CD30 CAR for Relapsed/Refractory CD30+ T Cell Lymphoma
CD30 CAR for Relapsed/Refractory CD30+ T Cell Lymphoma
This is a research study to determine the safety and tolerability of ATLCAR.CD30 for treating
 relapsed/refractory Peripheral T Cell Lymphoma. Blood samples will be collected from study
 participants and the immune T cells will be separated. T cells will be genetically modified
 in a laboratory at UNC-Chapel Hill to enable them to produce CD30 antibody. The modified T
 cells, called ATLCAR.CD30, will be able to target and attach to lymphoma cancer cells that
 carry the CD30 antigen. Once they are attached, the T cells will attack and destroy the
 lymphoma cancer cells. To prepare the body for the ATLCAR.CD30 cells, participants will
 complete lymphodepletion with two chemotherapy agents. Lymphodepletion will happen over three
 days prior to ATLCAR.CD30 infusion. If participants respond to this treatment, and there are
 sufficient unused ATLCAR.CD 30 cells, they may be eligible to receive a second infusion. The
 second infusion will be given after a second lymphodepletion chemotherapy. Most of the clinic
 visits in this research will last between 1-8 hours.

 Participants will be followed closely for 4 consecutive weeks after ATLCAR.CD30 infusion(s).
 Other follow-up visits will happen on Weeks 6 and 8, and continue every 3 months for the
 first year after infusion. Long-term follow up will continue annually for up to 15 years
 after the last ATLCAR.CD30 infusion.

 There are risks associated in participating in this research study. Risks of treatment
 include pain, fever, nausea, vomiting, and neurotoxicity. Other risks are associated with
 study procedures, such as biopsies, imaging, infusion, and breach of confidentiality.
This multicenter, open-label phase II study will determine the efficacy and safety of
 autologous activated T lymphocytes (ATLs) expressing the chimeric antigen receptor specific
 for CD30 (ATLCAR.CD30) administered in two sequential infusions in subjects with
 relapsed/refractory CD30+ PTCL. Up to 20 subjects will receive 2 infusions of 2 × 108
 cells/m2 of ATL product expressing the CAR.CD30. Subjects will have cells procured to
 manufacture the ATLCAR.CD30 cells and during the time period required to manufacture the
 product the subjects will be able to receive standard of care bridging therapy to be
 determined by their primary local oncologist. Prior to receiving the first cell infusion,
 subjects will undergo lymphodepletion with fludarabine and bendamustine. Any subject with
 prior hypersensitivity reaction to bendamustine will be considered for an alternative
 lymphodepletion regimen. Subjects will have their disease assessed at week 8 by either CT
 chest, abdomen and pelvis or PET/CT. Subjects who have stable disease (SD), partial response
 (PR) or complete response (CR) without subsequent progressive disease and meet the
 eligibility criteria for a second infusion, will receive lymphodepletion followed by a second
 infusion. The lymphodepletion for the second infusion will consist of cyclophosphamide and
 fludarabine.

 OUTLINE

 Cell Procurement Up to 300 mL of peripheral blood (in up to 3 collections) will be obtained
 from subjects for cell procurement. Additionally, leukapheresis may be performed to isolate
 sufficient cells in subjects with a low absolute lymphocyte count or who had inadequate
 peripheral blood collection. The parameters for apheresis will be up to 2 blood volumes.

 Bridging Chemotherapy Subjects will be allowed to receive additional standard of care therapy
 (e.g., chemotherapy or radiation therapy) to stabilize their disease if the treating
 physician feels it is in the subject's best interests.

 Lymphodepleting Chemotherapy Prior to the initial cellular product administration subjects
 will receive a lymphodepleting regimen of bendamustine 70 mg/m^2/day administered IV over 1
 hour followed by an IV dose over 30 minutes of fludarabine 30 mg/m^2/day administered over 3
 consecutive days. These agents will be administered per institutional guidelines. Prophylaxis
 (e.g., hydration, antiemetics, etc.) needed prior to fludarabine and bendamustine
 chemotherapy will be provided per institutional guidelines 2-14 days prior to the initial
 cell product administration. Subjects who have previously had hypersensitivity to
 bendamustine may receive a lymphodepletion regimen of cyclophosphamide 300 mg/m^2 IV and
 fludarabine 30 mg/m^2 each as a daily infusion for 3 days per institutional guidelines 2-14
 days prior to the initial cell product administration.

 Two to 14 days prior to the second infusion, subjects will receive a lymphodepletion regimen
 of cyclophosphamide 300 mg/m^2 IV and fludarabine 30 mg/m^2 each as a daily infusion for 3
 days per institutional guidelines. Subjects whose absolute neutrophil count and/or platelet
 count takes >/= 3 months (from the first day of lymphodepletion prior to the initial cellular
 product administration) to recover to levels required to meet eligibility for lymphodepletion
 (ANC >/= 1.0 x 10^9/L and platelet count >/= 50 x 10^9/L) prior to the second infusion will
 receive a 25% dose reduction in cyclophosphamide and fludarabine lymphodepletion for the
 second round of lymphodepletion.

 ATLCAR.CD30 Cell Administration The cellular product consisting of ATLCAR.CD30 cells will be
 administered by a licensed healthcare provider (oncology nurse or physician) via intravenous
 injection over 5 - 10 minutes through either a peripheral or a central line. The volume of
 infusion will depend upon the concentration of the cells when frozen and the size of the
 subject. The expected volume will be 1 - 50 mL. Post lymphodepletion, subjects who meet
 eligibility criteria for cellular therapy will receive ATLCAR.CD30 cells within 2 - 14 days
 after completing the lymphodepleting chemotherapy regimen. The recommended phase 2 dose
 (RP2D) determined in the phase 1 study of ATLCAR.CD30 will be administered to subjects (2 ×
 108 CAR-T/m2).

 If a subject only has enough ATLCAR.CD30 cells product for one infusion, they will still be
 able to receive one infusion of cells and will not have a 2nd lymphodepletion or infusion of
 cells. These subjects will be replaced for the purposes of efficacy determination.
Inclusion Criteria for the Study

 1. Written informed consent and HIPAA authorization for release of personal health
 information explained to, understood by and signed by the subject or legally
 authorized representative.

 2. Age ≥ 18 years at the time of consent.

 3. Karnofsky score of >60%

 4. Histological or cytological evidence/confirmation of CD30+ peripheral T-cell lymphoma
 per the 2017 World Health Organization Classification of Haematopoietic and Lymphoid
 Tissues.

 5. CD30+ disease determined by biopsy after the subject's most recent anti-CD30 therapy
 prior to ATLCAR.CD30 (result can be pending at the time of cell procurement, but must
 be confirmed prior to treatment with the first infusion of ATLCAR.CD30 cells). NOTE:
 CD30+ disease requires documented CD30 expression by immunohistochemistry based on the
 institutional hematopathology standard.

 6. Subjects must have received at least two prior lines of therapy for their lymphoma. If
 transplant is given as a preplanned consolidation in first remission, it will not be
 counted as a second line of therapy.

 7. Subjects relapsed after autologous stem cell transplant are eligible for this study.

 8. Subjects relapsed after allogeneic stem cell transplantation are eligible provided the
 patient is >180 days from transplant, not on immunosuppresive therapy to treat/prevent
 graft-versus-host disease, and has no evidence of active graft-versus-host disease.

 9. Female subjects of childbearing potential must have a negative serum pregnancy test
 within 72 hours prior to cell procurement. Note: Females are considered of
 childbearing potential unless they are surgically sterile (have undergone a
 hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are
 naturally postmenopausal for at least 12 consecutive months. Documentation of
 postmenopausal status must be provided.

 10. Female subjects of childbearing potential must be willing to abstain from heterosexual
 activity or to use 2 forms of effective methods of contraception from the time of
 informed consent until 6 months after study treatment discontinuation. The two
 contraception methods can be comprised of two barrier methods, or a barrier method
 plus a hormonal method or an intrauterine device that meets <1% failure rate for
 protection from pregnancy in the product label. Women of childbearing potential will
 also be instructed to tell their male partners to use a condom.

 11. Subject is willing and able to comply with study procedures based on the judgement of
 the investigator or protocol designee.

 Exclusion Criteria for the Study

 1. Subject is pregnant or lactating (Note: Breast milk cannot be stored for future use
 while the mother is being treated on study).

 2. Subject has a known additional malignancy that is active and/or progressive requiring
 treatment; exceptions include basal cell or squamous cell skin cancer, in situ
 cervical or bladder cancer, or other cancer for which the subject has been
 disease-free for at least five years.

 3. Subjects diagnosed with cutaneous T-cell lymphoma including mycosis fungoides, Sézary
 syndrome, or any other variant of cutaneous T-cell lymphoma.

 4. 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.

 5. Active infection with HIV, HTLV, HCV (tests can be pending at the time of cell
 procurement; only those samples confirming lack of active infection will be used to
 generate transduced cells). Note: To meet eligibility subjects are required to be
 negative for HIV antibody, negative for HTLV1 and 2 antibody or PCR negative for HTLV1
 and 2, negative for HCV antibody or HCV viral load.

 6. Subjects who are positive for hepatitis B surface antigen (can be pending at the time
 of cell procurement; only those samples confirming lack of active infection will be
 used to generate transduced cells) 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.

 Eligibility Criteria Prior to Cell Procurement

 1. Informed consent to undergo cell procurement understood by and signed by the subject
 or legally authorized representative; subject and/or legally authorized representative
 given a copy of informed consent form for cell procurement.

 2. Subject has life expectancy ≥ 6 weeks.

 3. Subject has evidence of adequate organ function as defined by:

 -  Hemoglobin ≥8.0 g/dL (transfusion independent for 2 weeks prior to procurement)

 -  Total bilirubin ≤ 2 × ULN, unless attributed to Gilbert's Syndrome

 -  AST ≤ 3 × ULN

 -  ALT < 3 x ULN

 -  Creatinine ≤ 2 × ULN

 -  Pulse oximetry of >90% on room air

 4. Imaging results from within 90 days prior to procurement to assess presence of active
 disease.

 5. 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
 (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy)
 or they are naturally postmenopausal for at least 12 consecutive months.

 Eligibility Criteria Prior to Lymphodepletion #1

 1. Written informed consent explained to, understood by and signed by the subject or
 legally authorized representative; subject and/or legally authorized representative
 given a copy of informed consent form.

 2. Imaging results from within 10 days prior to lymphodepletion. Imaging must occur at
 least 3 weeks after most recent therapy (used as baseline measure for documentation of
 progression before the lymphodepletion) to document measurable or assessable disease.

 3. Subject must demonstrate adequate organ function prior to lymphodepletion as defined
 below. All tests must be obtained within 72 hours prior to lymphodepletion:

 -  Absolute neutrophil count ≥ 1.0 × 109/L

 -  Platelet count ≥ 50 × 109/L

 -  Total bilirubin < 2 x ULN unless attributed to Gilbert's syndrome

 -  AST </= 5 x ULN

 -  ALT < 5 x ULN

 -  Creatinine </+ 3 x ULN

 -  Pulse Oximetry of >90% on room air

 4. Subject must have available autologous transduced activated T cells product at a dose
 of 2x10^8 cells/m^2 and meets the Certificate of Analysis acceptance criteria.

 5. No major surgery within 28 days prior to lymphodepletion.

 6. Negative serum pregnancy test within 72 hours prior to lymphodepleting therapy for
 female participants of childbearing potential. Note: Females are considered of
 childbearing potential unless they are surgically sterile (have undergone a
 hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are
 naturally postmenopausal for at least 12 consecutive months.

 7. Subject has not received any investigational agents or any tumor vaccines within the
 previous six weeks prior to lymphodepletion.

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

 9. Subject has not received chemotherapy within the previous 3 weeks prior to
 lymphodepletion.

 10. Subject does not have rapidly progressive disease, per treating oncologist's
 discretion.

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

 12. 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. (This applies to subjects who receive bendamustine for
 lymphodepletion (required) up through 72 hours after the last dose of bendamustine.)

 13. Subject is not taking a prohibited or contraindicated medication prior to
 lymphodepletion.

 14. 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.

 Eligibility Criteria Prior to Cell Product Administration #1

 1. Subject has no evidence of uncontrolled infection or sepsis.

 2. Negative serum pregnancy within 7 days of cell product administration for females of
 childbearing potential (does not need to be repeated if pre-lymphodepletion pregnancy
 test is within window). Note: Females are considered of childbearing potential unless
 they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation,
 or bilateral oopherectomy) or they are naturally postmenopausal for at least 12
 consecutive months.

 3. Evidence of adequate organ function as defined by:

 -  Total bilirubin ≤ 2 × ULN, unless attributed to Gilbert's syndrome

 -  AST ≤ 5 × ULN

 -  ALT ≤ 5 × ULN

 -  Creatinine ≤ 3 × ULN

 -  Pulse Oximetry of >90% on room air

 4. Subject has no clinical indication of rapidly progressing disease in the opinion of
 the clinical investigator.

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

 Eligibility Criteria Prior to Lymphodepletion #2

 1. Imaging results from within 21 days prior to lymphodepletion to confirm that the
 subject has derived clinical benefit from the initial infusion as assessed by the
 investigator (stable disease or better after the first ATLCAR.CD30 infusion without
 subsequent progressive disease).

 2. Subjects who experienced Grade 4 CRS or Grade 4 ICANS as a result of the initial
 ATLCAR.CD30 infusion are only eligible for a second round of lymphodepletion and
 infusion if they have partial response or better to the initial ATLCAR.CD30 infusion.

 3. Subject must demonstrate adequate organ function prior to lymphodepletion as defined
 below. All tests must be obtained within 24 hours prior to lymphodepletion:

 -  Absolute neutrophil count ≥ 1.0 × 109/L

 -  Platelet count ≥ 50 × 109/L

 -  Total bilirubin ≤ 2 × ULN, unless attributed to Gilbert's syndrome

 -  AST ≤ 5 × ULN

 -  ALT ≤ 5 × ULN

 -  Creatinine ≤ 3 × ULN

 -  Pulse Oximetry of >90% on room air

 4. Subject must have available autologous transduced activated T cells product at a dose
 of 2x10^8 cells/m^2 and meets the Certificate of Analysis acceptance criteria.

 5. Negative serum pregnancy test within 72 hours prior to lymphodepleting therapy for
 female participants of childbearing potential. Note: Females are considered of
 childbearing potential unless they are surgically sterile (have undergone a
 hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are
 naturally postmenopausal for at least 12 consecutive months.

 6. Subject does not have evidence of uncontrolled infection or sepsis.

 7. Subject is not receiving a prohibited medication at time of starting lymphodepletion
 up through 72 hours after the last dose of cyclophosphamide.

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

 9. 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.

 Eligibility Criteria Prior to Cell Product Administration #2

 1. Subject has no evidence of uncontrolled infection or sepsis.

 2. Negative serum pregnancy within 7 days of cell product administration for females of
 childbearing potential (does not need to be repeated if pre-lymphodepletion pregnancy
 test is within window). Note: Females are considered of childbearing potential unless
 they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation,
 or bilateral oophorectomy) or they are naturally postmenopausal for at least 12
 consecutive months.

 3. Evidence of adequate organ function as defined by:

 -  Total bilirubin ≤ 2 × ULN, unless attributed to Gilbert's syndrome

 -  AST ≤ 5 × ULN

 -  ALT ≤ 5 × ULN

 -  Creatinine ≤ 3 × ULN

 -  Pulse Oximetry of >90% on room air

 4. Subject has no clinical indication of rapidly progressing disease in the opinion of
 the clinical investigator.

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