteroids at doses ≥10 mg prednisone daily or its equivalent; those receiving <10 mg daily may be enrolled at discretion of investigator. Inhaled steroids are allowed For pediatric subjects, physiologic replacement hydrocortisone at doses 6-12mg/m2/day is allowed. Equivalently dosed alternative steroids are allowed at discretion of investigator, though not to exceed 10mg prednisone per day. Inhaled steroids are allowed.

Active infection with HIV or HCV (can be pending at the time of cell procurement; only subjects meeting the criteria as so described will be infused). Subjects are required to be negative for HIV and negative for Hepatitis B surface antigen, and negative HCV antibody or viral load.

Hepatitis B: Subjects who are positive for Hepatitis B Surface Antigen are excluded. Subjects who are Hepatitis B Surface Antigen negative but hepatitis B core antibody positive 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. These subjects must be receiving antiviral prophylaxis initiated prior to lymphodepletion.

Eligibility Criteria Prior to Lymphodepletion for Second Infusion (Optional) Note: Subjects may receive a second infusion without prior lymphodepletion if they meet the eligibility criteria at the time of infusion, but do not meet the eligibility requirements for adequate bone marrow function and platelet counts.

Karnofsky or Lansky score of >60% (Karnofsky for ≥16 years old and Lansky for <16 years old).

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, or 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.

Subject must not be pregnant or lactating within 7 days of infusion.

Must not have tumor in a location where enlargement could cause airway obstruction.

Subjects must have imaging results confirming active disease from within 30 days prior to lymphodepletion with the exception of cutaneous lymphoma subjects who do not need to repeat scans prior to the second cell infusion if the baseline scans showed lymph nodes ≤ 1.5cm at baseline.

Must not have current use of systemic corticosteroids at doses ≥10 mg prednisone daily or its equivalent; those receiving <10mg daily may be enrolled at discretion of the Investigator

Evidence of adequate organ function as defined by:

• ANC>1.0 × 10^9/L
• Platelets >75 × 10^9/L
• Total bilirubin ≤1.5 × ULN, unless attributed to Gilbert's syndrome
• AST ≤3 × ULN
• Serum creatinine ≤1.5 × ULN
• Pulse oximetry of > 90% on room air
• For subjects <18 years old use following table for serum creatinine requirements:

Maximum Serum Creatinine (mg/dL) Age (years) Male Female 3 to <6 ≤0.8 ≤0.8 6 to <10 ≤1.0 ≤1.0 10 to <13 ≤1.2 ≤1.2 13 to <16 ≤1.5 ≤1.4 ≥16 and <18 ≤1.7 ≤1.4

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.

Subject 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. 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 is a good candidate for treatment with ATLCAR.CD30 per the investigator's discretion.

Eligibility Criteria Prior to Second Infusion (Optional)

No evidence of uncontrolled infection or sepsis.

Subject must not have undergone bridging chemotherapy (or other anti-cancer therapies, which are not mandated by the protocol) prior to the second infusion.

Evidence of adequate organ function as defined by:

• Total bilirubin ≤2 × ULN, unless attributed to Gilbert's syndrome
• AST ≤3 × ULN
• ALT ≤3 × ULN
• Serum creatinine ≤1.5 × ULN
• Pulse oximetry of >90% on room air
• For subjects <18 years old use following table for serum creatinine requirements:

Maximum Serum Creatinine (mg/dL) Age (years) Male Female 3 to <6 ≤0.8 ≤0.8 6 to <10 ≤1.0 ≤1.0 10 to <13 ≤1.2 ≤1.2 13 to <16 ≤1.5 ≤1.4

≥16 and <18 ≤1.7 ≤1.4

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

Subject is a good candidate for treatment with ATLCAR.CD30 per the investigator's discretion.

If subjects have had positive hepatitis B core antibody testing at baseline, they must not have had re-activation of the Hepatitis B virus since baseline testing.

Subject must not be pregnant or lactating within 7 days of infusion.