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CD30 CAR for Relapsed/Refractory CD30+ T Cell Lymphoma

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ClinicalTrials.gov Identifier: NCT04083495
Recruitment Status : Recruiting
First Posted : September 10, 2019
Last Update Posted : August 24, 2021
Sponsor:
Information provided by (Responsible Party):
UNC Lineberger Comprehensive Cancer Center

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Peripheral T Cell Lymphoma Biological: ATLCAR.CD30 T cells Drug: Bendamustine Drug: Fludarabine Drug: Cyclophosphamide Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of the Administration of T Lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) for Relapsed/Refractory CD30+ Peripheral T Cell Lymphoma
Actual Study Start Date : September 17, 2019
Estimated Primary Completion Date : August 2022
Estimated Study Completion Date : August 2037


Arm Intervention/treatment
Experimental: ATLCAR.CD30 cells
The cellular product consisting of ATLCAR.CD30 cells will be administered 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. Administration to eligible subjects will occur within 2 - 14 days after completing the lymphodepleting chemotherapy regimen
Biological: ATLCAR.CD30 T cells
Autologous T Lymphocyte Chimeric Antigen Receptor cells targeted against the CD30 antigen at dose of 2 × 10^8 CAR-T/m^2 with a maximum dose of 5 × 10^8 CAR-T cells

Drug: Bendamustine
70 mg/m^2 administered IV for 3 days for lymphodepletion 2-14 days prior to first cell infusion
Other Name: Bendeka

Drug: Fludarabine
30 mg/m^2 administered IV for 3 days for lymphodepletion 2-14 days prior to first and second cell infusion

Drug: Cyclophosphamide
300 mg/m^2 administered IV for 3 days for lymphodepletion 2-14 days prior to second cell infusion and 2-14 days prior to the first cell infusion for subjects who have previously had hypersensitivity to bendamustine




Primary Outcome Measures :
  1. Progression free survival (PFS) after administration of the ATLCAR.CD30 in subjects with relapsed/refractory CD30+ peripheral T cell lymphoma [ Time Frame: 8 weeks ]
    PFS is defined from day of initial lymphodepletion administration of the first ATLCAR.CD30 product infusion to the date of disease progression per the Revised Lugano Criteria or death as a result of any cause. Subjects who do not meet criteria for progression by the analysis data cut-off date will be censored at their last evaluable disease assessment date.


Secondary Outcome Measures :
  1. Best overall response rate (BOR) mediated by the ATLCAR.CD30 product administered in subjects with relapsed/refractory CD30+ peripheral T cell lymphoma [ Time Frame: 2 years ]
    The best overall response rate (BOR) will be defined as the best response recorded from the first administration of the ATLCAR.CD30 product to the date of disease progression per the Revised Lugano Criteria or death as a result of any cause.

  2. Objective response rate (ORR) mediated by the first infusion of the ATLCAR.CD30 product administered in patients with relapsed/refractory CD30+ peripheral T cell lymphoma. [ Time Frame: 8 weeks ]
    The objective response rate (ORR) will be defined as the rate of complete responses (CR) + partial responses (PR) by 8 weeks from the date of first lymphodepletion prior to the first administration of the ATLCAR.CD30 product per the Revised Lugano Criteria.

  3. Responses improved by the second infusion of the ATLCAR.CD30 product administered in subjects with either partial response or stable disease following the first infusion of ATLCAR.CD30 [ Time Frame: 8 weeks ]
    The percentage of subjects who have an improvement in their response after the second administration of ATLCAR.CD30 product will be defined at 8 weeks after the second administration of the ATLCAR.CD30 product per the Revised Lugano Criteria. Subjects entering the second infusion in a complete response will be reported as continued CR (CCR) but will not be included in percentage of improved responses after the second infusion.

  4. Incidence of Dose Limiting Toxicity (DLT) (safety and tolerability) when administering two sequential infusions of the ATLCAR.CD30 product in subjects with relapsed/refractory CD30+ peripheral T cell lymphoma [ Time Frame: 8 weeks ]
    DLT defined as ≥ Grade 3 cytokine release syndrome (CRS), Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), or any other ≥ Grade 3 non-hematologic toxicity, including allergic reactions to T cell infusions. Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. CRS toxicity will be graded according to CRS Grading Criteria and Management Guidelines Version 3.0 (March 14, 2019). ICANS toxicity will be graded according to the ICANS Grading Criteria for Management of Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) for CAR T-Cell Therapy.

  5. Overall survival (OS) after administration of the ATLCAR.CD30 administered to subjects with relapsed/refractory CD30+ peripheral T cell lymphoma [ Time Frame: 15 years ]
    Overall survival is defined from day of initial lymphodepletion for the first administration ATLCAR.CD30 product to date of death.

  6. Comparison of the expansion and persistence of ATLCAR.CD30 in peripheral blood when infused after a single infusion of ATLCAR.CD30 cells and after two infusions with ATLCAR.CD30 cells [ Time Frame: 1 year ]
    Persistence and expansion of ATLCAR.CD30 in peripheral blood after a single infusion and after two infusions will be determined by quantitative polymerase chain reaction (PCR) and flow cytometry in sample of peripheral blood. Feasibility is defined as ability of subjects to receive 2 sequential infusions taking into account manufacturing and any other limiting factors to receiving a second infusion of ATLCAR.CD30



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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 × 10^9/L
    • Platelet count ≥ 50 × 10^9/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 × 10^9/L
    • Platelet count ≥ 50 × 10^9/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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04083495


Contacts
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Contact: Catherine Cheng 919-445-4208 catherine_cheng@med.unc.edu
Contact: Spencer Laing 919-962-8618 spencer.laing@med.unc.edu

Locations
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United States, North Carolina
Lineberger Comprehensive Cancer Center at University of North Carolina Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Catherine Cheng    919-445-4208    catherine_cheng@med.unc.edu   
Contact: Spencer Laing    919-962-8618    spencer.laing@med.unc.edu   
Sub-Investigator: Natalie Grover, MD         
Sub-Investigator: Paul Armistead, MD         
Sub-Investigator: Jonathan Serody, MD         
Sub-Investigator: Maurice Alexander, PharmD         
Sub-Investigator: Tatjana Grgic, PharmD         
Sub-Investigator: Jonathan Ptachcinski, PharmD         
Sub-Investigator: James Shaw, PharmD         
Sub-Investigator: Edith Bowers         
Sub-Investigator: Faith Buchanan         
Sub-Investigator: James Coghill         
Sub-Investigator: Catherine Coombs         
Sub-Investigator: Christopher Dittus, MD         
Sub-Investigator: Katarzyna Jamieson         
Sub-Investigator: Emily Kassam         
Sub-Investigator: Winnie Lau         
Sub-Investigator: Yara Park         
Sub-Investigator: Alicia Pinto         
Sub-Investigator: Raghuveer Ranganathan         
Sub-Investigator: Marcie Riches, MD         
Sub-Investigator: Angela Spruill         
Sub-Investigator: Megan Sterlina         
Sub-Investigator: Hendrik VanDeventer, MD         
Sub-Investigator: Benjamin Vincent         
Sub-Investigator: Timothy Voorhees, MD         
Sub-Investigator: Kimberly Wehner         
Sub-Investigator: Michael Winstead         
Sub-Investigator: William Wood         
Sub-Investigator: Ashley Zanter         
Sub-Investigator: Megan McElfresh         
Wake Forest Baptist Medical Center Recruiting
Winston-Salem, North Carolina, United States, 27157
Contact: Jana Hall Project Manager    919-966-4432    jana_hall@med.unc.edu   
Contact: Caroline Jones Dinkins    919-966-4432    caroline_dinkins@med.unc.edu   
Principal Investigator: Rakhee Vaidya, MD         
Sponsors and Collaborators
UNC Lineberger Comprehensive Cancer Center
Investigators
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Principal Investigator: Anne Beaven, MD UNC Chapel Hill
Additional Information:
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Responsible Party: UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT04083495    
Other Study ID Numbers: LCCC1904-ATL
First Posted: September 10, 2019    Key Record Dates
Last Update Posted: August 24, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by UNC Lineberger Comprehensive Cancer Center:
lymphoma
CD30
peripheral T cell lymphoma
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, T-Cell
Lymphoma, T-Cell, Peripheral
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Cyclophosphamide
Bendamustine Hydrochloride
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists